Possible Role of Engraftment Syndrome in Myelodysplastic Syndrome after Autologous Transplants.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2156-2156
Author(s):  
Yi Kong Keung ◽  
Michael W Beaty ◽  
Mark Pettenati ◽  
Denise Levitan ◽  
Istvan Molnar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cells ◽  
Bone Marrow ◽  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Autologous Transplantation ◽  
Older Age ◽  
Prior Chemotherapy ◽  
Engraftment Syndrome ◽  
Conditioning Regimens

Abstract BACKGROUND: Autologous graft versus host disease (GVHD) and engraftment syndrome (ES) probably result from host immune dysfunction during the recovery from high dose chemotherapy and radiation. Since impaired immunity has been associated with myelodysplastic syndrome, we explore the risk factors of post-transplant myelodysplastic syndrome/acute myeloid leukemia (MDS), specifically, in relation to the GVHD and ES. PATIENTS AND METHODS: Consecutive patients with lymphoma undergoing autologous transplantation in our institution from 1991 to 2006. RESULTS: There is total of 452 lymphoma patients undergoing autologous transplants in this period; 274 males and 178 females, median age of 50 years (range 16–76). There are 85 patients with Hodgkin’s lymphoma (HL) and 367 non-Hodgkin’s lymphoma (NHL), of which, 291 are B-cell, 47 T-cell and 29 unknown. Total of 277 received TBI-based and 175 chemotherapy-alone conditioning regimens; 98 patients received transplantation of the bone marrow (BM), 343 peripheral blood stem cells (PBSC) and 11 both. Eleven patients had second autologous transplantation for progressive lymphoma and another four patients have second allogeneic transplant for MDS. Thirty-two patients (7%) died of regimen-related toxicity within 100 days of transplant. Eleven patients developed severe engraftment syndrome (high fever, skin rash ± pulmonary infiltrate requiring systemic steroid); 27 patients had skin and 2 patients had gastrointestinal biopsies consistent with GVHD. The median follow-up of the patients was 6.2 years and median overall survival 5.3 years. Univariate analysis using Kaplan-Meier plots and logrank tests, younger age, HL, B-phenotype, source of stem cells (BM vs PBSC), chemo-sensitivity, less prior chemotherapy are better prognostic indicators. Conditioning regimens (TBI-based vs non-TBI) do not affect the overall survival. Twenty-four patients (5.3%) developed MDS with median time of onset of 4.2 years (range 8 months-7.5 years). Additional 5 patients developed clonal karyotypic abnormalities in the bone marrow without clinical MDS. Actuarial probabilities of developing MDS 5 and 8 years after transplant are 5% and 15% respectively. The incidences of MDS are similar in HL and NHL. Significant risk factors of developing MDS include older age, advanced stage, onset of ES or GVHD, and longer intervals between the initial diagnoses to transplant. CONCLUSION: Although overall incidence of MDS is only 5.3%, the actuarial risk at 8 years is up to 15% and may be higher in selected patients such as older age, and prolonged interval from initial diagnosis to transplant (a surrogate for prior chemotherapy). The association of engraftment syndrome and GVHD to MDS is intriguing. It is conceivable that perturbation to the host immunity caused by either prior chemotherapy, conditioning regimens in the elderly may play a role in the development of MDS after autologous transplant.

scholarly journals Influence of height on endothelial maintenance activity: a narrative review

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Yuji Shimizu ◽  
Takahiro Maeda
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Inverse Association ◽  
Hematopoietic Stem ◽  
Genetic Characteristics ◽  
Maintenance Activity ◽  
Marrow Activity

AbstractRecent studies have revealed an inverse association between height and cardiovascular disease. However, the background mechanism of this association has not yet been clarified. Height has also been reported to be positively associated with cancer. Therefore, well-known cardiovascular risk factors, such as increased oxidative stress and chronic inflammation, are not the best explanations for this inverse association because these risk factors are also related to cancer. However, impaired blood flow is the main pathological problem in cardiovascular disease, while glowing feeding vessels (angiogenesis) are the main characteristic of cancer pathologies. Therefore, endothelial maintenance activity, especially for the productivity of hematopoietic stem cells such as CD34-positive cells, could be associated with the height of an individual because this cell contributes not only to the progression of atherosclerosis but also to the development of angiogenesis. In addition, recent studies have also revealed a close connection between bone marrow activity and endothelial maintenance; bone marrow-derived hematopoietic stem cells contribute towards endothelial maintenance. Since the absolute volume of bone marrow is positively associated with height, height could influence endothelial maintenance activity. Based on these hypotheses, we performed several studies. The aim of this review is not only to discuss the association between height and bone marrow activity, but also to describe the potential mechanism underlying endothelial maintenance. In addition, this review also aims to explain some of the reasons that implicate hypertension as a major risk factor for stroke among the Japanese population. The review also aims to clarify the anthropological reasons behind the high risk of atherosclerosis progression in Japanese individuals with acquired genetic characteristics.

