bluuebunny/crossref_metadata_2025_split huggingface dataset:
No Direct Effect of NOD2/CARD15 Variants On Clinical Outcome After Non-Myeloablative Allogeneic Stem Cell Transplantation.
Authors: van der Straaten Hanneke M. , Paquay Martine M. , Tilanus Marcel G.J. , Verdonck Leo F. , Huisman Cynthia 
Published: October 2019

Abstract
Abstract 4322

Background
Single nucleotide polymorphisms (SNPs) in the innate immunity receptor NOD2/CARD15 have been demonstrated to modulate the outcome of allogeneic haematopoietic stem cell transplantation. The effect of the NOD2/CARD15 polymorphism seems to be associated with donor source as well as type of conditioning regimen.

Methods
We reviewed NOD2/CARD15 mutations in all donor/recipient pairs of 192 consecutive patients who received non-myeloablative allogeneic stem cell transplantation(SCT) at our institution between 2002 and 2006. All patients were treated uniformly with fludarabine 30 mg/m2/day for 3 days followed by 200 cGy TBI (n=154) or TBI alone (n=38) and received grafts from HLA-matched related (n=132) or unrelated (n=60) donors.

Results
Mutated alleles were observed in 36 of 192 (19%) patients and in 35 of 192 (18%) donors. These SNPs, however, did not have a significant impact on clinical outcome data (P > 0.05, Kaplan Meier and Fine & Gray's test).
Acute graft-versus-host disease (GVHD) occurred in 24 of 61 (39%) patients with the polymorphism and in 66 of 131 (50%) patients without the polymorphism. Chronic GVHD developed in 28 of 55 (51%) patients with SNP pairs and in 79 of 121 (65%) patients with the wild type. The incidence of transplant-related mortality was 21% in both groups, 13 of 61 patients in the group with the polymorphism and 27 of 131 without the polymorphism. Relapse was seen in 23 of 61 (38%) patients with the SNP pairs and in 48 of 131 (37%) wild type patients. Finally, overall survival was 43% (26/61) in patients with the polymorphism and 39% (51/131) in patients without the polymorphism.

Conclusion
These data indicate that mutations in the NOD2/CARD15 genes do not influence the clinical outcome of non-myeloablative allogeneic SCT directly. Since NOD2/CARD15 variants are not recognized as a single significant prognostic factor, screening for NOD2/CARD15 when selecting a donor does not seem to have additional value in patients undergoing non-myeloablative SCT.

Disclosures:
No relevant conflicts of interest to declare.
Short Progression Free Survival Post Non-Myeloablative Sibling Allogeneic Stem Cell Transplantion for Multiple Myeloma.
Authors: Song Kevin , Sutherland Heather J. , Shepherd John D. , Abou Mourad Yasser , Barnett Michael J , Forrest Donna L. , Hogge Donna E. , Narayanan Sujaatha , Nantel Stephen H. , Power Maryse M , Toze Cynthia L. , Smith Clayton , Nevill Thomas J. 
Published: October 2019

Abstract 4323

Introduction
Allogeneic stem cell transplant has been considered the only potentially curative treatment for patients with myeloma. Due to the high treatment related mortality associated with myeloablative allogeneic stem cell transplantation, non-myeloablative allogeneic stem cell transplantion is being investigated.

Methods
Between May 2003 and June 2008, 23 patients received a non-myeloablative allogeneic stem cell transplant (NMT) using a fully matched sibling as the donor. All had received a previous autologous stem cell transplant (ASCT). 17 received the NMT as a part of a planned tandem transplant post ASCT. Six received the NMT after relapse post ASCT. Conditioning chemotherapy was a combination of cyclophosphamide 1000 mg/m2 daily x 2 days and Fludarabine 25mg/m2 daily for 5 days. Survival was measured from the date of allogeneic stem cell infusion.

Results
Median age at NMT was 52 years. Eight were female. Immunoglobulin isotype was 13 IgG; 5 IgA; 1 IgD; 4 light chain. ISS stage was 10 – stage 1; 8 – stage 2; 3- stage 3; 2 – insufficient information. 9/21 had del 13q; 3/9 t (4;14); 1/7 del 17p. Disease status at the time of NMT were 5 CR/nCR, 11 PR, 1 SD, 3 relapse chemo-sensitive, 3 relapse chemo-resistant. Median follow-up is 29 months (7 – 65 months). Median event free survival (EFS) for all patients is 17 months (95 % CI 8-26 months). Median EFS for the 17 patients who received NMT as a part of a planned tandem procedure was 18 months. Median overall survival (OS) for all patients is 29 months (95% CI unable to calculate). At the time of analysis 17 patients remain alive. Five patients are alive in continuous remission at a median of 40.9 months from NMT (13.5-47.6 months). Twelve patients have active disease requiring treatment. Three patients have died of myeloma, one of graft-versus-host-disease (GVHD) and two of other causes. Nineteen patients (83%) developed GVHD at some time post-transplant. Of 14 patients who have relapsed, eleven patients had GVHD at the time of relapse. Of the 6 patient who received the NMT after relapse post ASCT, 5 have relapsed post NMT and one died of GVHD within 9 months.

