bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib, Doxorubicin and Dexamethasone (PAD) Prior to High-Dose Melphalan / Autologous Stem Cell Transplantation for Newly Diagnosed Plasma Cell Dycrasias.
Authors: Lebon Delphine , Gruson Berengere , Garidi Reda , Dutel Jean Luc , Thevenot Corinne , Choufi Bachra , Ghomary Kamel , Kolb Brigitte , Leduc Isabelle , Vaida Ioana , Damaj Gandhi , Marolleau Jean Pierre , Royer Bruno 
Published: October 2019

Abstract
Abstract 4960
High-dose melphalan (HDM) with autologous stem cell transplantation (ASCT) is the standard of care for myeloma (MM) patients aged < 70 years. Achievement of complete/very good partial response (CR/VGPR) is prognostic for improvement overall survival (OS) and use of more effective induction regimens prior to HDT-ASCT may result in improvement post-transplant responses. We performed a retrospective analysis of newly MM pts treated with bortezomib-doxorubicin-dexamethasone (PAD) prior HDM-ASCT.
From October 2005 and July 2008, 20 previously untreated MM pts were enrolled: median age was 56 years (range 44-68), 50% male. Of them, 3 had primary plasma cell leukemia (pPCL), 5 were on dialysis for MM-related renal impairment. Cytogenetic was available for 9: 2 (1 pPCL and 1 MM) had t(4;14). PAD included Bortezomib (1.3 mg/m2 on D1, 4, 8, 11), doxorubicin (9mg/m2 D1-D4), dexametasone (40mg D1-D4): 4 cycles (13 pts), 3 (6 pts), and 2 (1). Response rates after PAD were CR 10%, VGPR 50%, PR 20%, SD 10%. 1 pt died of pulmonary hypertension related to MM after 2 cycles of PAD. Neurologic toxicity ' grade 2 was observed in 3 pts and DVT in 1.
Following induction, 17 pts underwent PBSC harvesting: cyclopsphamide + G-CSF (8), G-CSF only (10). Median yields were 7.9 106 CD34/kg (6-10.5). 17 pts underwent HDM: 200 mg/m2 (12 pts) and 140 mg/m2 (5 pts with renal insufficiency, including 3 on dialysis), followed with ASCT. 1 pt benefited a double HDM/ASCT and 1 (pPCL) a mini-allotransplant 3 monts after. There was no treatment related mortality.
Response rates 3 months post ASCT (17 pts) were: CR 18%, VGPR 70%, PR 6%, SD 6%. 1 SD post PAD obtained VGPR after Thal-Dex had double HDM/ASCT with CR.
With a median follow-up of 23 months (7-34), median OS has not been reached and 1-year survival was 95%. At the reference date of July 2009 85% are alive, 5 pts relapsed: median 12 months (6-14), EFS was 31 months and 2 pts with t(4;14) are alive in CR/VGPR at 23 and 31 months
Concerning the 3 pPCL pts: 1 remained alive in CR 12 months post allo-transplant (follow-up 23 months), 1 was in CR post PAD and relapsed 11 months post HDM/ASCT (survival = 20 months) and 1 is alive at 12 months from diagnosis with a refractory disease. Dialysis could be interrupted for 3 pts in CR/VGPR: 1 after PAD, 2 after ASCT..
In conclusion, according to previously published results (Popat R, British Journal of Haematology 2008), PAD regimen in preparation of HDM/ASCT is safe and highly active in MM patients. Moreover, prolonged remissions and survivals could be obtained in pPCL patients and reversal of severe renal insufficiency observed.

Disclosures
No relevant conflicts of interest to declare.
Telomere Elongation in Dyskeratosis Congenita Induced Pluripotent Stem Cells.
Authors: Agarwal Suneet , Loh Yuin-Han , McLoughlin Erin M , Huang Junjiu , Park In-Hyun , Miller Justine D , Huo Hongguang , Okuka Maja , Reis Rosana Maria dos , Loewer Sabine , Keefe David , Goldman Frederick D , Klingelhutz Aloysius , Liu Lin , Daley George Q. 
Published: October 2019

