bluuebunny/crossref_metadata_2025 huggingface dataset:
Monozygotic Twins Display Different Minor Histocompatibility Antigens.
Authors: Markiewicz Miroslaw , Siekiera Urszula , Mietla Monika Dzierzak , Karolczyk Agnieszka , Kruzel Tomasz , Helbig Grzegorz , Kyrcz-Krzemien Slawomira
Published: October 2019

Abstract 4324

Introduction

Albeit it is generally presumed that monozygotic twins are genetically identical and that phenotypic differences between twins are mainly due to environmental factors, large-scale variation in copy number of DNA segments recently evidenced by Bruder et al. (AJHG, 2008) showed presence of genotypic diversity in monozygotic twins. The rationale of this study was to test whether monozygotic twins display disparities of minor Histocompatibility antigens (mHags) which may play role in syngenic HCT. We and others have previously shown that mHags constitute an important immunogenetic factor influencing immune responses following transplantation from HLA-matched allogeneic donors.

Patients and Methods

mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17, HY genotypes were defined with use of Dynal AllSet kits by PCR-SSP method in secured DNA samples from 3 monozygotic twins pairs aged 34, 24 and 28, who underwent syngenic allo-HCTs due to different hematological malignancies (NHL, CML, AML) in the Department of Hematology and BMT in Katowice, Poland in years 2000-2004.

Results

In 2 out of 3 syngenic pairs we have found differences in genes encoding mHags: different allele of EB-1 was present in one pair (NHL) (recipient HH, donor HY), and two different alleles of HwA-9 (RR, RG) and HwA-10 (**, R*) were present in second pair (CML). No differences in mHags were observed in the third pair (AML).

Conclusions

Our results question the long-standing belief that monozygotic twins are genetically identical and open up a possibility to further study the role of disparate mHags in disease and transplantation.

Disclosures:

No relevant conflicts of interest to declare.
Induction with New Drugs and Planned Autologous Followed by Non-Myeloablative Allogeneic Transplantation in Newly Diagnosed Myeloma.
Authors: Giaccone Luisa , Festuccia Moreno , Sorasio Roberto , Mordini Nicola , Schianca Fabrizio Carnevale , Patriarca Francesca , Casini Marco , Iori Anna Paola , Foà Robin , Boccadoro Mario , Bruno Benedetto
Published: October 2019

Abstract 4330

Introduction

Immunomodulatory drugs have recently changed the treatment options in multiple myeloma. Moreover, thalidomide, bortezomib and lenalidomide have also been used in the setting of allografting as post-transplant salvage therapy or as maintenance. We are currently evaluating the impact of new drugs as induction therapy in newly diagnosed multiple myeloma before a planned standard autograft followed by a non-myeloablative allograft (Tandem auto-allo).

Patients and methods

Twenty-five newly diagnosed patients (median age 55 years old, range 26-65) entered a recently designed prospective phase II program of tandem auto-allo which included the use of so-called new drugs during induction. Here, we report data on the first 11 evaluable patients with a follow up of at least 1 month after the allograft. Induction consisted of lenalidomide and dexamethasone (n=5), thalidomide and dexamethasone (n=4), or bortemomib-containing regimens (n=2), followed by G-CSF mobilized peripheral blood stem cell harvest. A standard autograft after melphalan 200 mg/m2 was planned 2-4 months before a low-dose (2 Gy) TBI-based allograft from an HLA-identical sibling. GVHD prophylaxis consisted of cyclosporin and mycophenolate mofetil. Disease status at allografting and post-transplant outcomes were compared to those of 22 patients pair-matched for beta2microglobulin and age, who underwent tandem auto-allo after induction with VAD-based regimens without new drugs (Blood, 2009).

Results

At the time of allografting after induction with new drugs and the autograft overall response rate was 81% (9/11), including a immunofixation-negative complete remission (CR). Following allografting, all patients promptly achieved donor engraftment. After a median follow-up of 11 months (2-26), all patients are alive and the overall response rate was 91% (10/11). Incidence of grade II-IV GVHD was 34% (4/11), including 1 patient with grade III GVHD. Chronic GVHD was observed in 40% (4/10) of patients with at least 3 months of follow-up. The induction with new drugs did not increase allotransplant-related toxicity or incidence of acute GVHD (Table 1). We observed a higher response disease before allografting in patients treated with new drugs.

Conclusions

Induction with lenalidomide, thalidomide or bortezomib does not impact feasibility and safety of tandem auto-allo. Longer follow up and a larger cohort of patients are necessary to evaluate the impact of new drugs in improving disease control post-tandem auto-allo.