Conclusion
Non-myeloablative sibling allogeneic stem cell transplantation for myeloma produces short progression free survival in-spite of the presence of graft-versus-host-disease and only a limited number of patients benefit. Patient who receive this treatment after relapse from prior autologous stem cell transplant do particularly poorly. Improved overall survival is primary due to improvements in post-relapse myeloma therapy.
Comparison of Outcomes Between Transplantation From Unrelated Donor Umbilical Cord Blood and From Unrelated Donor Bone Marrow or Peripheral Blood in Children with Acute Leukemia.
Authors: Lee Soo Hyun , Chueh Heewon , Yoo Keon Hee , Sung Ki Woong , Koo Hong Hoe 
Published: October 2019

Abstract
Abstract 4340

Introduction
Although umbilical cord blood (UCB) is an accepted alternative to bone marrow or peripheral blood (BM/PB) for transplantation, allele-matched marrow or peripheral blood is generally regarded as the preferred graft source. Our aim is to compare leukemia-free survival after transplantation of unrelated donor UCB and allele-matched BM/PB, and to provide guidelines for selection of an appropriate donor and graft source in children with acute leukemia.

Patients and Methods
Outcomes of 22 children with acute leukemia and transplanted with single unit UCB were compared with outcomes of 34 BM/PB recipients. All transplantations were performed in Samsung Medical Center between May 2003 and June 2009. Recipients of UCB were transplanted with grafts that were HLA-matched (n = 3) or HLA-mismatched for one (n = 15) or two antigens (n = 4). BM/PB recipients were transplanted with grafts that were HLA-matched (n = 20) or mismatched (n = 14). While allele-level typing for HLA-A, HLA-B, HLA-DRB1 and antigen-level typing for HLA-C was used for BM/PB transplantation, antigen level typing for HLA-A, HLA-B and HLA-DRB1 was used for UCB transplantation. Myeloablative conditioning regimens were used for both BM/PB and UCB transplantation.

Results
The median times to neutrophil and platelet recovery were 15 (range 10–21) and 22 (12–29) days after BM/PB transplantation, and 17 (13–44) and 34 (24–148) days after UCB transplantation, respectively. The 4-year probabilities of leukemia-free survival were 58.0% after HLA-matched BM/PB transplants, 65.9% after HLA-mismatched BM/PB transplants, 66.7% after HLA-matched UCB transplants, 67.5% after one-mismatched UCB transplants with high cell dose (NC > 3.0 × 107/kg), 40.0% after one-mismatched UCB transplants with low cell dose (NC < 3.0 × 107/kg), and 33.3% after two-mismatched UCB transplants. The incidence of grade 3-4 acute graft-versus-host disease (GVHD) were 12.1% after BM/PB transplantation and 5.3% after UCB transplantation, respectively (P = 0.64). Rates of extensive chronic GVHD were 53.8% after BM/PB transplantation and 23.1% after UCB transplantation, respectively (P = 0.09). Transplant-related mortality rates were higher after UCB transplantation (21.7%) than BM/PB transplantation (2.9%) (P = 0.03). Relapse rates were similar after BM/PB transplantation (29.4%) and UCB transplantation (21.7%) (P = 0.56).

Conclusion
These results support the use of HLA-matched or one-antigen HLA mismatched UCB in children with acute leukemia who need transplantation. Faster identification of a suitable cord blood unit may result in a timely transplantation avoiding delay that could expose the patient to the risk of losing the eligibility for transplant due to relapse or other complications.

