Colony-Forming Unit Cell (CFU-C) Assays in Myelodysplastic Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2874-2874
Author(s):  
Bing Li ◽  
Jinqin Liu ◽  
Shiqiang Qu ◽  
Robert Peter Gale ◽  
Ruixian Xing ◽  
...  
Keyword(s):  
Overall Survival ◽  
Scoring System ◽  
Conflicts Of Interest ◽  
Unit Cell ◽  
International Prognostic Scoring System ◽  
Hematopoietic Stem ◽  
Colony Forming Unit ◽  
Significant Difference

Abstract Introduction: The myelodysplastic syndromes (MDS) are a group of clonal diseases derived from hematopoietic stem cells (HSC). Colony-forming unit cell (CFU-C) assay is an effective method to study the number and the function of HSC in vitro. In this study, we focus on the characteristics and the prognostic value of CFU-C in patients with MDS. Patients and Method: CFU-C assays were performed according to the protocol of MethoCultTM H4435 Enriched (STEMCELL Technologies). A colony was defined as an aggregate of >40 cells. Clusters consisted of 4 to 40 cells. 560 consecutive newly-diagnosed, untreated subjects with MDS diagnosed from March, 2001 to April, 2013 were studied. All subjects were reclassified according to the 2008 WHO criteria. 535 subjects with evaluable cytogenetics were classified using the International Prognostic Scoring System (IPSS) and the revised International Prognostic Scoring System (IPSS-R) criteria. Follow-up data were available for 470£¨84%£©subjects. Median follow-up of survivors was 26 months (range, 1-170) months. Subjects receiving an allotransplants were censored in survival analyses. Erythroid and myeloid colonies were isolated from each subject with one cytogenetic abnormality such as del(5/5q-) or +8. Cytogenetic abnormalities of each colony were analyzed by fluorescence in situ hybridization (FISH). SPSS 17.0 software was used to make statistical analysis. Results: Frequencies of burst-forming units-erythroid (BFU-E), colony forming unit-erythroid (CFU-E) and colony forming unit-granulocytes/macrophages (CFU-G/M) were significantly lower than normals (P<0.05) (Table 1). Subjects classified as lower risk in IPSS and IPSS-R had significantly higher numbers of BFU-E and CFU-E (P<0.05) but similar numbers CFU-G/M and clusters-G/M compared with higher risk subjects (Table 2). In 11 subjects with del(-5/5q-) or +8 identified by G- and/or R-banding, both normal and abnormal CFU-Cs were identified in 8 subjects studied by FISH. A high ratio of cluster- to CFU-G/M (>0.6) was associated with poor-risk cytogenetics (Table 2) and with worse overall survival in univariable (Figure 1, P=0.001) and multivariable analyses (HR 1.748, [1.01-3.0]; P=0.046) after adjusting for IPSS. Conclusions: These data suggest abnormalities of proliferation and differentiation of erythroid and myeloid precursor cells in vitro parallel the ineffective hematopoiesis typical of MDS and may be useful in predicting outcomes of patients with MDS. Table 1. CFU-C in MDS subtypes N BFU-E CFU-E CFU-G/M N Ratio of cluster- to CFU-G/M RA 21 8 (0-44) 40 (0-134) 14 (0-127)1 6 0.25 (0.40-1.00) RT 4 18 (4-55) 75 (60-90)1 30 (18-70)1 2 2 RARS 27 12 (0-33) 35 (1-140) 12 (0-70)1 10 0.45 (0.17-0.80) RCMD 275 10 (0-80) 33 (0-178) 14 (0-100) 126 0.35 (0-0.83) RAEB1 112 10 (0-258) 32 (0-312) 14 (0-89) 53 0.47 (0-1.00) RAEB2 103 9 (0-46) 25 (0-120) 13 (0-72) 42 0.37 (0-1.00) MDS-U 15 4 (0-58) 25 (0-161) 10 (0-43) 3 2 Del(5q) 3 2 (2-4) 15 (0-20) 5 (5-41)1 1 2 1No significant difference compared with normals. 2Too few cases to analyze. Table 2. Associations between CFU-C and clinical and laboratory variables N BFU-E P CFU-E P CFU-G/M P Number Ratio of cluster- to CFU-GM P IPSS 0.064 0.006 0.361 0.089 Low 30 13 (0-44) 60 (0-169) 19 (0-45) 10 0.44 (0.24-0.70) Int-1 361 10 (0-258) 33 (0-312) 14 (0-127) 150 0.33 (0-1.00) Int-2 115 9 (0-61) 30 (0-137) 14 (0-72) 52 0.45 (0-1.00) High 29 7 (0-34) 21 (0-93) 12 (0-67) 12 0.44 (0-1.00) IPSS-R 0.003 0.003 0.125 0.209 Very low 7 16 (9-25) 30 (15-120) 18 (5-33) 2 0.29 (0.10-0.49) Low 130 14 (0-80) 42 (0-178) 17 (0-70) 48 0.31 (0-0.77) Intermediate 173 10 (0-66) 34 (0-161) 13 (0-127) 81 0.37 (0-1.00) High 139 9 (0-259) 29 (0-312) 11 (0-89) 51 0.33 (0-1.00) Very high 86 8 (0-61) 25 (0-137) 14 (0-91) 42 0.47 (0-1.00) Cytogenetics (IPSS) 0.867 0.055 0.290 0.007 Good 327 10 (0-258) 36 (0-312) 15 (0-89) 133 0.33 (0-1.00) Intermediate 133 10 (0-69) 30 (0-162) 12 (0-127) 63 0.45 (0-1.00) Poor 75 10 (0-61) 25 (0-137) 14 (0-91) 28 0.42 (0-1.00) Cytogenetics (IPSS-R) 0.990 0.090 0.676 0.022 Very good 7 11 (4-20) 48 (1-110) 14 (8-28) 2 0.49 (0.43-0.56) Good 324 10 (0-258) 35 (0-312) 15 (0-89) 132 0.33 (0-1.00) Intermediate 129 10 (0-69) 30 (0-162) 12 (0-127) 62 0.45 (0-1.00) Poor 27 10 (0-61) 35 (0-137) 16 (0-48) 8 0.36 (0.15-1.00) Very poor 48 11 (0-42) 22 (0-120) 14 (0-91) 20 0.53 (0-1.00) Figure 1. Overall survival in subjects with cluster- to CFU-G/M ratios ¡Ü or > 60%. Figure 1. Overall survival in subjects with cluster- to CFU-G/M ratios ¡Ü or > 60%. Disclosures No relevant conflicts of interest to declare.