Disclosures:

Patriarca: Janssen Cilag: Honoraria; Celgene: Honoraria. Boccadoro:Celgene: Consultancy, advisory committees, Research Funding; Pharmion: Consultancy, advisory committees, Research Funding; Janssen Cilag: Consultancy, advisory committees, Research Funding.
G-CSF Treatment May Prevent Telomere Attrition in CD34+ After Peripheral Blood Autologous Stem Cell Transplantation: Shortening Time to engrafting but Early Relapse in Non Hodgkin's Lymphoma. First Experience without Stem Cell Cryopreservation.
Authors: Silva-Moreno Mario , Murillo-Ortiz Blanca , Hernández-González Martha , Solorio-Meza Sergio , Martínez-Garza Sandra , Castillo-Valenzuela Rosa , Albarrán-Tamayo Froylán
Published: October 2019

Abstract 4358

Background

Hematopoietic reconstitution after stem cell transplantation requires excessive replicative activity because of the limited number of stem cells that are used for transplantation. Telomere shortening has been detected in hematopoietic cells after allogenic peripheral blood stem cell transplantation (PBSCT). Recent studies have demonstrated shortening of telomeres after chemotherapy, this shortening being equivalent to 15-40 years of ageing which has been related to genetic instability, increase risk of mutations, myelodysplastic syndromes, secondary malignancies and relapse.

Aims

To measure in vivo the effect of G-CSF administration, on the regulation of stem cells obtained from peripheral blood collected for autologous transplantation and to know its possible implications, on telomere dynamics following high-dose (HD) chemotherapy courses cyclophosphamide (CY) and HD-Ara-C for relapsed non Hodgkin's lymphoma.

Methods

Telomeric measurement was performed with real-time polymerase chain reaction (RT-PCR),in peripheral blood progenitor cells(PBPC) collected on day 5 and 10 of G-CSF administration from patients with Lymphoma, and day 0,+7,+14 and +17 post transplantation. For CD34+ cells selection, mononuclear cells were isolated from peripheral blood stem cell by Ficoll-Hypaque. The purity of CD34 selected cells was determined in a cell sorter (Becton Dickinson) using a fluorescein isothiocyanate (FICT)-conjugate monoclonal antibody (mAb).

Results

We have shown dynamic telomere length change during the immediate reconstitution, Telomere Lenght (TL) was shorter in PBPC collected after HD-Ara-C and CY compared to TL after G-CSF administration, 6526bp vs. 4582 bp (P < 0.01). This result was confirmed on CD34+ cells. Engraftment of granulocytes and platelets come on day +13 and +19 respectively An increase in telomere length to day +19 (5962 bp) was found. Unfortunately we face with an early relapse of the same non Hodgkin's lymphoma at day +60.

Conclusions

Administration of G-CSF increased TL in CD34+ prevents telomere attrition after allogenic peripheral blood stem cell transplantation. The size and composition of the transplanted stem cell pool determines the ultimate telomere length. Whether PBSCT with shortened telomeres has engraftment improvement with G-CSF but risking early relapse warrants more prospective studies. We suggest that measurement of telomere length in peripheral blood collected for transplantation could be useful as a prognostic marker for engraftment/relapse in non Hodgkin's lymphoma without stem cell cryopreservation.

Disclosures:

No relevant conflicts of interest to declare.
Multicenter Retrospective Analysis of High Dose Chemotherapy and Autologous PBSCT for Ovarian Cancer.
Authors: Kim Kyoung Ha , Won Jong-Ho , Park Hee-Sook , Jeong Seong Hyun , Lee Hyun Woo , Park Joon Seong , Cho Seok-Goo , Lee Joon Mo , Park Chong Won , Kim Dong Hwan (Dennis) , Jang Jun Ho , Lee Won Sik , Lee Jung Lim , Mun Yeung-Chul , Seong Chu-Myong , Kim Han Jo
Published: October 2019

Abstract 4365

Background

Ovarian cancer is one of the most chemotherapy sensitive solid tumors. However, the role of dose intensity in the chemotherapy of advanced epithelial ovarian cancer has remained controversial. Accordingly, the current study attempted to analyze the outcome of high dose chemotherapy and autologous peripheral blood stem cell transplantation for ovarian cancer retrospectively.

Methods

Clinical data were collected retrospectively from 6 transplant centers in Korea between January 1996 and July 2008.

Results

Twenty three patients of total 6 centers were analyzed. The median age of the patients was 52 years (40-62 years). Nineteen patients (82.6%) were platinum sensitive and 4 patients were not. The conditioning regimens were reported to be ICE (ifosfamide, carboplatin, and etoposide) in 43.5 %, CTM (cyclophospamide, thiotepa, and melphalan) in 26.1 %, melphalan in 13%, other in 17.4 %. The median time to attain a neutrophil count greater than 500/mm3, following the transplantation, was 13 days (4∼38), and to attain a platelet count greater than 20,000/mm3, was 13 days (4∼38 days). There was primary graft failure of platelet in 3 patients. The median duration of progression free survival and overall survival were 6.3 months (95% CI, 0-19.3) and 19.7 months (95% CI, 10-29.4). The median overall survival was 25.9 months in the platinum sensitive patients and 17.4 months in the platinum resistant patients, however, there was no statistically significant difference in PFS between two groups. Poor prognostic factor for survival which retained statistical significance at multivariate level were platinum resistance (p=0.06, RR 3.99; 95% CI, 0.94-16.97) and clear cell type (p=0.015, RR 9.63; 95% CI, 1.56-59.45).

Conclusion

Some subgroups (non clear cell types, platinum sensitive groups) of patients with ovarian cancer seem to have good outcomes after high dose chemotherapy with autologous stem cell transplantation, although several biases may have affected these observations.

