bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Analysis of 159 Times Acute Transfusion Reaction in Single Center.
Authors: Chen Qin-fen , Li Pei , Wang Xiao-Qin
Published: October 2019

Abstract 4196

Objective

Retrospective analysis of acute transfusion reactions occurred in our hospital in recent years.

Methods

Investigate all hospitalized patients who transfused various blood components from November 2006 to July 2009.

Results

During study period, there were 27,672 times transfusion with 80,112 units various blood components, mainly red blood cells(RBCs), frozen plasma(FP) and leukocyte-depleted platelets(PLTs). Acute transfusion reactions occured in 143 patients of 159 times transfusion, including febrile nonhemolytic transfusion reactions(FNHTR), allergic transfusion reactions(ATR), transfusion-related acute lung injury(TRALI), transfusion-associated circulatory overload(TACO) and hemorrhagic tendency. The 143 enrolled patients, 87male and 56female, were between the age of 16 and 94. The incidence rate of acute transfusion reaction was 0.57%, FNHTR and ATR accounted for 96.23%. Of all blood components, the incidence rates of acute reaction were 0.35%, 0.50% and 1.82% respectively in RBCs, FP and PLTs transfusions. In 159 times of acute transfusion reactions, the constituent ratios of 0∼3 times and more than 3 times transfusion were 23.27%, 18.87%, 7.55%, 4.40% and 45.91%, respectively.

Conclusion

Most of acute transfusion reactions were FNHTR and ATR. The highest incidence rate was in platelets transfusion, and the most constituent ratio was in patients who have received more than 3 times transfusion.

Disclosures:

No relevant conflicts of interest to declare.
Modulation of Prothrombinse Assembly and Activity by Phosphotidylethanolamine.
Authors: Majumder Rinku , Liang Xiaoe , Quinn-Allen Mary Ann , Lentz Barry R. , Kane William H.
Published: October 2019

Abstract 4207

Constituents of naturally occurring phospholipid membranes regulate the activity of the prothrombinase complex. In the present study we demonstrate that membranes containing phosphatidylcholine and phosphatidylethanolamine (PC:PE) bind factor Va with high affinity (Kd ∼10 nM) in the absence of phosphatidylserine (PS). These membranes support formation of a functional prothrombinase complex though thrombin generation at saturating factor Va concentrations is reduced approximately 60-70% compared to membranes containing 5% or more PS. The presence of PE markedly enhances the catalytic efficiency of the prothrombinase complex on membranes containing 1% PS with only modest effects on membranes containing 5% or more PS. The effect of PE on factor Va membrane binding appears to be due to direct interactions between PE and factor Va rather than to changes in membrane surface packing. Finally, we find that soluble C6PE is able to bind to factor Va (Kd ∼6.5 uM) and factor Xa (Kd ∼ 91 uM). We also show that soluble C6PE is able to stimulate formation of a partially active factor Va-factor Xa complex capable of catalyzing conversion of prothrombin to thrombin in the absence of a membrane surface. We further demonstrate that C6PE and C6PS binding sites in factor Xa are linked, as binding of one lipid enhances the binding and activity of the other. These findings provide important new insights into the role of PE in assembly of the prothrombinase complex that are relevant to understanding the activity of factor Xa on the surface of platelets particularly in the early phases of hemostasis when the concentration of PS may be limiting.

Disclosures:

No relevant conflicts of interest to declare.
Successful Treatment of Acquired Amegakaryocytic Thrombocytopenia with Rituximab: A Case Report.
Authors: Goldberg Laura R. , Glasser Lewis , Wu Tony , Shimizu Ikue , Quesenberry Peter J. , Butera James N.
Published: October 2019

Abstract 4223

Acquired amegakaryocytic thrombocytopenia is a rare disorder in which there is a marked decrease in bone marrow megakaryocytes leading to severe thrombocytopenia with preserved hematopoeisis in the remaining lineages. The clinical course is variable and no standardized treatment exists. Multiple cases in the literature report treatment using immunosuppressive agents including cyclosporine and antithymocyte globulin. In this case report, we describe the first successful use of rituximab in a patient with amegakaryocytic thrombocytopenia in the absence of any underlying autoimmune disorders. Our patient, an 86- year-old woman, presented with epistaxis, ecchymoses, and blood-tinged sputum. She had thrombocytopenia (platelets 6 × 109/L, MPV 8.3) with a normal hemoglobin and white blood cell count. Peripheral blood smear showed no obvious cause for thrombocytopenia. Bone marrow biopsy revealed focal lymphocytic infiltrates and severe megakaryocytic hypoplasia with nearly absent megakaryocytes. Cytogenetic and molecular analyses were normal, revealing no evidence of a clonal myelo- or lymphoproliferative disorder. The diagnosis of amegakaryocytic thrombocytopenia was made. She was started on prednisone 50mg per day. There was no significant improvement in her platelet count and she was then given IVIG without response. Repeat bone marrow biopsy showed persistent severe bone marrow hypoplasia with near absence of megakaryocytes. After 6 weeks of platelet transfusion dependence and steroids, she was tapered off her steroids and was given rituximab 375mg/m2 weekly for 4 doses. Three weeks after starting rituximab, her platelet counts began to recover and by day 37, her platelet counts normalized and remained within normal limits 12 months after treatment. This case demonstrates the possible utility of rituximab in treating patients with isolated acquired amegakaryocytic thrombocytopenia.