Abstract
Abstract 497
Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer premature degeneration of multiple tissues. Bone marrow failure is the principal cause of mortality, and allogeneic stem cell transplantation is limited by increased treatment-related mortality. Somatic cells can be reprogrammed using defined genetic and chemical factors, yielding “induced pluripotent stem” (iPS) cell lines which have the capacity to differentiate into any tissue. Patient-specific iPS cells therefore hold promise as therapeutic agents and disease models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, and we have found that telomere length is increased in human iPS cells relative to the normal primary somatic cells from which they are derived. Here we investigated whether defects in telomerase function would limit derivation or self-renewal of iPS cells from patients with DC. We reprogrammed primary fibroblasts from patients with X-linked and autosomal dominant DC, caused by mutations in the genes encoding dyskerin and telomerase RNA component (TERC), respectively. We were able to establish multiple DC-specific iPS lines showing all hallmarks of pluripotency, including the formation of hematopoietic progenitors in vitro. Unexpectedly, DC-specific iPS cells were able to sustain continual proliferation in vitro, in contrast to the premature senescence displayed by the DC fibroblasts. Although early passage DC iPS cells had shorter telomeres than donor fibroblasts, we found that telomere length in DC iPS cells increased with continued passage in culture. To explain this finding, we discovered that steady state levels of TERC, which are critically limiting in several forms of DC, are upregulated in normal and DC iPS cells. We found that TERC upregulation is a feature of the pluripotent state, that the TERC locus is a target of pluripotency-associated transcription factors, and that transcriptional silencing accompanies a 3' deletion at the TERC locus in autosomal dominant DC. Our results demonstrate that reprogramming restores self-renewal capacity in DC cells despite genetic lesions affecting telomerase, and suggest that strategies to enhance endogenous TERC expression may be feasible and therapeutically beneficial in DC patients. The studies demonstrate the value of patient-specific iPS cells for basic and translational discovery, and further the rationale for autologous iPS based cellular therapy of genetic hematologic disorders.

Disclosures:
Daley: MPM Capital: Consultancy; Solasia: Consultancy; Epizyme: Consultancy; iPierian: Consultancy, Equity Ownership.
Is JAK2 Inducible by Cytotoxic Chemotherapy?
Authors: Bendaly Edmond A. , Rahman Saud S. , Zafar Samiah , Haglof Karen , Ibrahim Sherif , Raphael Bruce G. 
Published: October 2019

Abstract
Abstract 4979

Introduction
The JAK2V617F mutation accounts for most cases of myeloproliferative neoplasms (MPN). Only a few case reports of MPN following cytotoxic chemotherapy have been reported, and all of them were published prior to the discovery of the JAK2V617F mutation. We report a series of 6 patients who developed a JAK2V617F positive MPN following cytotoxic chemotherapy.

Patients
From 2006 to 2009, 6 patients with a history of a hematologic or an oncologic malignancy who developed an MPN were identified and their medical records retrospectively reviewed. One patient had acute lymphoblastic leukemia, 1 had Hodgkin lymphoma, 1 had squamous cell carcinoma of the head and neck, 1 had cervical cancer, and 2 had breast cancer. All patients were in remission from their primary malignancies at the time the MPN was diagnosed. Five were females. The median age at diagnosis was 72 years. Median time to development of the myeloproliferative neoplasm was 14 years. Type of chemotherapy exposure, MPN diagnosis and time to MPN in each case is shown in the table below. The JAK2V617F mutation was detected either in the peripheral blood or the bone marrow of all patients. There was no predominance of any specific MPN diagnosis. Patients who received platinum-based chemotherapy developed the MPN sooner than those who received alkylators (6 vs 17.5 years respectively). Treatment consisted of phlebotomy, hydroxyurea, anagrelide, aspirin or a combination as deemed appropriate by the treating hematologist.

Conclusion
These findings lead us to hypothesize whether the development of JAK2V617F positive MPN may be related to prior exposure to cytotoxic chemotherapy. Exposure to platinum-based chemotherapy may cause the disorder to appear sooner compared with exposure to alkylators. Recently, JAK2V617F positive MPN was found to be strongly associated with a specific constitutional haplotype, 46/11 suggesting increased susceptibility to this mutation. Chromosomal analyses are planned to show whether any of the reported patients exhibit this haplotype.
Ref: 1.Jones et al, Nat Genet. 2009 Apr;41(4):446-9. 2009 Mar 15.
The authors have no relevant disclosure.