Disclosures:

No relevant conflicts of interest to declare.
Multimodal Bcl-2 Sub-Populations in CLL.
Authors: Degheidy Heba A. , Gadalla Shahinaz M. , Raveche Elizabeth , Stetler-Stevenson MA , Marti Gerald E.
Published: October 2019

Abstract 4391

Introduction

The Recently described NZB miRNA15a/16-1 mutation is syntenic to 13q14 deletion in CLL. The mir15a/16-1 complex is thought to regulate bcl-2 expression. Therefore the level of bcl-2 expression was examined more closely as it might be used to differentiate mono-allelic deletion from the diploid CLL clone.

Patients and Methods

Multicolor flow-cytometry using a panel of anti-bcl-2 FITC (clone 124, DAKO Cytomation, Glostrup, Denmark) and CD19, CD20, CD5, CD23, CD38, kappa, lambda, and CD45 was used. Bcl-2 expression was evaluated using the conventional bcl-2 index (Mean fluorescence intensity (MFI) B cell/ MFI T cells) in 25 untreated CLL patients, and 10 normal donor controls. A modified ratio based on normal remaining (NR) polyclonal B cells was also used (MFI clone/MFI NR) with a new gating strategy for bcl-2 expression analysis.

Results

The mean of the conventional bcl-2 index is significantly higher in CLL patients [1.52 ± 0.53(SD)] compared to the control [0.5 ± 0.19(SD)], p<0.001 Student‘s t test. When comparing the mean of conventional bcl-2 index (clone/T cell) versus the mean of the modified bcl-2 index (clone/NR) [1.78 ±0.61 (SD)] in only CLL patients there was no significant difference. On the other hand, the rank order analysis of the conventional and modified bcl-2 index showed an r=0.7, p< 0.001 indicating that both methods give similar results. In addition to the high correlation between the conventional and the modified ratio, the modified ratio was multimodal in distribution.

Conclusions

Bcl-2 expression varies largely among the lymphocyte sub-sets. The choice of the polyclonal B cells allows better segregation of multimodal bcl-2 expression. Since bcl-2 mRNA is a validated mir15a/16 target, increased bcl-2 expression maybe a direct result of and a surrogate marker for mir15a/16 levels and/or the 13q14 status. There are three possibilities: no deletion (diploid), heterozygous deletion, or homozygous deletion. This needs to be verified by fluorescence in situ hybridization (FISH) analysis of sorted CLL B cells based on bcl-2 expression.

Disclosures:

No relevant conflicts of interest to declare.
Neuropilin-1 – Novel, Promising Target for Chronic Lymphocytic Leukemia patients.
Authors: Giannopoulos Krzysztof , Omiotek Marcin , Mlak Radosław , Tomczak Waldemar , Rolinski Jacek M. , Dmoszynska Anna , Stilgenbauer Stephan , Bullinger Lars
Published: October 2019

Abstract 4392

Neuropilin – 1 (NRP-1) represents a receptor for VEGF, which has been reported to be overexpressed in several malignancies. NRP-1 expression was also found on plasmacytoid dendritic cells (PDC) as well as on regulatory T cells (Tregs). Both, PDC and Tregs represent cells that are involved in tolerance mechanisms. Thus, in addition to its role in angiogenesis, NRP-1 might be involved in tumor escape mechanisms, and expression of NRP-1 on tumor cells, Tregs and PDC might point to a promising target for therapy.

To further investigate this hypothesis we assessed NRP-1 expression on leukemic cells, Tregs and PDC in 38 CLL patients. Using five parameters flow cytometric assessment we found increased expression of NRP-1 on leukemic lymphocytes of all CLL cases compared to NRP-1 expression on lymphocytes derived from healthy volunteers (1.8% vs. 0.29%, respectively). There was no significant difference between patients of different Binet stages, between CD38 positive vs. negative patients as well as between ZAP-70 positive vs. negative patients. In accordance, the expression of NRP-1 did not influence the treatment-free survival. However, we also found expression of NRP-1 on Tregs as well as PDC derived from the CLL patients. The median expression of NRP-1 on Tregs was 42.6 % (range: 10-100%). NRP-1 was expressed on almost all PDC with median expression 100% (range: 98.2 – 100%). In additional studies, we found that NRP-1 expression might be regulated by the VEGF levels in CLL. Magnetically separated CLL cells increased expression of NRP-1 after treating cultured cells with different VEGF concentrations. While VEGF levels of 0.1 – 0.5ng/ml, which are in the range of VEGF concentration observed in CLL patient samples, effectively induced expression of NRP-1, higher VEGF concentrations inhibited NRP-1 expression. Interestingly, we also observed that VEGF can also regulate the NRP-1 expression on Tregs.

In conclusion, we found NRP-1 expression on CLL cells, and for the first time demonstrated that CLL derived Tregs as well as PDC also express NRP-1. Furthermore, our data provide evidence that NRP-1 expression might be regulated by VEGF levels in CLL. Thus, NRP-1 might not only be involved in angiogenesis, but also in tolerance mechanisms. Therefore NRP-1 might represent an interesting molecule for therapy of CLL since it could target both leukemic cells as well as the main players such as Treg and PDC causing escape of tumor cells from the immunosurveillance.