Disclosures:

No relevant conflicts of interest to declare.
Multi-Drug Resistance Phenotype in Myeloid Leukemia Cells Confers Radiation Resistance Via DNA Damage Sensor Uncoupling.
Authors: Seideman Jonathan H. , Scheinberg David A.
Published: October 2019

Abstract 4243

We have found that a stable multi-drug resistant (MDR) variant of the myeloid leukemia line, HL60, called RV+, which was selected for drug resistance in the presence of vincristine, is clonogenically cross-resistant to gamma radiation (RV+ Do= 0.81 Gy, HL60 Do = 0.49 Gy). At equal doses, these two different cell lines incurred equivalent DNA double strand breaks (DSBs) upon irradiation as measured by pulse-field electrophoresis, and showed nearly identical bulk DSB repair capacity and efficiency, suggesting that the resistence phenotype is not due to a reduction in DSBs. Interestingly, an early and proximal marker of DSBs, phosphorylation of the histone variant H2AX, is up to seven-fold lower in RV+ cells, despite equivalent bulk DNA damage. This discrepancy between physical damage and proximal signaling is accompanied by dramatically attenuated early and late G2/M checkpoint responses in RV+ cells, which require nearly 10 times the radiation dose of HL60 cells (2.0 Gy compared to 0.2 Gy) to elicit a full early G2/M check, and up to four times the dose (4.0 Gy compared to 1.0 Gy) for an equivalent late G2/M response. Consistent with decreased checkpoint stringency, up to eight time as many RV+ cells were found to be entering mitosis after radiation, with 62.7% unresolved DSBs as measured by micronuclei formation. Although HL60 had a comparable percentage of cells with unresolved breaks (72.6%), the total number of cells entering mitosis with intact nuclei was proportionally much lower. Moreover, in the same dose range, RV+ cells have a marked decrease in radiation-induced apoptosis compared to HL60, which has been shown to be an important clonogenic predictor in hematopoietic cells. As RV+ cells are 10-fold more sensitive to cytarabine-induced apoptosis, RV+ cell insensitivity is likely not due to a global anti-apoptotic phenotype. Increased clonogenic survival suggests that RV+ have partially decoupled sensing of extant DNA damage from checkpoint and apoptotic responses, possibly through downregulation of phospho-H2AX or its cognate upstream kinases. Current research seeks to determine a causal relationship between these unique radioresistance phenomena.

Disclosures:

No relevant conflicts of interest to declare.
Deguelin Induces Cell Growth Arrest and Cell Death Via the Suppression of BCR-ABL and Survivin Expression in BCR-ABL-T315I Mutant Cells.
Authors: Oyake Tatsuo , Ito Shigeki , Kowata Shugo , Murai Kazunori , Ishida Yoji
Published: October 2019

Abstract 4255

Development of kinase domain mutation is a major drug-resistance mechanism for tyrosine kinase inhibitor (TKI) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) where TKI STI571 is ineffective against the BCR-ABL mutant, E255K or T315I. Therefore, new agents that effectively kill these cells with kinase domain mutation are absolutely necessary. Deguelin is a rotenoid from African plant Mundulea sericea, which has been recently shown to suppress the lung tumorigenesis via inhibiting the activation of PI3kinase-Akt signaling. More recently, deguelin has been shown to bind to ATP-binding pocket of heat shock protein (Hsp) 90 and inhibit functions of Hsp90 client proteins. However, the effects of deguelin on BCR-ABL mutant transformed cells are poorly understood. We investigated the effects of deguelin on the cell growth and cell death of BaF/3 pre-B-cells transformed with BCR-ABL-wild type (WT), BCR-ABL-E255K and BCR-ABL-T315I (kindly provided by Dr. Kimura, Saga University, Saga, Japan), by trypan-blue exclusion and Annexin V stain. Deguelin inhibited the proliferation of these transformed cells in a time-and a dose-dependent manner (IC50=1.0mM). In addition, flow cytometric analysis revealed a higher frequency of Annexin V(+) cells in deguelin-treated cells (mean ± SD : WT 80.1±15.3%, E255K 82.3±3.5%, T315I 94.0±0.4%, P< 0.05, respectively), compared to that in untreated cells (WT 11.5±1.6%, E255K 11.9±2.0%, T315I 15.3±4.8%, respectively). These results indicate that deguelin induces the cell-growth arrest and cell death in these cells. To better understand the mechanism of these effects, we examined the intracellular signaling and the expression of apoptosis associated proteins by immunoblot analysis. We found that deguelin suppressed BCR-ABL protein expression and prevented CrkL phosphorylation in these cells. In addition, the inhibitor of apoptosis protein, survivin expression was decreased at 24 hours after deguelin treatment. These results suggested that deguelin suppresses BCR-ABL and survivin expression, and inhibits CrkL phosphorylation in BCR-ABL mutant and WT cells. Since deguelin has been shown to inhibit the function of Hsp90 client proteins, deguelin may destabilize BCR-ABL and survivin by inhibiting Hsp90 function. Taken together, deguelin appears to induce cell growth arrest and apoptosis of BCR-ABL mutant and WT transformed cells via the suppression of BCR-ABL and survivin expression. Thus, deguelin merits further investigation as a potential therapeutic agent for CML with T315I ABL mutation.

Disclosures:

No relevant conflicts of interest to declare.
Effect of the Tyrosine Kinase Inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) On Blood Glucose Levels in Diabetic and Non-Diabetic Patients.
Authors: Agostino Nicole M. , Chinchilli Vernon M , Koszyk-Szewczyk Anita , Gingrich Rebecca , Sivik Jeff , Drabick Joseph
Published: October 2019

Abstract 4265

Background

Tyrosine kinase is a key enzyme utilized in many intracellular messaging pathways. Understanding of the role of particular tyrosine kinases in various malignancies has allowed for the design of compounds, the tyrosine kinase inhibitors (TKIs), which can specifically target these enzymes and hence, interfere with downstream signaling. TKIs have proven to be very successful in the treatment of a wide variety of malignant diseases including chronic myeloid leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia, renal cell carcinoma and gastrointenstinal stromal tumors. Given the widespread nature of tyrosine kinase as a target and the promiscuous nature of the various inhibitors, it would not be surprising that these drugs would have effects beyond the expected result of targeting merely the tyrosine kinase of interest. Scattered reports have suggested that these agents appear to affect blood glucose levels.