scholarly journals Korszakváltás a gyermekkori szerzett csontvelő-elégtelenséggel járó kórképek kezelésében Magyarországon

2018 ◽  
Vol 159 (42) ◽  
pp. 1710-1719
Author(s):  
Krisztián Kállay ◽  
Judit Csomor ◽  
Emma Ádám ◽  
Csaba Bödör ◽  
Csaba Kassa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Survival Rate ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Juvenile Myelomonocytic Leukemia ◽  
Reduced Intensity Conditioning ◽  
Myelomonocytic Leukemia ◽  
Reduced Intensity

Abstract: Introduction: Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes. Aim: To analyse and compare the results of treatment before and after our joining. Method: A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia. Results: In the whole patient cohort, the time from diagnosis to treatment was median 92 (3–393) days, while in severe aplastic anemia median 28 (3–327) days only. Grade II–IV acute graft versus host disease occurred in 22.6%, grade III–IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1–62.5) months. There was a remarkable increase in overall survival comparing the data before (1992–2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome. Conclusion: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710–1719.

scholarly journals Prognostic Significance of Reduced BCAS4 expression in Bone Marrow Cells of Patients with Myelodysplastic Syndromes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4258-4258
Author(s):  
Masayuki Shiseki ◽  
Mayuko Ishii ◽  
Mari Ohwashi ◽  
Kentaro Yoshinaga ◽  
Naoki Mori ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Risk Groups ◽  
Older Age ◽  
Expression Level ◽  
Expression Of Genes ◽  
Kaplan Meier ◽  
Lysosome Related Organelles

Deletion of long arm of chromosome 20 (del(20q)) is commonly observed in myelodysplastic syndromes (MDS). Reduced expression of genes located within the common deleted region (CDR) of del(20q) due to haploinsufficiency may play a role in molecular pathogenesis of MDS. In the previous study, we examined expression of genes located within the CDR which we determined using array-CGH, in bone marrow mononuclear cells in MDS patients with or without del(20q), indicating that BCAS4 expression was significantly reduced in bone marrow cells in MDS patients with or without del(20q). The BCAS4 gene, which was identified as a fusion transcript expressed in MCF7 cells, encodes 23kD protein. Although function of BCAS4 protein remains unclear, it could be a member of "cappuccino" family, which belong to lysosome-related organelles. Abnormality of genes encoding lysosome-related organelles cause variety of congenital disorders, including the Hermansky-Pudlak syndromes, which is characterized by oculocutaneous albinism and bleeding tendency due to platelet dysfunction as a result of lysosome abnormalities. In the present study we investigated clinical implication of BCAS4 expression level in MDS patients. Mononuclear cells separated from bone marrow samples taken at the time of MDS diagnosis were used for analysis. Written informed consent was obtained from patients before study. To analyze BCAS4 expression, quantitative RT-PCR was performed using cDNA from mononuclear cells as template by the TaqMan probe method (Applied Biosystems) with co-amplification of the endogenous control gene, human GAPDH (Applied Biosystems). Samples from 103 MDS patients, 64 males and 39 females with median age of 67 years (range: 20-91 years), with (n=14) or without (n=89) del(20q), were examined in the present study. Patients were classified as RCUD (n=12), RCMD (n=55), RARS (n=9), RAEB-1 (n=10), and RAEB-2 (n=13), according to WHO 2008 classification, and in RAEB-T (n=4) according to FAB classification. They also were categorized in four IPSS risk groups, low risk (n=30), intermediate-1 risk (n=46), intermediate-2 risk (n=18), and high risk (n=9). There was no significant difference in relative BCAS4 expression level between patients with del(20q) and those without del(20q), and among WHO subtypes. Higher IPSS risk groups (INT-2 and High) showed trend in association with reduced BCAS4 expression compared with lower IPSS risk groups (Low and INT-1) (P=0.104). We analyzed impact of BCAS4 expression on overall survival (OS). Based on BCAS4 expression level, 103 patients were divided into four groups, highest (Q1), intermediate (Q2, Q3), and lowest (Q4) quartiles. The Kaplan-Meier analysis demonstrated that Q4 showed significantly worse OS compared with remaining quartiles (Q1-Q3) (log-rank test, P=0.0031). The estimated 2-year OS rates in Q1-3 group and Q4 group were 75.1% and 48.9%, respectively. According to the COX proportional hazards model, univariate analysis showed lower BCAS4 expression (Q4 vs Q1-Q3) was associated with worse OS (hazard ratio 3.43, 95%CI 1.89-6.11, P=0.0001) as well as older age (65 years or older vs less than 65 years), and higher IPSS risk groups (INT-2 and High vs Low and INT-1). Multivariate analysis indicated that lower BCAS4 expression showed trend for association with worse OS (hazard ratio 1.90, 95%CI 0.96-3.64, P=0.0651) by analyzing with two variables (older age and higher IPSS groups). Next, we investigated whether OS is predicted by combination of three variables, BCAS4 expression level, IPSS risk groups, and age at diagnosis. We defined lower BCAS4 expression (Q4), higher IPSS (INT-2 and High), and older age (65 years or older), as risk factors. The Kaplan-Meier analysis showed that survival curves were well separated according to number of risk factors (0, 1, and 2 or more) (P<0.0001). The estimated 1-year, 2-year, and 5-year survival rates were 100%, 100%, and 86.5% in patients without risk factor, 75%, 70.2%, and 51.7% in patients with one risk factor, and 54%, 34.3%, and 11.4% in patients with two or more risk factors. The present study demonstrated that reduced BCAS4 expression is associated with inferior clinical outcome, indicating that BCAS4 expression level could be a useful prognostic marker in MDS, especially by combination with IPSS risk and patients age at diagnosis. Disclosures Tanaka: Bristol-Myers Squibb: Research Funding.