Disclosures:

No relevant conflicts of interest to declare.
Reversal of Multidrug-Resistance in Human Leukemia Cell Line K562/A02 by Tyrosine Kinase Inhibitors.
Authors: Chen Bao-An , Shan Xue-Yun , Cheng Jian , Gao Feng , Ding Jia-Hua , Gao Chong , Chen Ning-Na , Pei Xiao-Ping , Xia Guo-Hua
Published: October 2019

Abstract 4828

Objective

This study was aimed to investigate the reversible effect of tyrosine kinase inhibitors(TKI)on Multidrug resistance cell line K562/A02.

Methods

The expression levels of mdr-1 mRNA and bcr-abl mRNA were assayed by RT-PCR. The protein levels of P-glycoprotein (P-gp) and P210 were detected by Western blot. The DNR accumulation of K562/A02 cells were analyzed by flow cytometry (FCM).

Results

Analysis of the inhibition rate showed that 0.0625μmol/L Imatinib or 5nM Nilotinib alone had no effect on the inhibition of K562/A02 cells. The fluorescence intensity of intracellular DNR of Imatinib, Nilotinib in K562/A02 cells was 7.85%, 12.02% (respectively of that in K562 cells). Imatinib or Nilotonib alone could decrease the mdr-1 mRNA and bcr-abl mRNA expression levels (Imatinib 0.65±0.02, 0.87±0.02; Nilotinib 0.48±0.04, 0.73 ±0.02) respectively, all these of which were significantly lower than the K562/A02 cells group 0.96±0.01, 1.87±0.04. The P-gp and P210 protein expression levels were also down after treated with different drugs (Imatinib 0.74±0.02, 0.68±0.01; Nilotinib 0.61±0.05, 0.60±0.01; the K562/A02 cells group 0.93±0.01, 1.25±0.03).

Conclusion

It is concluded that multidrug resistance (MDR) can be partially reversed by Imatinib or Nilotinib. The effect of Nilotinib was greater than Imatinib.

Disclosures

No relevant conflicts of interest to declare.
Azacitidine Is Effective in Patients with Intermediate-2 / High IPSS Risk Myelodysplastic Syndrome Managed in Community Based Practice: Preliminary Data From the Spanish Azacitidine Compassionate Use Registry.
Authors: Garcia Regina , González José Ramón , Bailen Alicia , Falantes Jose F , Sanchez Joaquin , Duarte Rafael F , Besalduch Juan , Lapiedra Andreu
Published: October 2019

Abstract 4835

Background

Myelodysplastic syndrome (MDS) is comprised of a group of heterogeneous hematological disorders. Although the decision regarding treatment of a patient with MDS is based on performance status, age, patient preference and concomitant illnesses, NCCN-recommended treatment approaches vary according to IPSS risk score. Azacitidine (AZA) is a hypomethylating agent recently approved in Europe for the treatment of MDS. AZA was available in Spain under compassionate use before its regulatory approval and marketing authorization from the Spanish Medicines Agency in May 2009.

Material and

Methods

We present the preliminary analysis of the clinical data from a longitudinal, multicenter Spanish patient registry. Data on the disease course and management of patients with MDS treated with AZA under compassionate use conditions were retrospectively collected from community-based hematology clinics. As of August 1, 2009, 65 patients with intermediate-2 / high IPSS-risk MDS diagnosed according to WHO criteria had been included.

Results

At baseline the median age was 69 years, the male/female ratio was 60/40, and the majority of patients had primary MDS (56 patients; 88%) and an ECOG performance status of 0-1 (43 patients; 67%). The most frequent initial dose of AZA applied was 75 mg/m2 (53 patients, 83%), and the most common dosing schedules were as follows: days 1-7 (82%), and days 1-5 and 8-9 (5%) in a 28-day cycle. AZA was administered mostly subcutaneously (56 patients, 89%). The mean number of cycles administered was 6 (range 2-29). The overall treatment response was 59% (International Working Group 2006 criteria): 16% complete response, 13% complete bone marrow response, 13% partial response and 18% hematological response. In addition, 23% achieved stable disease. AZA was generally well tolerated. The grade 3/4 adverse events documented in these patients, regardless of their relationship to active treatment, were neutropenia (37%), thrombocytopenia (26%), anemia (17%), febrile neutropenia (8%), rash (2%), vomiting or nausea (2%), and constitutional symptoms (2%).

Conclusion

These preliminary data do not differ from those previously obtained from clinical trials (Silverman et al 2006, Fenaux et al 2009). Our results demonstrate that in a community-based setting, patients with intermediate-2 / high-risk MDS respond to treatment with AZA. In line with previous clinical trials, we expect this could point to a better prognosis for MDS patients in Spain, with prolonged survival and a better quality of life.