Disclosures
No relevant conflicts of interest to declare.
Jak2 Mutation in Myeloproliferative Neoplasms: Is It Just An Exon Episode?.
Authors: Sun Xuemei , Xu Zuqiong , Lai Rengsheng , Zhang Wenxi , Zhu Xuejun , Jiang Pengjun , Xie Ling 
Published: October 2019

Abstract
Abstract 4982
The discovery of the V617F point mutation of JAK2 has revolutionized the understanding of the pathogenesis of BCR-ABL-negative myeloproliferative neoplasms (MPNs). Further discoveries of other JAK2 exon 12-15 and MPL mutations have extended the scope of the research in this field. However, a very small proportion of patients with polycythemia vera (PV) and 50% of patients with essential thrombocythemia (ET), as well as primary myelofibrosis (PMF), are negative for JAK2 or MPL mutations. This indicates that other forms of the mutations may exist and needs further evaluation
Recently, we treated a patient with ET who did not carry JAK2 V617F or JAK2 exon 12 mutations. The genomic DNA of mononuclear cells from heparin-treated bone marrow as well as he gastric tissue from paraffin embedding samples obtained from the patient was extracted using a DNA extraction kit, according to the manufacturer's instruction (Promega, Madison, WI, USA), and stored at -20°C. For mutation analysis of the JAK2 exon 12 and exon 14, genomic DNA was amplified respectively by polymerase chain reaction. And the PCR products either 358bp or 308bp were generated by forward primers within the exon 12 or exon 14 and forward primers within the intron 12 or intron 14(primer sequences and PCR conditions are provided on request). The direct sequencing on ABI-3100-Avant was used for mutation detection.
No mutation was found within JAK2 exon 12 or exon 14. However, a C/T mutation was detected in intron 14 at the position 14 downstream of the exon 14 in bone marrow cells. Informatively, this mutation was not found in genomic DNA of the gastric tissue. Further more, this novel mutation was not found in all samples from 59 MPN patients in our institute, among which 23 were diagnosed with PV, 22 ET, 12 PMF and 2 MPN-U. No such mutation was demonstrated in bone marrow mononuclear cells from 10 normal subjects. Preliminary results by flow cytometric analysis showed that hematopoietic cells including granulocytes, erythrocytes and megakaryocytes all showed elevated tyrosine kinase activity.
We concluded that mutations in JAK2 mRNA splicing region might also contribute to the aberrant signal transduction in hematopoiesis. And direct sequencing for JAK2 whole genomic DNA might be a suitable method for finding novel JAK2 novel mutation in JAK2 negative patients. Further functional study for evaluation of the effect of nucleotide changes within mRNA splicing sequences in wild type and mutated JAK2 cell lines as well as animal models would provide more convincing evidence of the relationship between JAK2 intron mutation and MPNs..

Disclosures
No relevant conflicts of interest to declare.
Progression Free Survival Is Predicated by Categorical Response, and Supports the Attainment of VGPR/CR as An Objective for Long Term Disease Control in Waldenstrom's Macroglobulinemia.
Authors: Treon Steven , Ioakimidis Thea , Hanzis Christina , Manning Robert , Patterson Christopher J , Hunter Zachary , Sheehy Patricia , Turnbull Barry 
Published: October 2019

Abstract
Abstract 4993
The attainment of higher response rates, as well as better categorical responses has occurred with the introduction of novel biological agents, including rituximab in the treatment of WM. However, there is a paucity of knowledge as to whether the attainment of better categorical responses is associated with improved outcomes. We therefore analyzed the impact of categorical responses on progression free survival (PFS) in 159 WM patients naïve to rituximab therapy and who received a rituximab based regimen: cyclophosphamide (n=58), nucleoside analogue (n=43), immunomodulatory agent (n=35), or bortezomib (n=23). The median follow-up for all patients was 83.5 months. Baseline characteristics were as follows: median age 62 years; serum IgM 3670 mg/dL; hematocrit 31.7%. Eighty-two patients had a B2M ≥3.0 g/L, and the IPSS score was I (n=64); II (n=57) and III (n=38). One hundred eight (68%) patients were previously untreated. Categorical responses were as follows: Complete Response (CR) defined as absence of clinically evident bone marrow or extramedullary disease, normal range serum IgM and negative immunofixation study (n=14); Very Good Partial Response (VGPR) defined as ≥90% reduction in serum IgM (n=21); Partial Response (PR) defined as ≥ 50% to <90% reduction in serum IgM (n=79); Minor Response (MR) defined as ≥ 25% to <50% in serum IgM (n=30); No Response (NR; n=14). No association between categorical response attainment and baseline serum IgM, B2M, Hematocrit or IPSS score was observed when employing a proportional hazards model. Achievement of better categorical responses was incrementally associated with improved PFS (p<0.0001 by log rank analysis), including attainment of a minor response, in both previously untreated and treated patients. No separation of curves was observed between VGPR and CR (Figure 1). Median TTP for patients achieving CR or VGPR was 71.8 months versus 38.6 months for those with PR or MR (Figure 2; p=0.008). Attainment of at least a VGPR served as an independent marker for improved PFS by univariate analysis. The results suggest that categorical responses, including MR and VGPR have prognostic value in WM, and that efforts aimed at improving categorical responses may lead to improved treatment outcomes in patients with WM.

