bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implementing Cybord As First-Line Therapy For Transplant-Eligible Multiple Myeloma Patients : A Single-Center Preliminary Comparaison
Authors: Duquette Dominic , Laroche Vincent 
Published: October 2019

Abstract

Introduction
The best induction regimen for first-line therapy in multiple myeloma patients who are eliglible for autologous stem cell transplant (ASCT) is still unknown. In 2009, we started to use CyBorD and gradually changed our first-line therapy from Vel-Dex to CyBorD based on published work from Princess Margaret Hospital in Toronto. Here, we describe the first 10 patients to have received CyBorD and compare them to an historical cohort from the same institution.

Methods
We conducted a retrospective review of patient’s charts and transplant database from 2009/10/02 to 2013/04/19. We collected information on blood labs, cytogenetics, immunofixation, response rates, adverse events and graft collection. Patients not receiving the anticipated protocol or less than 3 cycles of treatment arm were excluded from this review.

Results
All patients (100%) in both cohorts received an ASCT (CyBorD, n=10 and Vel-Dex, n=11). The 2 groups were comparable and there was 1 patient in each arm with unfavorable cytogenetics. The response rates pre ASCT were CR = 20%, >VGPR = 90% compared to CR = 0%, >VGPR = 81,8% in CyBorD and Vel-Dex patients respectively. Response rates at 100 days post-ASCT was CR = 60%, >VGPR = 100% compared to CR = 36.4%, >VGPR = 90.9% in CyBorD and Vel-Dex patients respectively. Patients in CyBorD had a median of 1 (1-2) day for graft collection and a median number of graft cells of 5,01 x 109(2,06-6,48) compared to 1 (1-2) and 4,46 x 109 (3-6,82) in the Vel-Dex group. The rate of grade 3/4 thrombocytopenia was 0%(n=0) vs 9%(n=1) in CyborD and Vel-Dex patients respectively. No case of neuropathy grade 3 or 4 was observed in the CyBorD arm.

Conclusion
CyBorD is an effective and safe induction regimen for first-line therapy in ASCT eligible multiple myeloma patients. It produces less neuropathy and has an easier schedule to administer. It is now our standard protocol for these patients but dexamethasone has been reduced to once weekly for every cycle since then.
NB: CyBorD (Cyclophosphamide 300 mg/m2 PO days 1,8,15,22; Bortezomib 1,5 mg/m2 SC days 1,8,15,22, Dexamethasone 20 mg PO bid days 1-4, 9-12, 17-20 for cycles 1-2, 20 mg PO bid once weekly for cycles 3-4.)

Disclosures:
Duquette: Janssen: Consultancy, Honoraria. Off Label Use: CyborD is a widely accepted regimen but has not been accepted by the FDA.
RARα2 Expression Confers Myeloma Stem Cell Features
Authors: Tricot Guido J. , Yang Ye , Gu Zhimin , Xu Hongwei , Huang Junwei , He Jie , Tao Yi , Zhan Fenghuang 
Published: October 2019

Abstract

Background
Despite the major advances in the therapy of MM, many patients ultimately relapse and die of this disease. This is most likely due to the persistence of multiple myeloma stem cells (MMSCs), which survive even after the most intensive treatments and are insensitive to non-transplant therapy. We have previously demonstrated that RARα2 expression increased in CD138 selected plasma cells of relapsed myelomas (MM) and that increased expression was linked to poor prognosis in newly diagnosed MM patients. In this study, we further explore the relationship between RARα2 and MMSCs.

Materials and Methods
RT-PCR was used to detect RARα2, induced pluripotent stem cell (iPS) gene, Wnt and Hedgehog (Hh) gene expression in MMSCs and bulk cells. Clonogenic formation assays were performed by plating RARα2 over-expressing ARP1 and OCI-MY5 MM cell lines in soft agar, treated with bortezomib, doxorubicin, etoposide, and MK-571. Side population (SP) fraction, ALDH activity and cell apoptosis in MM cells were detected by flow cytometry. Western blot were utilized to dissect RARα2-related signaling pathway. Effect of RARα2 on MM progression in vivo was also analyzed in 5TGM1 myeloma mice.