Disclosures

No relevant conflicts of interest to declare.
Attempts to Optimise Induction and Consolidation Chemotherapy in Patients with Acute Myeloid Leukaemia: Results of the MRC AML15 Trial.
Authors: Burnett Alan K , Hills Robert K , Milligan Donald , Hunter Ann E. , Goldstone Anthony H. , Prentice Archie , Gibson Brenda ES , Kjeldsen Lars , Yin John AL , Wheatley Keith , Russell Nigel H.
Published: October 2019

Abstract 484

On behalf of the NCRI AML Working Group, United Kingdom

There is a general acceptance that survival in younger patients (<60 years) with AML has improved over the last 20 years, the majority still fail treatment. While the induction rate is satisfactory at >75% relapse remains a problem. Optimisation of induction and defining the schedule and duration of post-induction chemotherapy remains important even as novel approaches such as antibody directed therapy or small molecule therapy are added. The MRC AML15 compared 3 induction chemotherapy schedules and 4 post induction options. In induction patients were randomised to two course of DA or ADE or FLAG-Ida. In each case patients were also eligible to be randomised to receive Gemtuzumab Ozogamicin (GO) or not, which has been separately reported. In consolidation patients were randomised to MRC schedule (MACE/MidAC) or two courses of High Dose Ara-C and for those randomised to Ara-C to a dose of 3g/m2 or 1.5g/m2. Finally patients could be randomised to receive, or not, a 5th course comprising Ara-C.

Between October 2002 and January 2009, 1982 patients were randomised between DA (n=994) and ADE (n=988); up to May 2007, patients could also be randomised to FLAG-Ida; the randomised comparison with ADE recruited 1266 patients (FLAG-Ida n=635, ADE n=631). For part of the trial patients could be randomised to GO or not (306 patients in the DA v ADE and 297 in the FLAG-Ida v ADE comparisons were randomised). The median age of patients in the randomised comparisons was 49 years. Overall the ORR was 85% (CR 80%, CRi 5%) and the OS at 5 years is 43%. The randomisations were balanced for age, sex, performance status, de Novo/secondary disease, cytogenetics, white cell count, and GO allocation.

With the exception of a suggestion of greater benefit on ORR with FLAG-Ida among patients given GO, overall outcomes were not affected by GO treatment. In consolidation 1445 patients were randomised between MRC (n=723) and HD Ara-C (n=722). Of the 723 Ara-C patients, 328 were randomised to 3g/m2 and 329 to 1.5g/m2: 227 of the 1619 patients who received 4 courses were randomised for a 5th course with 112 allocated 5 courses.

Conclusions:

There were no significant differences in the response rate between induction treatments. FLAG-Ida resulted in a reduced relapse rate but this was balanced by increased myelosuppression and deaths in CR resulting in no overall benefit in survival. No survival differences were seen in any of the post induction comparisons, but the MACE/MidAc arm produced more myelosuppression and required more supportive care, and led to increased death in remission.

Disclosures:

No relevant conflicts of interest to declare.
Prominent Elevation of Survivin Expression in High-Risk Myelodysplastic Syndrome.
Authors: Yoshida Akira , Tanaka Saki , Yamauchi Takahiro , Takagi Kazutaka , Kishi Shinji , Urasaki Yoshimasa , Tohyama Kaoru , Ueda Takanori
Published: October 2019

Abstract 4842

Survivin, a new member of the inhibitor of apoptosis protein (IAP) family, has been reported to be expressed in a variety of human malignancies. We identified a novel splice variant of survivin, designated as survivin-3B. Overexpression of survivin-3B in leukemia and colon cancer cells reduced cell death after etoposide and cisplatin treatment, suggesting that survivin-3B possesses anti-apoptotic activity. Using Taqman RT-PCR and flow cytometer, we examined the expression of wt-survivin and survivin-3B in 48 patients with MDS and 55 patients with de novo AML. We found that wt-survivin and surivivin-3B are especially overexpressed in high-risk MDS and overt AML following MDS. Expression levels of wt-survivin and survivin-3B are significantly associated with higher international prognostic index score of MDS. Flow cytometric analysis also revealed that myeloblast from high-risk MDS possesses abundant expression of wt-survivin, but erythoroblast dose not. In contrast, myeloblasts from de novo AML show quite low levels of wt-survivin expression (mean expression value of de novo AML is less than 8% compared with that of high-risk MDS and overt AML). Interestingly, lack of wt-survivin expression was found in 7 patients (2 MDS and 5 AML). Instead of wt-survivin, expression of survivin-3B can be detected in these samples, suggesting that survivin-3B may play an important role as an alternative apoptosis inhibitor and mitosis regulator. Our data suggests that high levels of wt-survivin and survivin-3B expression are distinctive molecular feature of high-risk MDS and overt AML following MDS.

Disclosures

No relevant conflicts of interest to declare.
Secondary Myelodysplastic Syndrome.(sMDS) Presentation and Evolution.
Authors: Kornblihtt Laura , Enrico Alicia , Milone Jorge , Prates Maria Virginia , Belli Carolina B , Arbelbide Jorge , Lafalce Diana , Penchasky Diana , Fantl Dorotea , Rivas Maria Marta , Cabrejo Maria , Caicedo Maria
Published: October 2019

Abstract 4850

Background

The Secondary Myelodysplastic Syndrome (sMDS) represents a severe complication in the treatment of cancer. They are associated to the use of alkylating agents, radiation and immunosuppressive therapy. Their prognosis is unfavorable. Conventional chemotherapy is mainly palliative whereas allogenic bone marrow transplantation allows the cure of a small percentage of cases. Aims: To characterize and to describe the clinical presentation, therapeutic conduct and evolution in sMDS. This results where compared with those of primary MDS (pMDS) in patients enrolled into the observational study of Sociedad Argentina de Hematología from January 2007 to June 2009