Results

We studied the blood glucose levels retrospectively in diabetic (19) and non-diabetic (82) patients treated with dasatinib (8), imatinib (39), sorafenib (23) and sunitinib (30). All 4 drugs resulted in statistically significant decreased blood glucose levels in both diabetic and non-diabetic patients that resolved with cessation of treatment. Mean decreases blood glucose values for both non-diabetic and diabetic patients for dasatinib were – 53 mg/dl, imatinib – 9 mg/dl, sorafenib – 12 mg/dl and sunitinib -14 mg/dl. While diabetic and non-diabetic patients had the same decreases in blood glucose, on average, blood glucose values overall were 40 mg/dl lower in non-diabetic patients than in diabetic patients on dasatanib and imatinib. Non-diabetics had an overall mean blood glucose value of 24 mg/dl lower than diabetic patients on sorafenib, and 15 mg/dl lower than diabetic patients on sunitinib. Diabetic patients required some modifications of their medications including cessation of insulin or other hypoglycemic agents. One diabetic patient developed symptomatic hypoglycemia on sunitinib.

Discussion

The mechanism for the hypoglycemic effect of these drugs is unclear, but of the 4 agents tested, c-kit is a common target. C-kit has been shown to play a role in pancreatic β-cell survival in mouse models, so it is unclear why an inhibitor of the c-kit tyrosine kinase would improve blood glucose levels. It is important for clinicians to keep the potentially hypoglycemic effects of these agents in mind in their patients since symptomatic hypoglycemia can occur and modification of hypoglycemic agents may be required. These results also suggest that inhibition of a tyrosine kinase, be it c-kit or some other undefined target, may improve diabetes mellitus and deserves further study as a potentially therapeutic option.

Disclosures:

No relevant conflicts of interest to declare.
Experience in Second Line TKI Treatment in 6 Million Region of Russia (St-Petersburg and Leningrad region).
Authors: Abdulkadirov Kudrat , Lomaia Elza , Abdulkadirova Alla , Shuvaev Vasiliy , Udalieva Vera , Usacheva Elena , Machulaitene Elena , Zotova Irina , Poznyak Ekaterina , Koryagina Elena , Ilina Natalia , Shneider Tatiana , Stepanova Svetlana , Romanova Ekaterina , Salamatova Eugenia , Goryunova Elena , Lazorko Natalija , Martinkevich Irina , Zaritskey Andrey
Published: October 2019

Abstract 4288

Resistance to imatinib could be overcome by new generations of TKIs. Data about the efficacy of second line TKI treatment may help to create a system for prognosing the duration of 2nd line TKI treatment and time of switching from second line TKI treatment to hematopoietic stem cell transplantation.

The aim of the study was to evaluate the results of 2nd line TKI treatment in patients resistant or intolerant to imatinib.

Patients and methods

44 resistant and 3 intolerant to imatinib pts were included. Cytogenetics with G-banding and PCR with sequencing were performed for evaluation the response and mutations. There were 39, 7 and 1 pts in CP, AP and BP respectively, Patients were treated by three different ATP-pocket inhibitors. The follow-up on 2nd line TKIs was 0.9-48mons (Median - 15.9 mons), median follow-up from diagnosis was 73,9 mons. In prognosis analysis (CHR, cytogenetics, Sokal) intolerant patients were not included.

Results

Probability of overall survival from diagnosis by 10 years was 85%. Probability of survival from the start of TKI2 by 4 y -90%. There were no differences in survival in pts with primary and secondary resistance, in CP and AP. Patients with low and intermediate Sokal risk did better than patients with high risk (p=0.014, Fig. 1.).

8 pts had T315I mutation when studied on second line TKI therapy.

Achievement of CCyR was 50% (58% when T3151 patients were excluded), it was higher in low+intermediate in comparison with high risk pts (60% vs 30%, p=0.091), in CP than in AP (56% vs 20%,p=0.07), in patients with CHR at switching than in those without CHR (72% vs 18%, p=0.014). We failed to find any differences in CCyR achievement in pts with different best cytogenetic response on imatinib (complete, major, minor, minimal responses, absence of cytogenetic response).

MCyR depended on the type of resistance - it was higher in secondary, than in primary resistant pts (80% vs 45%,p=0.06, Fig2). Probability of MCCyR loss was 20%, all of them appear during the first year of treatment. It was higher in AP than in CP (40% vs 12%,P=0.04).

Probability of 4 years PFS was high - 75%, also without differences in primary vs secondary resistance and even in AP vs CP.

Conclusion

Second line TKI treatment is very efficacious in imatinib resistant pts. The effect depended on the type of resistance and phase of the disease, CHR at the moment of switching to 2nd line treatment.

Disclosures:

No relevant conflicts of interest to declare.
Effects of Reduced Dose of Imatinib to Korean Chrionic Myeloid Leukemia in Chronic Phase.
Authors: Lee Se Ryeon , Park Yong , Seo Hee Yun , Sung Hwa Jung , Kim Seok Jin , Choi In keun , Choi Chul Won , Kim Byung Soo
Published: October 2019

Abstract 4290

Background

Some patients of CML in chronic phase receive reduced doses of imatinib due to some adverse effects. Recently, the efficacy of reduced dose of imatinib for the patients with small BSA was reported by our group and Japanese group, recently. This study was tried to verify the hypothesis of which BSA of CML patients might be an important factor to predict the effect of reduced dose imatinib.