Results
Higher expression of RARα2 was identified in the multiple myeloma stem cell (MMSC) fraction. Over-expression of RARα2 in MM cell lines resulted in 1) increased drug-resistance 2) increased clonogenic potential 3) activation of both Wnt and Hedgehog (Hh) pathways 4) increased side population (SP) and aldehyde dehydrogenase1 (ALDH1) levels and 5) increased expression of iPS genes. The opposite effects were seen with RARα2 knockdown. RARα2 induced drug resistance by activating the drug efflux pump gene ABCC3 and anti-apoptotic Bcl-2 family members. Inhibition of Wnt signaling or ABCC3 function could overcome drug resistance in RARα2 over-expressing MM cells. Our In vivo study indicated that targeting Wnt and Hh pathways using CAY10404, cyclopamine or itraconazole could significantly reduce tumor burden and increase survival time in the 5TGM1 mouse model. We confirmed these findings in primary myeloma stem cells. Finally, we showed that primary myelomas with high RARα2 expression possess similar features as myeloma stem cells.

Conclusion
This study demonstrates that RARα2 plays a crucial role in MMSCs by activating Wnt and Hh pathways, regulating the transcription of iPS genes and conferring drug resistance.

Disclosures:
No relevant conflicts of interest to declare.
Immune Regulatory Properties Are a Common Feature Of Stem Cells
Authors: Di Trapani Mariano , Bassi Giulio , Ricciardi Mario , Fontana Emanuela , Bifari Francesco , Pacelli Luciano , Giacomello Luca , Pozzobon Michela , Feron Francois , De Coppi Paolo , Anversa Piero , Fumagalli Guido , Decimo Ilaria , Menard Cedric , Tarte Karin , Krampera Mauro 
Published: October 2019

Abstract
Allogeneic stem cell-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some stem cell (SC) types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ecto-mesenchymal stem cells, leptomeningeal stem cells, and three different c-Kit-positive SC types, i.e. amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers, modulatory activity towards immune effector cells, immunogenicity and molecular inhibitory pathways, with some SC type-related peculiarities. In addition, we found that the inhibitory behaviour is not a constitutive property of SCs, but is acquired as a consequence of immune effector cell activation, as previously described for MSCs. Thus, immune regulation is a general property of stem cells and the characterization of this phenomenon may be useful for a proper therapeutical use of SCs.

Disclosures:
No relevant conflicts of interest to declare.
Immunological Characterization Of Multipotent Mesenchymal Stromal Cells. The International Society For Cellular Therapy (ISCT) Working Proposal
Authors: Krampera Mauro , Galipeau Jacques , Shi Yufang , Tarte Karin , Sensebé Luc 
Published: October 2019

Abstract
The large number of experimental approaches, culture conditions, qualitative and quantitative methods, and in vitro and in vivo models employed so far to assess immune regulatory properties of multipotent mesenchymal stromal cells (MSC) has led to an excess of literature data that sometimes are poorly comparable, redundant, and even contradictory. Thus, quite paradoxically, the risk is that pre-clinical literature data may become eventually weak and scarcely useful, in both researchers’ and Regulatory Authorities’ opinion, for supporting experimentally specific MSC-based clinical trials aimed at treating autoimmune and inflammatory diseases. However, some data in this field appear more solid and reproducible and may be generally accepted to suggest reproducible immunological assays to quantify the differences in immune modulatory properties of MSCs produced according to Good Manufacturing Practice (GMP).
The MSC Committee of the International Society of Cell Therapy (ISCT) released a statement paper in 2006 that established the minimal criteria characterizing human MSC, without focusing particularly on their immunological properties. In the 7 years following the publication of this statement paper, more than 10,000 manuscripts on MSC, and many of them deal with immune regulation. To consolidate the scientific research in this field, the MSC Committee of the ISCT is publishing a working proposal paper aimed at stimulating the general discussion about the need of shared guidelines for the immunological characterization of MSCs for clinical use:
1. A standard immune plasticity assay should be implemented by using IFN-γ + TNF-α as model in vitro priming agent
2. Functional analysis of an expanded cell product may provide mechanistic insights on intra- and inter- study variance in clinical response amongst patients
3. The use of purified responders would be widely practicable and should provide more generalizable guidance on relative functional potency of MSC and as a companion to clinical trials
4. Interrogating the IDO response as part of an in vitro licensing assay should be considered central
5. Conclusions based on xenorecipient animal models on how to conduct clinical trials should be drawn with caution
6. The prospective hypothesis-driven analysis of lymphocyte populations in patients groups treated with MSC should be encouraged
7. Clinical analysis should also include the monitoring of whether injected MSCs are the target of an immune response.