Disclosures
No relevant conflicts of interest to declare.
Clinical Characteristics and Outcomes of 102 Patients with Adult T-Cell Leukemia/Lymphoma in Peru.
Authors: Beltran Brady , Morales Domingo , Quinones Pilar , Castillo Jorge 
Published: October 2019

Abstract
Abstract 5001

Background
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease associated with the human T-lymphotropic virus type-I (HTLV-I). ATLL has heterogeneous clinical presentations and outcomes. Shimoyama's ATLL classification includes acute, lymphomatous, chronic and smoldering subtypes. The objective of this study is to define prognostic factors for survival in patients with ATLL.

Methods
102 ATLL cases were collected in our center between January 1997 and September 2008. A diagnosis of ATLL was made according to the following criteria: a clinical history consistent with ATLL, a positive HTLV-1 antibody by ELISA and Western Blot or evidence of HTLV-1 proviral integration by PCR, and histological findings compatible with ATLL. Descriptive statistics were used to assess categorical and continuous variables. Survival curves for OS were estimated using the Kaplan-Meier method and compared using the log-rank test. For the multivariate analysis, the Cox Proportional-hazard regression test was used.

Results
The median age at diagnosis was 60.5 years (range 23–92 years), with a female-to-male ratio of 1.2:1. Forty nine cases (48%) had a performance status ≥ 2. Clinical types were acute (n=45), lymphomatous (n=43), smoldering (n=3), cutaneous (n=10) and chronic (n=1). Median hemoglobin was 12.0 g/dl (range 5.2–17.4 g/dl), median albumin was 3.3 g/dl (range 1.8–4.6 g/dl), median beta-2 microglobulin was 4.4 g/dl (range 1.1–16.9 g/dl), and LDH was 808 UI/ml (range 298–13000 IU/ml). Twenty nine patients with acute ATLL were treated with chemotherapy obtaining an overall response rate (ORR) of 14% (4/29), 3 complete responses (CR) and 1 partial response (PR), while in 38 patients with lymphomatous ATLL, an ORR of 32% (12/38) was obtained, 8 CR and 4 PR. Smoldering and cutaneous ATL types received mainly topic treatments. Median overall survival (OS) was 2.4 months for the acute type, 11.4 months for the lymphomatous type, 17.2 months for the smoldering type and 39.4 months for the cutaneous type (p<0.00001 for trend). In the univariate analysis, presence of B symptoms (median OS 5.4 vs. 20.2 months; p=0.005), performance status ≥ 2 (median OS 3.5 vs. 15.6 months; p<0.005), clinical stage > 2 (median OS 5.7 vs. 39.4 months; p<0.005), high LDH levels (median OS 4.3 vs. 15.4 months; p<0.005), and bone marrow involvement (median OS 3.3 vs. 15.6 months; p<0.005) were associated with worse prognosis. In the multivariate analysis, bone marrow involvement and elevated LDH remained as adverse prognostic factors for survival.

Conclusions
ATLL is a heterogeneous disease with poor outcomes. Each ATLL subtype has distinct clinical features, including response rates and survival times. In this cohort of 102 cases, bone marrow involvement and elevated LDH levels were independent prognostic factors. Prospective studies are needed to further validate these observations.

Disclosures
No relevant conflicts of interest to declare.
A Review of HIV Related Burkitt's Lymphoma/Leukemia in Sub Saharan Africa.
Authors: Novitzky Nicolas , Singh Jaimendra 
Published: October 2019

Abstract
Abstract 5016

Introduction
Burkitt's malignancies have increased substantially in frequency In HIV infected patients regardless of CD4 count. There is limited information about the clinical presentation and outcome of adult HIV+ patients with Burkitt's malignancies (BM) outside the endemic areas of Africa.