Method

Fifty-six patients having record of BSA from the Korea University Medical Center who were treated with imatinib were retrospectively analyzed.

Result

All of the patients started the imatinib therapy with 400mg/day dose. 20 patients (35.7%) among them were reduced dose to 300mg and 4 of them were further reduced to 200mg/day. The main reasons for dose reduction were severe neutropenia or thrombocytopenia (grade 3 or 4) (89.4%). Following the dose reduction, the rate of toxicity was reduced and treatment was resumed and the dose was gradually increased until 9 patients tolerated a maintenance dose of 400mg/day and remainder had been taken the reduced dose. The cumulative CCR at 12 months was similar in both group (P = 0.89, 70.0% in reduced dose vs 72.7% in standard dose). The mean imatinib dose/BSA was significantly lower in patients receiving the reduced dose compared with those receiving the standard dose (P < 0.001)(183.4 ± 26.9 vs 230.5 ± 21.4), although the mean BSA didn't show the difference according to reduction of dose (P = 0.079)(1.62 ± 0.20 vs 1.75 ± 0.13). After median follow-up period of 37.3 months (6.0-76.1 months), 15 patients (75.0%) have sustained CCR in patients receiving reduced dose of imatinib.

Conclusion

From this study, we could find that the reduced dose of imatinib in CML patients might assure the relatively satisfactory response with low intolerable adverse effects. But we could not verify that BSA was the main factor to predict the effect of reduced dose of imatinib. So, further studies including though level of imatinib will be needed to clarify the effect of reduced dose of imatinib.

Disclosures:

No relevant conflicts of interest to declare.
Multicenter Retrospective Analysis of Second Allogeneic HSCT Outcomes for Hematologic Malignancies in Korea.
Authors: Ha Kim Kyoung , Kim Dong Hwan Dennis , Jang Jun Ho , Kim Kihyun , Jung Chul Won , Won Jong-Ho , Moon Joon Ho , Sohn Sang Kyun , Kim Yeo-Kyeoung , Yang Deok-Hwan , Lee Je-Jung , Kim Hyeoung-Joon , Kim Jin Seok , Min Yoo Hong , Kim Dae-Young , Lee Je-Hwan , Lee Jung-Hee , Lee Kyoo-Hyung , Kim Inho , Yoon Sung-Soo , Park Seonyang , Lee Sang Min , Joo Young-Don
Published: October 2019

Abstract 4298

Background

Increasing number of autologous or allogeneic HSCT in Korea in this decade resulted in increasing requirement for second allogeneic hematopoietic stem cell transplantation (HSCT) as a result of the recurrence of primary disease or graft failure. Since Dec 2008, second HSCT has been approved by Korean government to be covered by national health insurance reimbursement system. However, there is no available data on the transplant outcomes following second allogeneic HSCT in Korea. Accordingly, the current study attempted to analyze the outcome of second allogeneic HSCT retrospectively.

Methods

Transplant data were collected retrospectively from 8 transplant centers in Korea. Inclusion criteria are as follows. 1) Age equal or over 15 years old, 2) Hematologic malignancies excluding aplastic anemia, PRCA, PNH or solid tumor, 3) Patients who underwent second alloHSCT receiving cord blood transplantation (CBT).

Results

Sixty four pts were included with following diagnoses: AML (n=28), ALL (n=5), CML (n=3), lymphoma (n=22), myeloma (n=5), and others (n=1). The median age was 37 (range 16-65). The first transplantation had been performed with autologous (59.4%) or allogeneic (40.6%) donors. The donors for second HSCT were HLA-identical sibling 32(47%), unrelated 28(49%), or haploidentical donor 2(4%). Conditioning regimen included TBI-based myeloablative 6(9%), non TBI myeloablative 19(30%), or reduced intensity regimen 38(60%). With median 16 months of follow up (range, 3 to 93 months), 40 pts died of transplant related toxicity (n=28; 70%), recurrence of primary disease (n=9; 22.5%) or other (n=3; 7.5%). After second HSCT, 56% were in complete remission, 38% in partial remission, and 6% were refractory. The 1- and 2- year overall survival rate was 42% and 29%, respectively.

Conclusion

The patients received non TBI conditioning regimens were shown longer survival.

Disclosures:

No relevant conflicts of interest to declare.
Dasatinib After Allogeneic Stem Cell Transplantation in Philadelphia-Positive Leukemias.
Authors: Scheid Christof , Chemnitz Jens , Holtick Udo , Krause Anke , Bergwelt-Baildon Michael , Hallek Michael
Published: October 2019

Abstract 4304

Dasatinib is a second generation tyrosine kinase inhibitor for the treatment of Ph+ chronic myeloid leukemia. However many patients recieving dasatinib are candidates for an allogeneic transplantation and will receive a transplant eventually. The use of dasatinib after an allogeneic transplant is very controversial: First the allogeneic antileukemic immune effect should theoretically obviate the need for further tyrosine kinase inhibition. Second the considerable hematological toxicity of dasatinib might impair the fragile donor hematopoiesis, at least given at full dosage. And third there is evidence that dasatinib inhibits both effector and regulatory T-cells which might hamper the graft-versus-leukemia effect and/or inrease the risk for Graft-versus-host disease.

We report our experience with dasatinib in 3 patients with relapsing or persisting Ph+ leukemias after allogeneic stem cell transplantation.

Pat. 1 is a 66yr old female patient with an imatinib-resistant lymphoid blast crisis who responded to dasatinib and was transplanted from an unrelated donor. After achieving a complete molecular remission she experienced a molecular relapse and was started on dasatinib 20 mg daily. 3 months later she reached a complete molecular remission without any major changes in blood counts and continued on dasatinib 20 mg.