Disclosures:
No relevant conflicts of interest to declare.
CD26+ (dipeptidyl peptidase IV positive) Cells In Harvest Material For Multiple Myeloma Autotransplantation
Authors: Kopinska Anna , Krawczyk-Kulis Malgorzata , Suszek-Dziaczkowska Joanna , Bieszczad Katarzyna , Jagoda Krystyna , Kyrcz-Krzemien Slawomira 
Published: October 2019

Abstract
Dipeptidyl peptidase IV(DDP IV) known as CD26 can play a role in the process of mobilization as well as in regeneration during hematopoietic cells transplantation. As we know from the studies conducted in vitro and in animals models DDP IV inactivates chemokine CXCL12 (stroma direct factor 1) causing interruption the connection between marrow stoma and hematopoietic cells through CXCR4 receptor.In physiological conditions on the surface of hematopoietic cells concentration of CD26 is low.The purpose of this study was to examine a correlation between the number of CD26+ and CD34+ cells collected during mobilization in multiple myeloma (MM)patients (pts) and investigate the expression of CD26+ on monoclonal cells’. The second purpose was to examine whether CD34 cells have expression of CD26 parallel.30MM pts were mobilized in our department between 2011-2013. For harvest intermediate dose of cyclophosphamid and G-CSF were administered. The number of CD26+ cells and CD34+ cells were measured using immunophenotyping method before starting the procedure in peripheral blood and in collected materialResults All pts collected sufficient for AutoHCTnumber of CD34+ cells,the medianwas 3,8 (2,05-11,1x10^6/kgb.w.).Before mobilization 49,65% of blood nucleated cells showed CD26 expression while in collected material -79,95%. The CD34+ cells in peripheral blood showed low expression of CD26 – median 4,5%. In thecollected material the expression of CD26in CD34+ cells did not increase –median 2,5%, but the number of CD34+ cells (p=0,0003)increased. On mononuclear cells (monocytes and lymphocytes) there were demonstrated also the increase ofCD26 expression after mobilization chemotherapy and G-CSF (p=0,0002).Conclusion In MM patients after mobilization chemotherapy (cyclophosphamide+G-CSF) statistically significant increase ofnumber of CD26+ cellswere observed. It will be interesting to investigate the role of CD26+ cells during autotransplantation.

Disclosures:
No relevant conflicts of interest to declare.
Recombinant Thrombomodurin For The Treatment Of Transplantation-Associated Coagulopathy After Allogeneic Stem Cell Transplantation
Authors: Ishii Kazuyoshi , Nomura Shosaku , Ito Tomoki , Katayama Yuta , Kyo Taiichi , Ota Shuichi , Seki Masanori , Chiba Shigeru , Maeda Yoshinobu , Tanimoto Mitsune , Ikezoe Takayuki , Yagi Hideo , Ishida Yoji , Fujishima Naohito , Sawada Kenichi 
Published: October 2019

Abstract

Background
Levels of cytokines, chemokines and soluble molecules fluctuate after allogeneic hematopoietic stem cell transplantation (HSCT). These biomarkers are possible to be a diagnostic and prognostic value for transplantation-associated coagulopathy (TAC). In the present study, we investigated the effects of recombinant thrombomodulin (rTM) on levels of the cytokines, chemokines, and soluble factors registered in the ‘SIGHT’ research. SIGHT comprises the capital letters of five complications after HSCT, namely sinusoidal obstruction syndrome (SOS same as VOD), infection, GVHD, hemophagocytic syndrome and thrombotic microangiopathy.

Methods
The subjects were 159 patients who underwent allogeneic HSCT (bone marrow = 83, peripheral blood stem cells = 31, cord blood = 45). Blood samples were collected before and after transplantation. Levels of cytokines (interleukin-6, tumor necrosis factor-α, high-mobility group box (HMGB) 1), chemokines (monocyte chemotactic protein (MCP)-1, RANTES), and soluble molecules (soluble vascular cell adhesion molecule (VCAM)-1, soluble E-selectin, plasminogen activator inhibitor-1, platelet-derived microparticles (PDMP)) were measured by enzyme-linked immunosorbent assay. The rTM was administered as a therapy for transplantation-associated coagulopathy (TAC). This protocol was completed in day 4-14 after HSCT and consisted of day doses of 380 unit/kg with every days. Control group was also used heparin or no anti-coagulation therapy.

Results
MCP-1, IL-6, and TNF-a exhibited more significant elevations on days 7–14 after HSCT. In contrast, the levels of HMGB1, sE-selectin, sVCAM-1, PAI-1 and PDMP exhibited significant changes on days 14–28. There were significant improvements in TNF-a, sE-selectin, sVCAM-1, HMGB1, PAI-1 and PDMP after rTM-treatment (n=73), but not after rTM-untreatment patients (n=86).