Disclosures:
No relevant conflicts of interest to declare.
The Transplant Outcomes of a 10/10 Matched Unrelated Donor (MUD) Stem Cell Transplant (SCT) Is Similar to a HLA Identical Related Donor (RD) Transplant.
Authors: Veeder Catherine , Davies Sheila , Havey Christina , Maciejewski John J. , Nathan Sunita , Gregory Stephanie A. , Venugopal Parameswaran , Shammo Jamile , Fung Henry C. 
Published: October 2019

Abstract
Abstract 4346

Background
Allogeneic SCT is a potential curative treatment for many hematological malignancies. Unfortunately, approximately 70% of patients who may benefit from an allogeneic SCT can not find a HLA identical related donor. Through National Marrow Donor Program, about 60-70% patients will be able to identify a suitable donor for transplant. However, prior studies suggested that MUD-SCT was associated with increased transplant related morbidity and mortality when compared with RD-SCT. Hence, many hematologists/oncologists were hesitant to recommend a MUD-SCT even when a matched related donor is not available. We hypothesized that through optimal HLA typing and using a 10/10 molecularly matched unrelated donor, the outcomes for a MUD-SCT will be similar to RD-SCT.

Method
Beginning in 2004, we adopted a new policy in HLA typing and all patients and donors will be tested for HLA: A, B, C, DR, and DQ using molecular techniques. Here, we report the outcomes on 24 consecutive patients who revived a 10/10 MUD-BMT at our institution.

Results
Between February, 2004 and April, 2008, 24 patients (8 males & 16 females) with various hematological malignancy and life threatening hematological disorders underwent a 10/10 molecularly matched MUD-SCT at Rush University Medical Center. Median age at SCT was 43 (range 18-67). Diagnoses included acute myeloid leukemia:11, myelodysplasia:3, non-hodgkin lymphoma:3, chronic myeloid leukemia:2, acute lymphoblastic leukemia:2, severe aplastic anemia:2 and hodgkin lymphoma:1. While 9/24 (38%) has early disease, 15/24 (62%) had advanced disease at SCT. All patients received a myeloablative conditioning regimen. Four patients (4/24, 17%) died before day 100 post-SCT from treatment related toxicity; all 4 pts > 55 years old. The 1-year survival was 62.5% with a minimal follow-up of 1 year for surviving patients. At last follow-up, 9 patients survived greater than 3 years post-SCT. The cumulative incidences of acute GVHD Grades ≥ 2 and 3 - 4 were 42% and 13% respectively.

Conclusion
We conclude that the transplant outcomes of 10/10 matched unrelated donor stem cell transplant appears similar to matched related donor stem cell transplant. Thus, matched related donor stem cell transplant should be considered for patients lacking a HLA identical donor whenever an allogeneic SCT is clinically indicated.

Disclosures:
No relevant conflicts of interest to declare.
PAD Induction Therapy Followed by Autologous Peripheral Blood Stem Cell Transplant (APBSCT) as Upfront Treatment for Myeloma (MM) in Chinese Patients.
Authors: Lie Albert Kwok Wai , Wu DePei , Wang Chun , Chim Chor Sang , Liang Raymond , Fu Zhengzheng , Wan Liping 
Published: October 2019

Abstract
Abstract 4367

Introduction
The anti-myeloma effect of bortezomib, used as a single agent or in combination chemotherapy, is well recognized in various clinical studies. The aim of this study is to determine the feasibility of using the PAD combination (bortezomib, doxorubicin and dexamethasone) as upfront treatment in Chinese patients with newly diagnosed MM, followed by APBSCT.

Method
Patients between the ages of 18 to 65 year-old with newly diagnosed MM were recruited. PAD (bortezomib 1.3 mg/m2 on days 1, 4, 8 & 11; doxorubicin 9 mg/m2 on days 1 & 4; dexamethasone 40 mg on days 1-4, 8-11 & 15-18 during cycle 1 and days 1-4 during cycles 2-4) induction therapy was administered for four 28-days cycles, followed by autologous peripheral blood stem cell mobilization with cyclophosphamide 3 g/m2 plus G-CSF 5 mg/kg/BD. Subsequently, APBSCT was performed with high dose melphalan 200 mg/m2 conditioning.