Pat. 2 is a 42yr old male with Ph+ CML and a paraspinal extramedullary lesion who responded to dasatinib after being resistant to imatinib. After an allogeneic transplant from his HLA-compatible brother he was in complete hematologocial and major molecular remission but relapsed 3 months later. Ciclosporin A was stopped and dasatinib introduced at 70 mg once daily. 2 months later he achieved a complete hematological and molecular remission. No hematological toxicity was found.

Pat. 3 is a 41yr old female patient with a Ph+ c-ALL with a history of liver cancer and a partial liver transplantation. After achieving a complete remission with chemotherapy with imatinib she reveived an allogeneic stem cell transplantation from her brother who also had donated the liver graft. She lost her remission 9 months after transplant and was retransplanted with the same donor but without immunospuppression. Due to the lack of a complete molecular remission she started dasatinib at 50 mg/d and became bcr-abl negative 3 months later. Blood counts improved during treatment with dasatinib.

In summary all patients showed stable responses to dasatinib at low doses without any major hematological toxicity. With a follow up of 8-12 months we did not observe any GvHD during dasatinib treatment. In our hands low dose dasatinib is a feasible treatment option for relapse after allogeneic transplantation in Ph+ leukemias.

Disclosures:

No relevant conflicts of interest to declare.
The ANALYSIS of Chimerism IN ACTIVATED T Lymphocites CD25+ Improves the CAPACITY of the T Lymphocytes CD3+ Chimerism Dinamic to Predict COMPLICATIONS AFTER Allogenic STEM CELL TRANSPLANTATION.
Authors: Victor Noriega Concepcion , Jorge Gayoso , Serrano David , Gabriela Rodriguez Macias , Balsalobre Pascual , Borde Ismael Buno , Diez-Martin Jose L
Published: October 2019

Abstract 4307

Introduction

Complications after Allogenic Stem Cell Transplantation (Allo-SCT) are influenced by the immunological fenomena associated to the alloreactivity/allotolerance between donor and recepient. In this context, the usefulness of chimerism quantification in T lymphocytes for the prediction of complications after Allo-SCT is well known. However, to our knowledge, there is no information on the utility of chimerism analysis in activated lymphocytes (CD25+).

Objective

To stablish an asociation betwen the more common complications post Allo-Tph (aGVHD, cGVHD, relapse, reject), and the chimerism dynamics in CD25+ activated lymphocytes in the early period post-transplantation, trying to predict the patients with more risk of suffering from this complications.

Materials and Methods

The study included 38 Allo-SCT (17 NMA, 21 MA; 7 Haploidentical, 13 non-related donor, 18 identical donor; 7 UCB, 5 BM, 26 PB). Chimerism analysis was performed every 2 weeks until complete chimerism (CC) was achieved, and every 3 months thereafter. Follow up was censored when patients received DLI or 2nd Allo-SCT.Chimerism quantification was performed by microsatellite PCR (STR-PCR; AmpFlSTR SGM Plus; Applied Biosystems) on DNA obtained from peripheral blood and purified cell lineages (95% putity) by immunomagnetic technology (Miltenyi Biotec).

Results

Table 1 shows the results at day +30 for T and activated lymphocytes (CD3+ and CD25+) allocating patients in two groups depending on the relative percentage of recipient cells (% rec) in both cell lineages. 20 patients were in CC in CD25+, maintening this CC during the study. 18 patients were found in MC in CD25+ (18/38 MC). 1/18 was in CC in CD3+ TL, and 10/18 were in CC in whole blood. 17/18 were in MC both in CD3+ and CD25+ lymphocytes,

Although no statistical significance is achieved due to the reduced sample size, patients in the first group (% rec higher in activated that in T lymphocytes) tend to achieve CC later and to show higher risk of developing complications such as acute and chronic GVHD, relapse or rejection.

Conclusions

A higher incidence of complications post Allo-SCT (aGVHD, cGVHD, relapse, rejection) in patients with % of recipient in CD25+> % recipient in CD3 at day 30. Chimerism analysis in activated lymphocytes (CD25+) is of great utility after Allo-SCT since it allows beter prediction of complications than standard follow up of whole blood or T lymphocytes.

Disclosures:

No relevant conflicts of interest to declare.
Effect Analysis of Antithymocyte Globulin Versus Antilymphocyte Globulin for Graft Versus Host Disease Prophylaxis in 102 Cases of Allogeneic Hematopoitic Stem Cell.
Authors: Fu Chengcheng , Qu Shiqiang , Depei Wu , Sun Aining , Jin Zhengming , Qiu Huiying , Chang Weirong , Tang Xiaowen , Miao Miao , Ma Xiao , Wang Ying , Xue Shengli , Zhao Ye , Liu Yuejun , Hu Xiaohui , Wang Xiuli , Wu Xiaojin
Published: October 2019

Abstract 4325

Objective

Retrospective analysis the therapeutic and side effect of the rabbit antithymocyte (ATG) versus swine ALG within the preparative regimen of allogeneic hematopoietic transplantation (allo-HSCT) for graft versus host disease (GVHD) prophylaxis.

Methods

Totally 102 patients who had admitted to our hospital and been treated by allo-HSCT with the preparative regimen including ATG/ALG were followed up from June 2002 to June 2008. They were divided into ATG group and ALG group. The allergic reaction, effect of GVHD prophylaxis, transplantation related mortality (TRM), disease free survival (DFS) and relapse rate (RR) of these groups were retrospectively analyzed. Cumulative rate were analyzed by the Kaplan-Meier method and the factors associated with the III?‘‡W AGVHD were analyzed with the COX regression model.