Methods

There were analyzed 253 patients with diagnosis of MDS. sMDS correspond to 12.2 % (31/253)of the total, mean age 71 years old (r 23-84), relation M: F of 1:2.8 (being 1:2.2 in pMDS). Previous pathologies were: solid tumors in 17 patients (54%); 6 prostate Ca, 5 breast Ca, 4 GI Ca, 1 thyroid Ca, 1 bladder Ca, 1 pharynx Ca. Hematology malignancies were found in 7 patients: 2 Non Hodgkin Lymphoma, 2 Hodgkin Lymphoma, 1 Myeloma Multiple, 1 Chronic Myelomonocyticleukemia, 1p aplastic anemia. Six patients (23%) received immunosuppressive treatment for kidney transplantation, Wegener disease and glomerulonephritis. 85% of the patients received previous chemotherapy and/or radiotherapy. Result: There were analyzed 217 karyotypes (85.7%), 25 in the sMDS group and 189 in the pMDS, abnormal karyotypes in 14/25 (56%) vs 55/189 (29%) (p=0.006), complex karyotypes (unfavorable): 6/25 (24%) vs 8/189 (7%) (P=0.002). Twenty eight patients requiered treatment 28/31 (90.3%) vs 167/222 (75.2%) (p=0.09), transfusional therapy 23/31 (77.55%) vs 93/222 (42%) (p=0.001). Hypomethylating agents were used in 22,5% in sMDS vs 21,1% in pMDS and Erythropoyetin in 45,2% vs 48,6%. With a median follow up of 136 days (r:4-650), 8/31 progressed to AML (25.8%) vs 28/222 (13%) (p=0.005). Fourteen patients (45%) were death vs 47/222 (20.6%) (p=0.005); 17/31 (54.8%) of patients were alive in the sMDS group and 153/189 (80%) in the pSMD group (p= 0.005). Summary and

Conclusions

sMDS constituted 12.2% of the total of MDS that were reported. This entity has in our experience presence of unfavorable karyotype in more than the 50% of the cases, greater transfusion request, greater evolution to acute myeloid leukemia with high mortality and greater mortality than pMDS. This results confirm the bad prognosis of sMDS.

Disclosures

No relevant conflicts of interest to declare.
Clinical and Prognostic Relevance of Magnetic Resonance Imaging of the Spine in Newly Diagnosed Multiple Myeloma Patients Receiving Autologous Stem Cell Transplantation.
Authors: Tosi Patrizia , Petrucci Alessandro , Pantani Lucia , Zamagni Elena , Tacchetti Paola , Perrone Giulia , Brioli Annamaria , Ceccolini Michela , Baccarani Michele , Cavo Michele
Published: October 2019

Abstract 4885

Magnetic resonance imaging (MRI) of the spine has demonstrated to be a useful tool for a correct staging of multiple myeloma (MM), as it is more sensitive than plain x-rays in detecting vertebral lesions. Furthermore, both pattern of bone marrow involvement (focal, diffuse or normal), and number of focal lesions can be detected, and this could contribute to better define the prognosis and the outcome of newly diagnosed patients. In the present study we prospectively evaluated the clinical and prognostic role of spinal MRI in 152 newly diagnosed MM patients (89M, 63F, median age = 56yrs) that subsequently received high-dose chemotherapy and autologous stem cell transplantion, either single (n=43) or double (n=109). Pattern of marrow involvement was normal in 11% of the cases, diffuse in 20% and focal in 69%, with 34% of the patients showing > 7 focal lesions. Patients with a diffuse pattern or a focal pattern with > 7 lesions showed a significantly higher bone marrow plasma cell infiltration (p=0.04) and beta2 microglobulin values (p= 0.04) as compared to patients with a focal pattern with < 7 lesions. Response rate to the assigned treatment program was similar in the three groups of patients, with > VGPR obtained in 63% of the patients with a diffuse pattern, and in 70% of those with a focal pattern. Median progression-free survival (PFS) was significantly longer in patients with < 7 focal lesions as compared to those with >7 lesions or a diffuse pattern (55 vs 46 months p=0.05). Normalization of MRI was more frequently obtained in patients with < 7 lesions (67% vs 38% in patients with > 7 lesions, p=0.005); patients achieving a normal MRI pattern showed a significantly longer PFS (67 months) as compared to patients failing to achieve a negative MRI at the end of treatment (p=0.0000). According to our data, MRI confirms its prognostic role in newly diagnosed MM receiving high-dose therapy and autologous stem-cell transplantation; a diffuse pattern of bone marrow involvement or a focal pattern with > 7 lesions are predictive of a more aggressive outcome of the disease; furthermore normalization of MRI pattern after therapy is predictive of a longer progression-free survival

Disclosures

No relevant conflicts of interest to declare.
Myeloid-Derived Suppressor Cells in Patients with Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance.
Authors: Parrinello Nunziatina , La Cava Piera , Tibullo Daniele , Giallongo Cesarina , Di Bartolo Orazio , Spina Eleonora , Cavalli Maide , Schinocca Luciana , Triolo Anna , Romano Alessandra , Chiarenza Annalisa , Palumbo Giuseppe A , Di Raimondo Francesco
Published: October 2019