Autologous Stem Cell Transplantation (ABMT) for Recurrent Hodgkin’s Disease from 1990–2005: Factors Contributing to Post-Transplant Relapse.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2083-2083
Author(s):  
Brian Bolwell ◽  
Brad Pohlman ◽  
Matt Kalaycio ◽  
Steve Andresen ◽  
Elizabeth Kuczkowski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Prior Chemotherapy ◽  
Post Transplant ◽  
Peripheral Stem Cells

Abstract Long-term results of conventional therapy of Hodgkin’s disease (HD) has demonstrated the importance of long-term and ongoing follow-up given the potential for later complications after curative therapy. While many transplant series report follow-up of several years after ABMT, few report a 15-year experience from a single institution. This report examines the outcomes of 220 patients receiving high-dose chemotherapy and autologous stem cell transplant (ABMT) at The Cleveland Clinic Foundation from January 1990 through June 2005. Median age was 33 years (range, 14–70 years); median time from diagnosis to transplant was 19 months; 47% received prior radiation therapy; 82% had nodular sclerosis histologic subtype; number of courses of prior chemotherapy were: 1 (16%), 2 (66%), 3 (14%), 4 or more (4%). All patients received salvage therapy prior to transplant: 29% were in a complete remission (CR), 55% in a partial remission (PR), and 16% refractory. All patients received a chemotherapy-only preparative regimen, most commonly Bu/Cy/VP (73%), followed by CBV (17%). 78% received peripheral stem cells alone; 22% received either autologous bone marrow or a combination of bone marrow plus peripheral stem cells. At the present time 60% of patients are alive. Of the 88 patients who died, the most common cause of death is relapse (69% of deaths). Secondary malignancy occurred in 11 patients (5%); 9 of these cases were secondary AML/MDS and 5 of these patients with secondary malignancies have died. 44% of the entire cohort has relapsed, at a median of 9 months post-transplant (range, 1.4–76 months). 10-year overall survival is 47%. A multivariable analysis showed that the two significant variables that correlated with post-BMT relapse were the number of prior chemotherapies (p = 0.011), and patients treated in remission vs. those not in remission (p = 0.002). Of patients receiving 2 or more prior courses of chemotherapy, 60% have relapsed 8 years post-transplant, compared to 40% of those receiving one course of prior chemotherapy. The risk of relapse by the number of prior chemotherapy courses is shown graphically below: Figure Figure In conclusion, this very large series of ABMT for recurrent HD with long-term follow-up demonstrates the importance of timely autografting in relapsed HD patients. The optimal time to proceed with ABMT is after failing one, and only one, course of chemotherapy. Delaying transplant for unrealistic long-term salvage with other courses of traditional chemotherapy will negatively affect the outcome of subsequent ABMT.