Results

ALG group had more allergic reaction than ATG, but ATG group had more bacteremia and cytomegalovirus (CMV) antigenaemia. The haematopoiesis reconstitution was comparable in two groups. The III?‘‡W AGVHD, two-year TRM,DFS and RR were (40% vs 21%,p=0.028),(54% vs 29%,p=0.039),(41% vs 53%,p=0.174),(10% vs 24%,p=0.306),respectively in ATG/ALG groups. In multivariate analysis,10mg/kg ATG as a protective variable to III?‘‡W AGVHD occurrence(RR=0.53 ;95%CI, 0.38?‘0.71),The CD3+ cell counts of administration was associated with an increased risk for III?‘‡W GVHD(RR=4.43 ;95%CI, 3.87?‘4.95).

Conclusion

10mg/kg ATG significantly decreased the risks for III?‘‡W AGVHD and extensive chronic GVHD(ecGVHD); The lethal infections became the most important cause of death in the ATG group, but the increased risk for infection did not neutralize the reduction of TRM induced by the decrease of severe GVHD.

Disclosures:

No relevant conflicts of interest to declare.
Frequency of Allogeneic Stem Cell Transplant(SCT) in Patients Presenting with Newly-Diagnosed AML or AML at Time of First Salvage Therapy.
Authors: Sandhu Ravinder , Petersdorf Stephen , Sandmaier Brenda M. , O'Donnell Paul , Becker Pamela S. , Deeg H. Joachim , Appelbaum Frederick R , Estey Elihu H.
Published: October 2019

Abstract 4332

Allogeneic SCT is widely considered the therapy most likely to prolong survival in pts with AML in first CR(CR1) or relapse (REL). Questions have arisen regarding the frequency with which the procedure is undertaken in a defined population of pts presenting with newly-diagnosed AML and subsequently followed through REL and after, or in pts presenting in REL. We first analyzed 26 consecutive UW pts age < 70 who did not have CBF AML, who were not NPM1+/FLT3,- and who achieved CR1 with at least 4 months have elapsing from presentation date. These patients would typically be considered candidates for SCT in CR1 Eleven of the 26(42%, 95% CI 23-63%) received SCT at a median of 3.5 months (range 0.5-9.0) from CR date. Rates of SCT were 42% both in pts age <60(8/19) and in pts ≥ 60 (3/ 7). In contrast to a report from another institute in which 14/99 pts age ≥50 received SCT in CR1 7/16 of the current pts did so (p=0.01). Rates of SCT were 6/13 in pts at highest risk based on cytogenetics and FLT3 status and 3/11 in pts at lower (i.e. “intermediate” risk; risk status not known in 2) Three of the 15 pts who did not receive SCT had available donors, but 12 were not HLA –typed. Age distribution was similar (p=0.31) in pts who were and were not HLA-typed and in only 2 non-typed pts were financial considerations or pt refusal an issue. Rather, notes suggested that physicians felt that pts were doing well and might not need SCT. We also examined our 21 consecutive pts who were under age 70, did not receive SCT in CR1, and were given first salvage therapy (S1) for relapse, again with at least 4 months follow-up from relapse date. These 21 included patients referred to us at initial diagnosis or only at time of S1. The frequency with which they were transplanted (8/21; 38% 95%CI 18-62%) did not differ from the frequency with which SCT was done in CR1. However SCT was most commonly done as 2nd salvage therapy (4 cases), with 3 pts transplanted in CR2 or CR and only 1 given SCT as S1.10 of the 13 S1 pts never given SCT had available donors (3 related, 3 unrelated, 4 cord) with SCT not done because of high blasts and/or poor performance status. We conclude that although older and younger pts may be equally likely to receive SCT in CR1, failure to HLA type may be a major impediment to increasing rates of SCT in CR1. Although relapsed pts are transplanted as often as pts in CR1, such transplants are only rarely used as initial therapy of relapse.

Disclosures:

No relevant conflicts of interest to declare.
High Risk Factors of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) for Leukemia.
Authors: Chen Jia , Chen Feng , Depei Wu , Sun Aining , Qiu Huiying , Jin Zhengming , Tang Xiaowen , Miao Miao , Fu Chengcheng , He Guangsheng
Published: October 2019

Abstract 4345

Object

To screen the high risk factors of relapse after allo-HSCT in acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) respectively, then to compare the contribution to relapse of each risk factor and explore the mechanisms which the factors take part in. Furthermore, to discuss the subsequent surveillance and treatment strategy after transplantation.

Method

This is a retrospective study of single center experience. We conduct 262 evaluable cases of leukemia which accepted allo-HSCT between the November, 2001 and the December, 2008, with 69 cases in ALL, 90 cases in AML and 103 cases in CML. Cox proportional hazard regression model is applied in single and multiple analysis to screen the high risk factors. Donor lymphocyte infusions(DLI) were administrated in 18 patients who relapsed after transplantation, and we describe the characteristics of this approach.

Results

The risk factors which affect relapse significantly are: ALL: Cytogenetic risk classification, the cycles of initial induction chemotherapy; AML: Cytogenetic risk classification, minimal residual disease (MRD) level before transplant, reconstitution of WBC, CD4+/CD8+ lymphocyte ratio in the graft; CML: disease stage before transplant. 9 of the 18 patients who had a lower tumor load benefited from the DLI.

Conclusion

Cytogenetic risk classification is the most relevant predictor of relapse after transplantation. DLI hold great promise to overcome the barrier of relapse, especially for patients with lower disease burden.

Disclosures:

No relevant conflicts of interest to declare.
Excessive Toxicity of Once Daily Intravenous Busulfan, Melphalan, and Thiotepa Followed by Autologous Stem Cell Transplantation On Patients with Non-Hodgkin's Lymphoma.
Authors: Won Jong-Ho , Lee Sang-Cheol , Kim Seok Jin , Lee Dae Ho , Kim Won Seog , Suh Cheolwon , Park Hee-Sook
Published: October 2019

Abstract 4361

The busulfan, melphalan, and thiotepa (BuMelTT) regimen has shown high activity in the treatment of patient with breast cancer, ovarian cancer, aggressive lymphoma, and relapsed Hodgkin's disease. Given the limited toxicity observed with intravenous busulfan and the known activity of BuMelTT regimen in NHL, we developed a protocol utilizing once-daily intravenous busulfan/melphalan/thiotepa (ivB-MT) regimen as a conditioning for HDT in the patients with high risk or relapsed NHL.