Abstract 4890

Background

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells of myeloid origin, and include immature macrophages, granulocytes, dendritic cells (DC) and other myeloid cells. In mice, are phenotypically characterized as CD11b+Gr-1+. Humans MDSC have an immature phenotype, including lineage negative (Lin-), CD14-, HLA-DR-, CD15+, CD34+, CD11b+, CD33+, and CD13+ cells. MDSC impair T-cell functions through secretion immunosuppressive cytokines, perturbation of the arginine metabolism by inducible nitric oxide synthase (iNOS), up-regulation of reactive oxygen species (ROS), therefore are considered an important tumor escape mechanism. These cells, also promote tumor-dependent angiogenesis as well as tumor metastasis, and to provide tumor resistance to antiangiogenic drugs. Their accumulation has been described in the peripheral blood of patients affected by breast, lung, renal and neck carcinoma, melanoma, chronic infections, inflammatory diseases, and traumatic stress.

We investigate MSDC in patients with multiple myeloma (MM) and monoclonal gammopathy undetermined significance (MGUS) by flow cytometry

Methods

We studied 22 patients with MM at diagnosis, 20 patients with MGUS, and 10 healthy controls (HC).

Results

we observed that patients with MGUS showed the same number of MDSC (CD11b+,CD13+,CD34+,CD14-,CD45+) in the peripheral blood compared to HC (1,90±1,03/mmc, p=0,23). On the contrary, patients affected by MM showed a significant increase of MDSC vs HC (6,80±8,79/mmc vs 1,45± 0,98/mmc, p=0,003).

Conclusion

Our results suggest that these myeloid-derived suppressor cells, through their mechanisms immunesuppressive and proangiogenesis, could be involved in the progression of MGUS towards overt MM.

Disclosures

No relevant conflicts of interest to declare.
Myeloma Treatment Side Effects and Unmet Patient Needs 2009: Results of An International Comparative Survey Conducted by Myeloma Euronet (ME), the European Network of Myeloma Patient Groups.
Authors: Waldmann Anita , Barragán Begoña , Cursaru Viorica , Heberlein Candy , Hrianka Miroslav , Richter Friedrich , Sadżuga Roman
Published: October 2019

Abstract 4900

Recent advances in the treatment of multiple myeloma have increased response rates and treatment outcomes and raised hopes that myeloma may soon be turned into a chronic disease. However, myeloma treatment is often associated with various side effects that can sometimes have a significant impact on the quality of life of myeloma patients and also affect the overall treatment plan. An international comparative survey of myeloma patients and patient relatives and healthcare professionals is conducted to assess perceptions of how myeloma patients are informed about potential side effects of myeloma treatment options, the impact of treatment side effects on a myeloma patient's overall well-being and on the course of myeloma treatment, the satisfaction concerning the management of treatment side effects, potential side effects that myeloma patients don't feel comfortable reporting to their doctor as well as potential reasons for not reporting them, and the satisfaction concerning access to information and support, access to novel treatments, coverage of treatment costs, overall quality of treatment and care, and psycho-social and emotional support. The comparative survey is conducted based on 2 comparable two-page questionnaires, 1 for healthcare professionals and 1 for myeloma patients and patient relatives. The survey consists of 9 multiple-choice and ranking format questions. The questionnaires were developed by ME. They were pre-tested with both professional and patient communities and are available in 6 languages: DE, EN, ES, FR, IT, PL. The survey is distributed by mail or e-mail, it can be taken online via accessing the organisation's web site, and it is conducted on paper at haematological and oncological congresses and patient information days. To date, a total of 272 healthcare professionals from 44 countries and 257 myeloma patients and patient relatives from 21 countries have responded to the survey. Data gathering will continue until mid OCT 2009 and final survey results will be presented at ASH 2009. The survey was made possible through an unrestricted grant from Ortho Biotech, Biopharmaceutical Division of Janssen-Cilag.

Disclosures

No relevant conflicts of interest to declare.
The Incidence of Corrected Hypercalcemia and Its Relationship with Prognosis for Chinese Multiply Myeloma.
Authors: Zhang Xi , Chang Chunkang , Li Xiao , Su Jiying , Wu Lingyun , Zhou Liyu , He Qi , Xu Li , Song Luxi , Pu Quan
Published: October 2019

Abstract 4903

Purpose

This paper is to study and analze the serum calcium level after corrected for serum albumin and its effect on prognosis in Chinese multiple myeloma (MM).

Methods

Serum calcium levels before and after corrected by serum albumin were retrospectively analyzed in 165 Chinese multiple myeloma patients. Corrected serum calcium (mmol/L)=serum calcium (mmol/L) – 0.025 x serum albumin (g/L)+1.0 (mmol/L). We also analyzed the relationship of serum calcium, serum creatinine and disease categories in Durie-Salmon (DS) staging system with patients' long-term overall survival rate.