Conclusion
We believe one of causes for TAC is pro-inflammatory cytokine including HMGB1. For this reason, it is thought that the direct anti-inflammatory effect of rTM’s lectin domein plays an important role in therapeutic mechanism for TAC. The present findings suggest the possibility that rTM can play a therapeutic role for TAC after allogeneic HSCT.

Disclosures:
No relevant conflicts of interest to declare.
Subsequent Malignant Neoplasms After Allogeneic Hematopoietic Stem Cell Transplantation Using Reduced-Intensity Conditioning and Outpatient Conduction
Authors: Zamora-Ortiz Gabriela , Velazquez-Sanchez-de-Cima Sara , Ponce-de-Leon Sergio , Gutiérrez-Aguirre César H. , Ruiz-Delgado Guillermo J. , Gomez-Almaguer David , Ruiz-Arguelles Guillermo J. 
Published: October 2019

Abstract
Abstract 5502
Patients given allogeneic hematopoietic transplants (HSCT) may develop subsequent malignant neoplasms (SMN). Several variables have been identified but there are no data about the incidence of this complication in individuals given HSCT using reduced-intensity conditioning (RIC) methods. The objective of this study is to define the incidence of SMN in patients given HSCT using a RIC preparative regimen conducted on an outpatient basis. Patients given HSCT in two institutions between October 1998 and 2012 were analyzed. Overall survival was analyzed with the Kaplan-Meier procedure. Patients alive at the closure of the study or those lost to follow up were censored. To appraise the SMN appearance, those patients dead were also regarded as censored at that moment, as well as those lost to follow up and those alive at the closing of the study. 95% confidence intervals for the survival or failure estimate were calculated with the Greenwood’s method. All the survival analyses were processed with the StataCorp 2005. Stata Statistical Software: Release 9. College Station, TX: StataCorp LP. A total of 416 allografted patients with a Karnofsky performance index of 100% were included in the study. All patients received PBSC allografts using reduce-intensity conditioning. Engraftment occurred in 350 patients (84%). The conditioning regimen was delivered as an outpatient procedure in all individuals. No patient was given radiotherapy nor antithymocyte globulin during the conditioning. Three hundred and sixty five patients (88%) were never admitted to the hospital, whereas 12% were admitted because of grade III-IV aGVHD, fever or mucositis. Median survival time was 15.7 months. Survival at 6 months (95% CI): 66.4% (61.5- 70.8%), at 12 months: 53.3% (48.1 -58.1%), at 60 months: 30.6% (30.5-41.5%). Eight patients with a SMN were identified in the group of 416 allografted patients, the cumulative probability of SMN being 6.8 at 10 years. Since the number of expected cases in the general population is 0.62, the ratio of observed to expected cases is 3.2 (p < 0.001). This figure means that the risk of developing a malignant neoplasm in allografted individuals using our method is 3.2 times higher than that in the general population. There were three non-Hodgkin´s lymphomas (NHL), two M2 acute myelogenous leukemias (AML), one hairy cell leukemia, one tongue epidermoid carcinoma and one breast carcinoma. In conclusion, we have found a diminished incidence of SMN in this group of Mexican patients allografted with the Mexican reduced-intensity conditioning method. Possible explanations for this difference are discussed, focusing on the RIC preparative regimen.

Disclosures:
No relevant conflicts of interest to declare.
Biosimilar Compared With Originator Filgrastim For Related-Donor Allogeneic Stem Cell Mobilisation: A Prospective-Historical Control Study
Authors: Lefrère Francois , Ribeil Jean-Antoine , Turner Matthew , Hermine Olivier , Blanche Stephane , Cavazzana-Calvo Marina 
Published: October 2019

Abstract

Introduction
Biosimilars of filgrastim have been available for over five years In Europe, where their use now exceeds that of the originator product. However, some professional bodies have raised concerns over their use in healthy donors for allogeneic mobilisation given the absence of clinical data in this setting. Here we report the use of biosimilar filgrastim compared with a matched historical control group in allogeneic transplant.

Methods
A total of 26 healthy related-donors (parent or sibling) received biosimilar filgrastim (HX575) for allogeneic stem cell mobilisation at a single centre between 2011 and 2013. Donors and recipients were compared with a matched historical control group (n=48) who had been treated with original filgrastim (Neupogen) at the same centre between 2005 and 2011. Donors and patients in both groups were treated according to the same clinical protocol, with G-CSF 10 µg/kg/day administered to donors on days 1-5 with leukapheresis performed on day 5.