Between March and December 2008, 13 patients with relapsed or primary refractory NHL but sensitive to salvage chemotherapy or chemo-sensitive high risk NHL underwent HDT with ivB-MT regimen followed by autologous SCT at the Soonchunhyang University Hospital, Asan Medical Center of Ulsan University, and Samsung Medical Center of Sungkyunkwan University, Seoul, Korea. The conditioning regimen consisted of busulfan 130mg/m2/day i.v. on day -8, -7, and -6, melphalan 50mg/m2/day i.v. on day -5 and -4, and thiotepa 250mg/m2/day i.v. on day -3 and -2. One patient did not recovered neutrophil and platelets and the disease relapsed on day 30 and another patient died on day 74 due to sepsis without recovery of platelets. The remaining patients achieved an ANC > 500/mm3 at a median of 10 days (range 9-30) and an unsupported platelet count of > 20,000/mm3 at a median 20 days (range 11-35) after infusion of peripheral blood stem cells(PBSC). Grade 3-4 regimen related toxicities (RRT) occurred in eight of 13 (61.5%) patients, mainly including mucositis, GI, and hepatic toxicity. Six patients (46%) developed hepatic VOD including one severe type and three patients documented infections (klebsiella pneumonia, streptococcal pneumonia, and sepsis due to MRSA and CMV bacteremia), one died of sepsis on post-transplant day 74. In all, one patient was not evaluable for response because of septic death. Four (80%) out of five patients with PR state before HDT achieved CR after HDT and one out of seven patients with CR state progressed during HDT, resulted 10 out of 12 patients achieved or maintained CR after HDT. During the follow up period (median 312 days, range 74-467), four patients were relapsed after CR and EFS were 60, 102, 104, and 203 days, respectively.

In the current study, grade 3 to 4 mucositis and liver toxicity occurred in 65% and VOD developed in 46%. It is assumed that such toxicities may be relevant to regimen with triple alkylating drugs. Despite of comparable efficacy, ivB-MT regimen was too toxic to apply to the patients with NHL undergoing HDT and autologous SCT.

Disclosures:

No relevant conflicts of interest to declare.
The Normal IGHV1-69-derived B Cell Repertoire Contains “Stereotypic” Patterns Characteristic of Unmutated CLL.
Authors: Forconi Francesco , Potter Kathleen N , Wheatley Isla , Darzentas Nikos , Sozzi Elisa , Lauria Francesco , Stamatopoulos Kostas , Mockridge Christopher Ian , Packham Graham , Stevenson Freda K
Published: October 2019

Abstract 4370

The cell of origin of chronic lymphocytic leukemia (CLL) has long been sought and immunoglobulin gene analysis provides new clues. The immunoglobulin heavy variable gene (IGHV) status has clinical relevance in CLL, where two subsets, delineated by the absence or presence of somatic mutation, have markedly different prognoses. The unmutated subset (U-CLL), of inferior prognosis, appears to derive from a pre-germinal center B cell. In U-CLL, there is strikingly increased usage of the 51p1-related alleles of the IGHV1-69 gene, often combined with selected IGHD genes and with IGHJ6. Shared sequence “stereotypic” characteristics of the HCDR3 result, and suggest antigen selection of the leukemic clones. In this study, we have analyzed 147 51p1/IGHJ6 rearrangements from 3 healthy individuals (>51yr) and sought sequence patterns parallel to those of U-CLL. A pre-established dataset of 313 51p1/IGHJ6 rearrangements from patients with U-CLL was used as a reference. A high proportion (49/147, 33.3%) of normal sequences revealed stereotypic patterns, several (22/147, 15%) being similar to those described in U-CLL. Additional CLL-associated stereotypes, not yet reported, were detected in 7/147 sequences (4.8%). Stereotypes (13.6%) not detected in CLL were also found in 20/147 (13.6%) 51p1/IGHJ6 combinations. The HCDR2-IGHJ6 sequences were almost exclusively unmutated (143/147, 97,3% sequences had ≥98% homology to germline). Junctional amino acids in normal B cells were heterogeneous, as in the cases of CLL with stereotyped 51p1/IGHJ6 B-cell receptors. Normal B cells expressing 51p1-derived IgM (4.8% of all B-cells) had a phenotype of naïve B-cells, similar to 51p1-negative (CD27-) B cells, i.e. IgM+ IgD+ CD23+ CD38+, with a small percentage of CD5+ B cells, not found in the memory B-cell subset. This snapshot of the naïve B-cell repertoire reveals subsets of B cells closely related to those characteristic of CLL. Conserved patterns in the 51p1-encoded IgM of normal B cells suggest a restricted sequence repertoire shaped by evolution to recognize common pathogens. Proliferative pressure on these cells is the likely route to U-CLL.

Disclosures:

No relevant conflicts of interest to declare.
DETECTION of CHROMOSOMAL 14q32 ABNORMALITIES IN B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA.
Authors: Mura Mariangela , Trojani Alessandra , Soriani Silvia , Tedeschi Alessandra , Lodola Milena , Colombo Chiara , Ricci Francesca , Morra Enrica , Montillo Marco
Published: October 2019

Abstract 4385

Introduction

Conventional cytogenetic and FISH studies with the standard panel (13q14, 11q22.3, 17p13, 12, 6q23) are used to detect chromosomal abnormalities of clinical significance in patients with chronic lymphocytic leukemia (B-CLL). Recently, translocations and 5'IGH deletions involving chromosome14q32 are associated with B-CLL.