Results
A total of 25 patients has been recruited so far (male:female = 14:11). The age ranged from 44 to 65 year-old (median 53). Eleven patients were of IgG subtype, 6 were IgD, 4 were IgA and 4 were kappa light chain disease. By Durie-Salmon staging, 22 were stage III, 2 were stage II and 1 was stage I. Seventeen (68%) patients have completed the four cycles of PAD induction therapy, while 3 (12%) are still having on-going PAD induction. Five (20%) patients withdrew from the PAD therapy. One patient developed disease progression after 2 cycles of PAD, while the other 4 developed serious adverse events with the first cycle of PAD, including 1 patient each with severe bradycardia, atrial fibrillation, severe sensory neuropathy and pulmonary haemorrhage. Of the 18 patients who had evaluable response to PAD (i.e. 17 patients who completed four cycles of PAD and 1 who progressed on PAD induction), the results were 3 CR, 7 VGPR, 5 PR and 3 NR. Fourteen of the patients with at least PR received APBSCT. Post-APBSCT responses were so far evaluable in 11 patients with 6 CR, 4 VGPR and 1 PR. Hence, PAD is a feasible and effective upfront induction therapy for Chinese patients with MM resulting in a satisfactory response rate. Nevertheless, significant adverse events may occur even early on with the treatment. Subsequent APBSCT further improved the response rate but long-term survival rate remains to be established.

Disclosures:
No relevant conflicts of interest to declare.
The Significance of Elevated Beta 2-Microglobulin (b2-m) in B-CLL: Evidence of in Vitro b2-m Secretion Following Activation of B-CLL Cells.
Authors: Berrebi Alain , Shvidel Lev , Arditti Fabian David , Bassous Lucette , Haran Michal , Shtalrid Mordechai 
Published: October 2019

Abstract
Abstract 4380
Beta 2-microglobulin (b2-m) is an 11-kDa protein recognized as the light-chain component of the MHC-I molecule. It is produced by nucleated cells membranes and is detectable in the serum and other body fluids. The link between the b2-m/ MHC-1 molecules and membrane structure has been associated with lymphocyte activation. Serum b2-m is elevated in a variety of disorders and has a prognostic value in lymphoprolifera! tive diseases such as multiple myeloma and CLL. High b2-m in CLL, has been found to correlate mainly with the advanced stage of the disease and high lymphocyte count and is routinely used as a bad prognostic factor (Keating, 1995, Montillo, 2005). Previous studies from our Institute have shown significantly higher level of b2-m in CLL/PL and PLL and in cases associated with autoimmune disorders close to levels found in active myeloma (Shvidel, 1996, Duek, 2006). We suggested that b2-m levels are increased during B-cell activation which not necessarily correlates with aggravation of CLL. In an attempt to further evaluate the correlation of bm-2 and B-cells activation we stimulated B-CLL cells in vitro with pokeweed mitogen (PWM) and compared the results with CLL controls after 3 and 7 days of culture. Level of b2-m in supernatants was tested using a microparticle enzyme immunoassay. B-CLL cells from 8 patients (4 in stage Binet A, 3 B and 1 C) were studied. Except for stage A, the serum b2-m was mildly increased. The results showed a significant in vitro secretion of b2-m after three and seven days in supernatants of PWM-activated cells compared to unstimulated controls: mean values after 3 days were: 188 ng/ml (range 96-279) in activated B-cells versus 57ng/ml (25-103) in controls; and after 7 days 599 ng/ml (401-914) versus 164 (67-267) in controls. Interestingly, CD8+ T-cells from a T-large granular leukemia patient stimulated with PHA do not secrete significant amount of b2-m in vitro (156 ng/ml versus 87 at day 7). Our results demonstrate that activation of B-CLL cells in vitro induced a marked secretion of b2-m. Thus, the significance of b2-m in CLL may correlate with degree of activation of B-CLL cells. This hypothesis is supported by the increase of CD38 (an activation marker) in CLL cases with high b2-m serum level. Moreover, the results of our study suggest that progression of disease may be the results of in-vivo activation of the cells and lends support to previous studies showing that CLL cells are G0 cells with a potential to progress in the cell cycle after stimulation.

Disclosures:
No relevant conflicts of interest to declare.
Plasma Circulating Caspase-3 Index as a Biomarker in Patients with Chronic Lymphocytic Leukemia.
Authors: Bruey Jean-Marie , Estrov Zeev , Kantarjian Hagop , O'Brien Susan , Keating Michael , Wierda William , Albitar Maher 
Published: October 2019