Results
Donor and recipient characteristics (age, gender, body weight) were similar in both groups. Both the biosimilar and originator groups had similar donor mean white blood cell counts at baseline (6.13 vs 6.24 x 109/l) and on day 5 (46.9 vs 45.3 x 109/l). Mean donor CD34+ cell count on day 5 was 92/µl in the biosimilar group and 88/µl in the originator group (p=0.713). Mean number of CD34+ cells per recipient body weight was 9.7 x 106 in the biosimilar group and 8.00 x 106 in the originator group (p=0.437). Occurrence and intensity of bone pain was similar in donors in both groups. The majority of recipients in both groups had acute leukemia, myeloma, lymphoma or congenital immunodeficiency syndrome and around half underwent a non-myeloablative transplant. Median time to neutrophil engraftment (>500/µl) was similar in both the biosimilar and originator groups (16.5 [range 11-44] vs 15.0 [range 9-23] days; p=0.078), as was platelet recovery (>20 g/l) (12.5 [range 8-28] vs 12.5 [range 3-38] days; p=0.990). Acute graft-versus-host disease (GVHD) occurred in 27% of patients in the biosimilar group and 38% patients in the original group, while chronic GVHD occurred in 15% and 19% of recipients, respectively.

Conclusions
Biosimilar G-CSF is as effective and well tolerated as originator G-CSF for related-donor allogeneic stem cell mobilisation. Long-term follow-up of donors is required to confirm the safety of biosimilar and originator G-CSF.

Disclosures:
Lefrère: Sandoz Biopharmaceuticals: Consultancy, Honoraria. Turner:Sandoz Biopharmaceuticals: Employment.
Acceptable Results Of Allo-HSCT From Unrelated Donors In AML Patients Who Failed To Achieve The Complete Remission
Authors: Markiewicz Miroslaw , Dzierzak-Mietla Monika , Rybicka Malwina , Gaj Magdalena , Koclega Anna , Zielinska Patrycja , Bialas Krzysztof , Kyrcz-Krzemien Slawomira 
Published: October 2019

Abstract

Introduction
Despite the development of a variety of new investigational therapies for patients diagnosed with acute myeloblastic leukemia who either fail to achieve remission or who relapse thereafter, identifying suitable patients for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and choosing a best tolerable therapy that is most likely to succeed remains a difficult clinical problem. The rationale of this study was to evaluate results of allo-HSCT in AML patients who have failed to achieve complete remission pre-transplant.

Patients and Methods
33 pts with refractory or relapsed AML with no (18) or with partial remission (15), aged 35 (15-64) years received allo-HSCT from 10/10 (19) or 9/10 (14) HLA-matched Unrelated Donors (UD) in Hematology and BMT Center in Katowice, Poland, from Dec 2000 to Jan 2013. The myeloablative preparative regimen consisted of busulfan 4x4 mg/kg plus cyclophosphamide (Cy) 4x30 mg/kg (18 pts), TBI (12 Gy) plus Cy 3x40 mg/kg (6 pts), or treosulfan 3x14 g/m2 plus either fludarabine 5x30 mg/m2 (7 pts) or Cy 3x40 mg/kg (2 pts). Standard GVHD prophylaxis consisted of cyclosporine-A, methotrexate and pre-transplant ATG or thymoglobulin. Source of cells was peripheral blood (22 pts) or bone marrow (11 pts) with median 6.8 or 3.9 x10(6)CD34+cells/kg, respectively.

Results
All but 4 pts engrafted. The 2-year estimated overall survival rate was 47%. 17 pts died 4 (0.3-16) months following allo-HSCT due to relapse (7) infection (5), GVHD (1) GF (1) and unknown cause (3). Acute GVHD grade I, II, III and IV was observed in 15, 6, 2 and 1 pt (serious aGVHD grade III-IV in 3 pts (9%)), limited or extensive chronic GVHD was present each in 5 (20%) of 25 evaluable pts. Other complications included CMV reactivation (13), hemorrhagic cystitis (7), serious 3-4 grade mucositis (8), SOS (3) and renal failure (1). 16 pts (48.5%) are alive 45 months (4 months-10 yrs) post-transplant. No difference in survival has been observed between pts transplanted in PR or NR stages nor between pts treated with variable preparative regimens.

Conclusions
Allo-HSCT from UD with myeloablative conditioning is a feasible and effective curative therapy providing acceptable rates of long-term remission or cure in refractory or relapsed AML in patients who fail to achieve CR with conventional treatment.

Disclosures:
No relevant conflicts of interest to declare.