Aim

Our aim was to investigate the presence and the characteristics of chromosome 14q32 aberrations in a group of patients with B-CLL.

Patients and Methods

A total of 58 patients with B-CLL were investigated by conventional cytogenetic, in addition the cultures were stimulated with CpG oligodeoxynucleotide plus IL2. FISH studies with 14q32/IGH break-apart probe designed to detect chromosomal breakage of the IGH (14q32) locus, were done for 59 patients.

Results

Chromosomal abnormalities were detected in 60.3% of cases by cytogenetic. 14 patients showed complex cariotype while trisomy 12 was the most frequent anomaly found in 8 patients. Among the twelve other patients several chromosomal aberrations were noted: del(13)(q14), del(13)(q12q21),

del(13)(q12q14), del(13)(q13q32), +21, t(11;13)(q23;q14), +12 t(1;4)(q31;p14), t(3;14)(p21;q22), del (11)(q12) +21, del(6)(q21), inv3(?p13q21), del(11)(q12). Abnormalities of chromosome 14 were found in 23.8% of patients. Deletion of 5'IGH, corresponding to the variable IGH segment, was the most frequent anomaly found in 8 patients. Interesting, a 3'IGH deletion was detected in two patients, while only one patient showed a complete deletion of chromosome 14 (47,XXY,add14q32). Three patients showed 14q32 translocations involving the IGH locus.

Conclusions

Based on our findings, deletions of the variable region of the IGH gene (IGHv) and 14q32/IGH translocations are involved in B-CLL. As these preliminary data are based on small sample size, our goal will be to study the cytogenetic profile of a large number of CLL patients. Future studies will permit the identification of 14q32 translocations and the type and the frequency of IGH rearrangements. Finally, chromosome 14 abnormalities will be correlated to other cytogenetic and FISH abnormalities, and associations with known prognostic markers, such as IGVH mutation status and ZAP-70 expression, will be investigated.

Disclosures:

No relevant conflicts of interest to declare.
Palonosetron Uniquely Inhibits Substance P-Mediated Neuronal Responses in Rat Nodose Ganglia.
Authors: Li Ying , Wu Xiaoyin , Rojas Camilo , Cantoreggi Sergio , Sebastiani Silvia , Slusher Barbara
Published: October 2019

Abstract 4826

Introduction

Clinical studies have shown that palonosetron is more effective than first generation 5-HT3 receptor antagonists (5HT3RAs) for preventing chemotherapy induced nausea and vomiting (CINV). In addition, NK-1 receptor antagonists have been shown to augment the the antiemetic activity of the 5HT3RAs and dexamethasone to inhibit CINV. While palonosetron is effective in preventing delayed CINV, it does not directly bind to the NK-1 receptor. Recent data, however, has revealed significant receptor “cross-talk” between the NK-1 and 5HT3 signaling pathways. Alteration of 5HT3 receptor activity has been shown to cause downstream effects on NK-1 signaling, and vice versa. We postulated that if palonosetron differentially inhibited the NK-1/5HT3 crosstalk, this could help explain the differences observed in the clinic.

Methods

We carried out in vivo electrophysiology experiments in rats where single neuronal recordings of nodose ganglia expressing both NK-1 and 5HT3 receptors were collected.

Results

First, we showed that neuronal responses to substance P (SP), a known non-selective agonist of the NK-1 receptor, were significantly enhanced in the presence of cisplatin. Second, we found that palonosetron, but not ondansetron or granisetron (1st generation 5HT3RAs), could dose-dependently inhibit the cisplatin-induced SP enhancement. This inhibition was observed when palonosetron was administered 30 minutes before or 5 or 10 h after cisplatin administration.

Conclusion

The results are consistent with previous mechanism of action (MOA) experiments indicating that palonosetron uniquely exhibits allosteric binding, positive cooperativity and receptor internalization at the 5HT3 receptor. Taken together, the MOA studies may help explain the unique results observed with palonosetron in the clinic.

Disclosures

Li: Eisai, Inc: Research Funding. Wu:Eisai: Research Funding. Rojas:Eisai, Inc: Employment. Cantoreggi:Helsinn Healthcare: Employment. Sebastiani:Helsinn Healthcare: Employment. Slusher:Eisai, Inc: Employment.
Differential Protein Expression of Serum in Patients with RAEB Myelodysplastic Syndromes.
Authors: Zhong Liye , Liu Tianhao , Li Yangqiu , Geng Suxia , Lu Zesheng , Weng Jianyu , Wu Suijing , Du Xin
Published: October 2019

Abstract 4845

To screen molecular markers for refractory anemia with excess blasts in transformation (RAEB) in myelodysplastic syndromes (MDS) by serum proteome profiling.

Methods

Serum protein were isolated respectively from patients with RAEB, acute myeloid leukemia or normal person by 2-dimensional electrophoresis(2-DE). The imaging films were obtained and the differential reacting protein spots were recognized. Then the differential reacting proteins were obtained in the replica gel by matching analysis,and identified by peptide mass fingerprint based on matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF-MS) and database searching.

Results

Seven differentially expressed proteins in RAEB were found by 2-DE. Of the 7 proteins, 4 were identified with significantly statistical difference, including dipeptidyl peptidase (DPP/CD26), polymerase (DNA directed) kappa, PRO2044 and albumin-like.

Conclusion

2-DE-based serum proteome profile can help to identify serum proteomic biomarkers related to MDS. DDP/CD26 has increased serum levels in RAEB subtype MDS, suggesting significant action in advanced MDS.

Disclosures

No relevant conflicts of interest to declare.