Methods
Patients with histologically confirmed BM were treated with antiretroviral medication and intense, anthracycline containing combinations (HyperC-VAD, COP-ADM). A retrospective review of the clinical characteristics and prognostic factors relevant for outcome was conducted comparing to an HIV –ve cohort.

Results
Between 1999 and 2009, 32 HIV positive patients and 9 HIV negative individuals with Burkitt's malignancy were referred to a single centre. The median age was 33 (13-61) years, 19 were female; 18 patients had leukemia while 23 patients had Burkitt's lymphoma. Extranodal disease was seen in 16 patients, the presentation serum median LDH was 1902 (292-45100) i.u., CNS disease was present in 7. In the HIV+ population, the median presentation CD4 count was 193 (10-967)/uL, 18% were on HAART prior to diagnosis but in the majority the malignancy led to the initial presentation. Of the 32 HIV+ve subjects who received intense cytotoxic therapy, at median follow up of 261 (146-2564) days, 14 (44%) survive, 12 longer than 1 year. The main cause of death was disease progression, relapse (particularly in CNS) and opportunistic infections. Male gender (p= 0.02), nodal presentation (p= 0.01), higher Hb (p= 0.001) and platelets (p= 0.03) predicted for better outcome. Cox analysis confirmed that male gender (p= 0.03), lower LDH (p= 0.02), and nodal presentation (p=0.03) were independent factors for survival. Non parametric statistics showed that HIV-ve Burkitt's patients were predominantly male (p= 0.01), Caucasian (p= 0.02), had significantly higher presentation serum albumin (p= 0.01) and lower creatinine (p= 0.02). In the HIV-ve group 78% survive longer than 1 year (log Rank p= 0.01).

Conclusions
In South Africa there are distinct clinical differences between HIV+ve and negative patients who present with Burkitt's malignancies. While outcome in the HIV –ve population is favourable, it is significantly worse in the HIV+ve cohort. For this group, a different strategy is required to improve outcome.

Disclosures
No relevant conflicts of interest to declare.
Upregulation of Krüppel-Like Factor 4 (KLF-4) Expression as a Potential Tumor Progression Gene Product in Non-Hodgkin's Lymphoma.
Authors: Vega Mario I. , vazquez-Islas Juan , Martinez-Paniagua Melisa , Hernandez-Atenogenes Miriam , martinez-Miguel Bernardo , Maldonado-Valenzuela Altagracia , Gonzalez-Bonilla Cesar , Huerta-Yepez Sara , Martinez-Maza Otoniel , Bonavida Benjamin 
Published: October 2019

Abstract
Abstract 5022
Krüppel-like factor 4 (KLF-4) is highly expressed in epithelial tissues such as the gut and skin. Several studies based on clinical evidence suggest that KLF-4 functions as a tumor suppressor in cancers of the colon, bladder, stomach and in leukemia. In contrast, KLF-4 expression is increased in primary breast ductal carcinomas and in oral dermal squamous cell carcinomas, suggesting that KLF-4 is important in tumor development and progression. However, KLF-4 expression in lymphomas has not been investigated. Our preliminary studies have examined KLF-4 expression in lymphoma cell lines and a TMA containing fresh tissues derived from patients with several types of lymphoma. There was a significantly higher expression of KLF-4 in Burkitt's lymphoma compared with other lymphomas such as follicular or DLBCL. These findings suggest that KLF-4 may be considered as a new biomarker in Non-Hodgkin's lymphoma (NHL). Further analyses based on the clinical outcome revealed that KLF-4 protein expression was significantly associated with poor patient's survival. The increased KLF-4 expression was associated with an inferior survival duration (P= 0.002). The survival for 12 patients who had a tumor with weak KLF-4 expression and 13 patients with negative KLF-4 expression was significantly longer than that for the 30 patients with strong KLF-4 expression (P< 0.001). Other variables that affected survival in univariate analyses included stages and completeness of resection were shown to have a statistically significant effect on survival (P=0.001), however age or sex did not have a statistically significant effect on survival. These data provide the first clinical and causal evidences that alterations of KLF-4 expression can play a critical role in the development and progression of NHL.

Disclosures
No relevant conflicts of interest to declare.