Lovastatin as Salvage Immunomodulatory Therapy in Patients with Refractory and Relapsed Multipla Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1567-1567 ◽  
Author(s):  
Marek Hus ◽  
Norbert Grzasko ◽  
Dariusz Jawniak ◽  
Marta Szostek ◽  
Anna Dmoszynska
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Light Chain ◽  
Protein Level ◽  
Mevalonate Pathway ◽  
Sinus Bradycardia ◽  
Autologous Transplantation ◽  
M Protein ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Abstract In the recent years the treatment of patients with multiple myeloma (MM) has changed because of the introduction of new agents, mainly thalidomide (THAL) and its derivatives and bortezomib, an inhibitor of the 20S proteasome. Lovastatin (LOV) and other inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, have been demonstrated to exibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines including our own experiments. This observation induced us to administer LOV in combination with THAL and dexamethasone (DEX). We report here our preliminary experiences with THAL and LOV therapy in patients with refractory and relapsed MM. We have treated 81 patients with THAL+DEX regimen (TD) or THAL+DEX+LOV regimen (TLD). Patients received drugs orally in 28 day cycles. THAL was given from day 1 to day 28 each cycle and it was started at a initial dose of 100 mg daily increased to 300 mg daily. DEX was administered at a dose of 40 mg daily in days 1–4 each cycle. LOV was administered at a dose of 2 mg/kg in days 1–5 and 8–12 and at a dose of 0.5 mg/kg in days 15–28 each cycle. TLD regimen was administered to 43 patients and TD regimen to 38 patients. Patients characteristics before treatment were as follows: the median age 61.2 years; 61% of patients IgG, 26% IgA, 7% light chain and 6% other; 76% of patients were light chain kappa and 24% lambda; median serum M-protein level was 4.2 g/dl, bone marrow plasma cells 47%, hemoglobin 10.1 g/dl, platelets 197 G/l, beta-2-microglobulin 4.2 mg/ml, albumin 3.9 g/dl and LDH 292 IU. The median follow-up was 29 month. A clinical response, defined as a reduction of M-protein level by 50% or more, was observed in 67.8% of patients in TD group and in 88.0% in TLD group. CR i NCR was observed in 35.0% and 62.7% respectively. In 11 TLD (25.5%.) and 4 TD (10.5%) patients successful stem cell harvest was performed and mean amount of collected CD34+ cells was 8.2*106/kg. Successful autologous transplantation was performed in 8 patients from this group. Overall survival in TLD group (median 23.0 months) was significantly longer than in TD group (median 18.0 months). Similarly event free survival was longer in TLD (median 7.0 months) group than in TD group (4.5 months). We observed significant negative correlation between response and bone marrow infiltration (p=0.008), M-protein level (p=0.0004) and positive correlation between response and albumin level (p=0.005). Short time to reduction of M-protein by 50% was connected with better response. Common side effects as somnolence, fatigue and constipation were observed in about 45% of patients in TLD and TD groups. In 2 TLD and in 3 TD patients we diagnosed deep vein thrombosis. In 2 TLD patients sinus bradycardia was observed. Our results suggest that addition of LOV to THAL and DEX improves response rate in patients with refactory and relapsed MM. Moreover it is possible to harvest stem cells and perform autologous stem cells graft in patients treated with such regimen. A future prospective randomised study is needed to confirm the value of LOV or other HMG-CoA reductase inhibitors in the treatment of MM patients.