Results

In 165 patients, the incidences of before and after corrected hypercalcemia were 8.7% and 40.6%, which were statistically significantly different (p=0.0245). Based on DS staging, the before and after corrected serum calcium levels of sixteen MM patients in I stage were 2.316±0.082 mmol/L and 2.344±0.073 mmol/L with a p value equal to 0.3236; the before and after correccted serum calcium levels of fifty MM patients in II stage were 2.314±0.17 and 2.407±0.235 mmol/L with a p value equal to 0.0251; the before and after corrected serum calcium levels of ninety-nine MM patients in II stage were 2.428±0.32 and 2.671±0.309 mmol/L with a p value equal to 0.0000. There is no significant difference in overall survival time between normal serum calcium group and elevated serum calcium group, p=0.8929. There is significant difference in overall survival time between normal serum creatinine patients and raised serum calcium patients with a p value equal to 0.0170. Patients in I stage in DS staging system have statistically significant longer overall survival time than those patients in II/III stage in DS staging system, p=0.0382.

Conclusion

The incidence of corrected hypercalcemia in Chinese MM is similar to foreign reports. Hypercalcemia has smaller or limit impact on patients' long-term overall survival compared to serum creatinine and DS staging.

Disclosures

No relevant conflicts of interest to declare.
Myeloma Treatment Compliance 2009: Results of An International Comparative Survey Conducted by Myeloma Euronet (ME), the European Network of Myeloma Patient Groups.
Authors: Waldmann Anita , Barragán Begoña , Cursaru Viorica , Heberlein Candy , Hrianka Miroslav , Richter Friedrich , Sadżuga Roman
Published: October 2019

Abstract 4907

Patients who follow all the instructions about a course of treatment as directed by their doctor or nurse can be described as ‘compliant’ with a treatment plan. It is well-understood that failure of patients to follow treatment plans or understand the requirements after leaving their care could result in poor treatment outcomes, compounding health problems and additional health care costs. An international comparative survey of myeloma patients and patient relatives and healthcare professionals is conducted to assess perceptions of how myeloma treatment plans are determined, the familiarity of myeloma patients with their treatment plan, the satisfaction concerning the level of treatment compliance-related information, the factors that might have a negative effect on treatment compliance, the effect of one exemplary treatment side effect (peripheral neuropathy) on treatment compliance, and overall myeloma treatment compliance. The goal of the survey is to help patient and medical communities recognise the importance of patient compliance and the issues and challenges patients face in complying with their treatment. Learnings from the survey will be used to help improve myeloma patient compliance. The comparative survey is conducted based on 2 comparable two-page questionnaires, 1 for healthcare professionals and 1 for myeloma patients and patient relatives. The survey consists of 9 multiple-choice and ranking format questions. The questionnaires were developed by ME. They were pre-tested with both professional and patient communities and are available in 6 languages: DE, EN, ES, FR, IT, TR. The survey is distributed by mail or e-mail, it can be taken online through accessing the organisation's web site, and it is conducted on paper at haematological and oncological congresses and patient information days. To date, a total of 129 healthcare professionals from 42 countries and 191 myeloma patients and patient relatives from 11 countries have responded to the survey. Data gathering will continue until mid OCT 2009 and the final survey results will be presented at ASH 2009. The survey was made possible through an unrestricted grant from Celgene International.

Disclosures

No relevant conflicts of interest to declare.
The Novel Histone Deacetylase Inhibitor RAS2410 (Resminostat) Interferes with Important Signalling Pathways and Induces Apoptosis in Multiple Myeloma Cells.
Authors: Baumann Philipp , Mandl-Weber Sonja , Meinel Felix , Jankowsky Ruediger , Oduncu Fuat S. , Schmidmaier Ralf
Published: October 2019

Abstract 4928

Inhibition of histone deacetylase (HDAC) is a promising target for novel, anti-myeloma agents. In this study we investigated the biologic effects of the novel HDAC inhibitor RAS2410 (also known as “4SC-201”, “resminostat”) on Multiple Myeloma (MM) cells in vitro. RAS2410 is a potent, direct inhibitor of HDACs 1, 3 and 6 (IC50 = 43-72nM) representing the HDAC classes I and II. Accordingly, RAS2410 induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of RAS2410 abrogate cell growth and strongly induce apoptosis (IC50 = 2.5-3μM in 3 out of 4 cell lines) in MM cell lines (NCI-H929, U-266, RPMI-8226, OPM-2) as well as in primary MM cells isolated from patients. At 1μM, RAS2410 induces G0/G1 cell cycle arrest in 3 out of 4 MM cell lines associated with decreased levels of cyclin D1, cdc25a, Cdk4, pRb and p53 as well as upregulation of p21. This cell cycle arrest is reflected by an inhibition of cell proliferation. RAS2410 decreases phosphorylation of 4EBP-1 and P70S6K indicating that RAS2410 induces apoptosis by interfering with Akt pathway signalling downstream of Akt. Treatment with RAS2410 results in increased protein levels of Bim and Bax and decreased levels of Bcl-xL. Caspases 3, 8 and 9 are activated by RAS2410. Furthermore, additive and synergistic effects in terms of apoptosis induction are observed for combinations of RAS2410 with melphalan, doxorubicin and the proteasome inhibitors bortezomib and S2209. In conclusion, we have identified potent anti-myeloma activity for the novel HDACi RAS2410. This study has yielded further insight into the biological sequelae of HDAC inhibition in MM and provides the rationale for in vivo studies and clinical trials using RAS2410 to improve patient outcome in MM.

Disclosures

Jankowsky: 4SC: Employment. Schmidmaier:4SC : Research Funding.
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 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.