Abstract
Abstract 4381
Because of the accumulation of lymphocytes and relative paucity of proliferating cells characteristic of B-cell chronic lymphocytic leukemia (CLL), defective apoptosis has been proposed as a key step in the pathogenesis of this disease. Activity levels of the proapoptotic enzyme caspase-3 have been used as a simple, quantitative measure of ongoing apoptosis in various cancers. Here we explored the clinical value of assessing apoptosis levels in patients with CLL, using caspase-3 activity in plasma as a surrogate marker for apoptosis. The study included 194 patients with CLL and 96 normal control subjects. Caspase-3 activity was measured in plasma samples by incubation with the substrate DEVD. Circulating caspase-3 activity was detectable in the plasma of all CLL patients and normal control subjects, but was significantly (P=0.005) lower in CLL patients (median=7.49; range=4.2-19.68 pmol/min/μL) than in controls (median=8.27; range=4.54-34.30 pmol/min/ul. Absolute levels of caspase-3 levels in plasma in CLL did not correlate with any of the laboratory variables examined (WBC, platelets, HGB, B2M), Rai stage, or performance status. To assess the extent of apoptosis in relevance to level of the disease or tumor load, the caspase-3 index was calculated by normalizing plasma caspase-3 activity to the number of circulating lymphocytes in peripheral blood. The circulating caspase-3 index correlated negatively with bone marrow cellularity (P<0.001), spleen size (P= 0.002), and number of sites of enlarged lymph nodes (P<0.001). Interestingly, the circulating caspase-3 index correlated positively with Rai stage (P=0.03, Kruskal-Wallis) but not IgVH mutation status (P=0.74) or performance status (p=0.72). More importantly, higher circulating caspase-3 index values (>8 pmol/min/1000 lymphocytes/ul) were significantly associated with poor overall survival (P=0.005). However, in multivariate analysis incorporating caspase-3 index along with beta-2 microglobulin level and IgVH mutation status showed that caspase-3 was not predictor of survival (p=0.7). In conclusion, apoptosis as determined using plasma caspase-3 activity is low in CLL. However, high circulating caspase-3 activity index values appear to reflect more aggressive disease. Further studies are needed to explore the possibility that this circulating caspase-3 index reflects the proportion of cells that are transformed into larger cells, with consequently higher proliferation and apoptosis rates, in patients with CLL.

Disclosures:
No relevant conflicts of interest to declare.
Alpha-Type 1-Polarized Dendritic Cells Pulsed with Apoptotic Allogeneic Myeloma Cell Line Could Induce the Strong CTL Responses against Autologous Myeloma Cells.
Authors: Yang Deok-Hwan , Kim Mi-Hyun , Hong Cheol-Yi , Ahn Jae-Sook , Kim Yeo-Kyeoung , Chung Ik-Joo , Kim Hyeoung-Joon , Lee Je-Jung 
Published: October 2019

Abstract
Abstract 4931
Cellular therapy using dendritic cells (DCs) is emerging as the one of useful immunotherapeutic modality in multiple myeloma (MM). In order to generate potent functional DCs, alternative approaches for using appropriate and effective tumor antigens, such as myeloma cell lysates, myeloma apoptotic bodies, DC-myeloma cell hybrids or DC-transfected with myeloma-derived RNA, in steady of idiotype protein having with weak antigenicity are tried in MM. However, it is laborious work to obtain sufficient autologous tumor cells as a source of tumor antigen in the clinical setting. We investigated the feasibility of immunotherapy in patients with MM using myeloma-specific CTLs, which were generated in vitro by alpha-type 1-polarized DCs (αDC1s) pulsed with UVB-irradiated allogeneic myeloma cell line, ARH77 cells.
Material and

Methods
Peripheral blood (PB) was collected from MM patients (IgG, Ü-type) or normal healthy donors with HLA-A0201+ with informed consent according to the protocol approved by the institutional ethical committee of the Chonnam National University Hwasun Hospital. Phenotypic analysis of aDC1s was performed using a FACS Aria cell sorter. Tumor antigen uptakes (CD83+/PKH67+), allogeneic mixed lymphocyte reaction (MLR) and induction of myeloma-specific cytotoxic T lymphocytes (CTLs) were analyzed.

Results
αDC1s were significantly increased the expression of several molecules without differences by loading tumor antigens. αDC1s showed high production of IL-12 during maturation and after subsequent stimulation of CD40L, but were not significantly affected by loading tumor antigens. Myeloma-specific CTLs against autologous myeloma cells from MM patients were induced by αDC1s pulsed with allogeneic apoptotic ARH77 cells. Autologous CTLs generated by pulsed αDC1s displayed a larger number of IFN-g secreting cells against autologous myeloma cells as a target cell for ELISPOT assay. Pre-incubation of the target cells with an anti-MHC class I or II mAb inhibited the IFN-g release, indicating MHC class molecule-dependent cytotoxicity (figure)

Conclusion
We suggested that autologous DCs pulsed with allogeneic myeloma cell line could generate potent myeloma-specific CTLs against autologous myeloma cells and could be practicable method for approaching cellular immunotherapy in MM.

Disclosures
No relevant conflicts of interest to declare.