Changes in the Hierarchy of Risk Factors with Older Age in De-Novo Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1977-1977
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Hubert L. Serve ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Complete Remission ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Age Group ◽  
Risk Profiles ◽  
Age Related ◽  
De Novo Aml

Abstract After recent reports addressed prognostic factors and outcome in older age AML (Burnett et al. Blood106:162a,2005; Wheatley et al. Blood106:199a,2005; Appelbaum et al. Blood107:3481–5,2006; Farag et al. Blood108:63–73,2006) we evaluated 764 patients of 60–85 (median 66) years reduced to those with de-novo AML, known karyotype, and identical consolidation-maintenance chemotherapy, who were part of the 1992 and 1999 multicenter randomized trials by the German AMLCG (Buchner et al. J Clin Oncol21:4496–504,2003;24:2480–9,2006). 521 patients were 60 -< 70 (median 64) and 243 patients were 70–85 (median 73) years of age. 64% and 50% patients respectively went into complete remission, 24% and 29% remained with persistent AML, 12% and 21% succumbed to early and hypoplastic death (p<.001). The overall survival in the younger (60- < 70y) and older (70+) patients was at a median of 13 vs 6 months and 18% vs 8% survived at 5 years (p<.001). Once in complete remission, the remission duration was 14 vs 12 months (median) and equally 18% at 5 years; the relapse-free survival is 13 vs 11 months (median) and 14% vs 13% at 5 years. While all patients were randomized up-front for 2 versions of induction either by TAD-HAM (HAM, high-dose araC 1g/m2x6 and mitox 10mg/m2x3) or by HAM-HAM, response and survival did not differ between the two arms in neither age group. In contrast to response and survival between the younger (60-<70y) and older (70+y) age group corresponding differences in the risk profiles were missing. Thus, favorable/intermediate/unfavorable karyotypes accounted for 8% vs 4% / 67% vs 73% / and 25% vs 24% of patients (p=.073); WBC > 20.000/ccm was found in 40% vs 39% (p=.52); LDH > 700U/L was remarkably 26% vs 18% (p=.014), and the day 16 b.m. blasts ≥ 10% accounted for 41% and 41% of patients. Conclusion: Approximately 50% of patients 70 years of age or older benefit from standard or intensive chemotherapy by complete remission which continues after 1 year in about 50% of responders. The inferior overall survival in the patients of 70+ versus those of 60- < 70 years is mainly explained by more frequent early and hypoplastic death (21% vs 12%) (p=.0016) and death with persistent AML (26% vs 18%) (p=.0145); while death in remission (7% vs 6%), relapse rate (50% vs 53%) and death after relapse (21% vs 26%) did not show this trend. In contrast to the important differences in outcome, established risk factors such as cytogenetic groups, WBC, and early blast clearance show concordance between the two age groups. The even lower LDH may support assumptions of older age AML as a less proliferative disease (Appelbaum et al. Blood 107:3481–5,2006). Thus, the hierarchical risk profiles cannot predict the age related outcome beyond 60 years in patients with de-novo AML.

Antibody-Based Depletion of Hematopoietic Stem Cells Empties Niches for Efficient Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. LB2-LB2
Author(s):  
Agnieszka Czechowicz ◽  
Daniel L. Kraft ◽  
Deepta Bhattacharya ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Exact Function ◽  
Potential Applications ◽  
Conditioning Regimens

Abstract Hematopoietic stem cells (HSCs) are used therapeutically in bone marrow/hematopoietic stem cell transplantation (BMT/HSCT) to correct hematolymphoid abnormalities. Upon intravenous transplantation, HSCs can home to specialized bone marrow niches, self-renew and differentiate and thus generate a new, complete hematolymphoid system. Unfortunately BMT has had limited applications, due to the risks associated with the toxic conditioning regimens, such as irradiation and chemotherapy, that are deemed necessary for HSC engraftment. Elimination of these toxic conditioning regimens could expand the potential applications of BMT to include many non-malignant hematologic disorders, a wide variety of autoimmune disorders such as diabetes and multiple sclerosis, as well as in the facilitation of organ transplantation. The exact function of these traditional myeloablative conditioning regimens is not clear. To elucidate the barriers of HSC engraftment, we transplanted 50–1000 purified HSCs (Ckit+Lin−Sca1+CD34+CD150−) into immunodeficient, Rag2−/− or Rag2−/−gc−/− recipient mice and show that HSC engraftment levels rarely exceed 0.5% following transplantation without toxic conditioning, indicating that the immune system is not the only barrier to engraftment. Additionally, we did not observe a significant increase in HSC engraftment when HSC doses of >250 cells were transplanted. Even when up to 18000 HSC were transplanted, we did not see a linear increase in HSC engraftment, indicating that the increased doses of HSCs transplant inefficiently. We believe this is due to the naturally low frequency of available HSC niches, which we postulate may result from the physiologic migration of HSCs into circulation. Conversely, separation of the graft into small fractions and the subsequent time-delayed transplantation of these doses did result in increased engraftment due to the natural physiologic creation of new available HSC niches. When 1800 HSC were transplanted daily for seven days, the engraftment was 6.1-fold higher than transplantation of 12800 HSC in a single bolus. Here, we provide evidence that, aside from immune barriers, donor HSC engraftment is restricted by occupancy of appropriate niches by host HSCs. Through elimination of host HSCs we are able to increase available HSC niches for engraftment. We have developed a novel system where HSCs can be eliminated by targeting C-kit, a cell surface antigen that is highly expressed on the surface of HSCs. Cultivation of HSCs with ACK2, a depleting antibody specific for c-kit, prevented stem-cell factor (SCF) dependent HSC proliferation in vitro and resulted in cell death. Administration of ACK2 to mice led to the rapid and transient removal of >98% of endogenous HSCs in vivo thus resulting in equal numbers of available niches for engraftment. Following ACK2 clearance from serum, transplantation of these animals with donor HSCs led to chimerism levels of up to 90%, representing a 180-fold increase as compared to unconditioned animals. This non-myeloablative conditioning regimen had few side effects, other than temporary loss of coat color. The HSCs in even untransplanted animals rapidly recovered and animals remained healthy and fertile. This work redefines the way we approach BMT/HSCT, and places great emphasis on the necessity to create available HSC niches prior to transplantation. Extrapolation of these methods to humans may enable efficient yet mild conditioning regimens for transplantation, thus expanding the potential applications of BMT/HSCT.

Identification and Characterization of Recurrent Venous Thrombosis In Cancer Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3328-3328
Author(s):  
Catherine Weber ◽  
Nelly G. Adel ◽  
Elyn Riedel ◽  
Gerald A. Soff
Keyword(s):  
Risk Factors ◽  
Lung Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Cancer Diagnosis ◽  
Hazard Ratio ◽  
Older Age ◽  
Recurrent Thrombosis ◽  
Recurrent Vte ◽  
The Impact

Abstract Abstract 3328 Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Standard of care for treatment is Low Molecular Weight Heparin, but recurrence of VTE remains a concern. We performed a retrospective analysis of our institutional experience, to characterize the patients who had a recurrence of VTE while on therapeutic doses of Dalteparin. Objectives: 1. To determine the VTE recurrence rate for cancer patients on therapeutic Dalteparin. 2. To elucidate potential risk factors for recurrence. 3. To determine the impact of recurrent VTE on overall survival. Methods: Patients beginning treatment for VTE with dalteparin between 1/1/2008 and 12/10/ 2009 were retrospectively identified through the hospital's electronic medical records system and cases of recurrent VTE were characterized. Overall survival was estimated using the Kaplan-Meier method and the influence of VTE recurrence on overall survival was analyzed as a time-dependent covariate using a Cox proportional hazards model. Results: 1,392 patients, treated for VTE with dalteparin were included in this study. 34 recurrent VTE episodes were identified. The overall incidence of recurrent thrombosis by six months was 2.3% (95% CI: 1.7%-3.3%). Older age was significantly associated with recurrence (p=0.04). Lung cancer patients had a significantly elevated risk of recurrence (5.6%, p=0.03). No other cancer types were associated with a significant trend to increased recurrent VTE rates. The incidence of recurrent VTE was higher among females compared to males (3.0% vs. 1.6%), although this trend was not statistically significant (P = 0.08). After adjusting for gender, sex and cancer diagnosis, developing a recurrent VTE was associated with a 3.0-fold hazard ratio of death (<0.0001). Conclusions: The rate of recurrent VTE in cancer patients at MSKCC is low in comparison with previously published reports. However, we identified both older age and lung cancer diagnosis as statistically significant risk factors for recurrent VTE. Females also experienced a higher rate of recurrent thrombosis when compared to males, although this result was not statistically significant. The hazard ratio for death was three times that for a patient with recurrent thrombosis when compared to one without subsequent VTE, suggesting recurrence of VTE remains an important influence on cancer-associated mortality. Disclosures: No relevant conflicts of interest to declare.

Long-Term Outcome After Matched Allogeneic Hematopoietic Stem Cell Transplantation for Fanconi Anemia On Behalf of the FA Committee of the Severe Aplastic Anemia Working Party (SAA WP) and the Pediatric Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 325-325
Author(s):  
Régis Peffault de Latour ◽  
Raphael Porcher ◽  
Jean-Hugues Dalle ◽  
Mahmoud Aljurf ◽  
Elisabeth T Korthof ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cells ◽  
Bone Marrow ◽  
Clonal Evolution ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Working Party ◽  
Secondary Malignancies ◽  
Hematopoietic Stem

Abstract Abstract 325 Background: Fanconi anemia (FA) is a rare, genetically and phenotypically heterogeneous inherited disorder. The natural history of FA is characterized by progressive bone marrow failure (BMF) and an increased risk for development of malignancies. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is considered the treatment of choice for FA patients with BMF or clonal evolution (acute myeloid leukemia or MDS). Most deaths related to HSCT occur within the first year after HSCT. Risk factors for the development of malignancies after HSCT are still incompletely defined in patients with FA. Our objectives were to evaluate risk factors for late mortality and secondary malignancies in 1-year survivors in the largest cohort of FA patients post-HSCT ever studied, so far. Patients and methods: Patients with FA reported to the European Blood and Marrow Transplant (EBMT) Group alive 1 year after a matched allogeneic HSCT were reviewed. Donor and recipient were matched if HLA A and B were identical at the generic level and HLA DRB1 at the allelic level. Cord blood as source of stem cells was excluded because of a few number of FA patients with very long-term follow-up (FU). Data was analyzed using proportional hazards and proportional cause-specific hazards models. Results: Between May 1972 and January 2009, 789 patients with FA who underwent first SCT were reported to the EBMT registry. 509 patients were alive 1 year post-HSCT and were included in the present study. 273 patients were male. Median age at HSCT was 9 years (range, 10 months to 44 years). The majority (77%) of patients had received stem cells from a related donor and bone marrow (80%) was the main source of stem cells. Irradiation was used as part of the conditioning regimen in 27% of the cohort, while fludarabine-based regimen was used in 29%. T-cell depletion (ex vivo and in vivo) was used in 41%. In January 2010, 15% (n=74) of the patients had died. Median age at death was 19 years. With a median FU of 6 years (1 to 28 years), the probability for survival after HSCT was 49% at 20 years (95%CI 38–65). The main causes of death were secondary malignancies in 52% of cases and treatment related mortality in 21%. Solid tumor represented 89% of the secondary malignancies. Cumulative incidence of death and secondary cancer are presented in Figure 1. A worse survival was observed in patients transplanted before year 2000 (Hazard ratio - HR: 2.24; 95%CI 1.06–4.71; p=0.034), in those transplanted because of clonal evolution (acute myeloid leukemia or MDS) (HR: 3.88; 95%CI 2.03–7.41; p<0.0001), in patients older than 10 years at SCT (HR: 2.00; 95%CI 1.26–3.18; p<0.004), and in patients transplanted more than a year after FA diagnosis (HR: 1.98; 95%CI 1.10–3.54; p=0.02). Without taking into account transplant period, HSCT after the age of 10 (HR 1.88 [1.17 to 3.03], P=0.009), clonal evolution before HSCT (HR 3.31 [1.72 to 6.39], P=0.0004) and previous chronic GVHD (HR 2.72 [1.65 to 4.46], P<0.0001) were associated with decreased survival. After adjustment for these factors, patients transplanted before 2000 still showed a worse survival (HR 2.09 [0.99 to 4.41], P=0.052). Using occurrence of a secondary malignancy as a time-dependent covariate, the hazard of death after this event was extremely high (HR 17.3 [9.70 to 30.7], P<0.0001). Independent risk factors for secondary malignancies included HSCT after the age of 10 (HR 2.89 [1.53 to 5.45], P=0.001), peripheral blood as source of stem cells (HR 3.06 [1.18 to 5.45], P=0.001) and previous chronic GVHD (HR 2.89 [1.53 to 5.45], P=0.001). Irradiation in the conditioning regimen and donor type (related versus unrelated) did not correlate with outcomes (both late survival and secondary malignancies). Conclusion: We found improved outcomes for patients with FA post-HSCT in recent years (>2000). However, long-term survival in FA patients after HSCT is still mainly affected by secondary malignancies (89% of solid tumors). Patients should be transplanted before the age of 10 with bone marrow as source of stem cells to try to avoid this complication. Moreover, chronic GvHD still emerges as a major cause for both secondary malignancies and mortality. Clearly improved method for prevention, early diagnosis and treatment of this complication are urgently needed. This study also highlights the need for very long-term FU for FA patients after HSCT. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

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