Validation of the EBMT Risk Score for Patients with Hematologic Malignancies Receiving Allogeneic Hematopoietic Stem Cell Transplant in a Transplant Center in Colombia over 20 Years

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5542-5542
Author(s):  
Virginia Abello ◽  
Carmen Rosales ◽  
Manuel Rosales ◽  
Javier Figueroa ◽  
Iris Cordoba ◽  
...  
Keyword(s):  
Overall Survival ◽  
Latin America ◽  
Risk Score ◽  
Conflicts Of Interest ◽  
Risk Groups ◽  
Hematologic Malignancies ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract INTRODUCCION EMBT the risk score has been validated in several studies in different types of diseases and modalities of transplantation. The conditions of the patients and the resources available in Latin America are different from those of European centers, so we consider important to validate this scale in our own patients. METHODS EBMT risk scale was validated in 965 of 1176 (750 autologous, allogeneic 426) transplanted from 1993 to 2014; that had all the information available and were not lost to follow up. Kaplan-Meier survival curves and log-rank test (p <0.05) were used to estimate the one (OS1) and three (OS3) probabilities of overall survival according to risk groups. RESULTS The mean age was 39.8 (SD 15.5). The median follow-up was 363 days (range: 179-1096) for the whole group. Most frequent diagnoses were Non-hodgkins lymphoma (314: 26.7%) and multiple myeloma (262: 22.22%). 96.3% transplants were performed using peripheral blood stem cells. Most donors were identical siblings; only 19.5% (n = 79) were transplanted before 2004. 81.9% of transplanted patients had 2-4 points on EBMT risk score. Upon analysis it became clear that at 1 and 3 years, two groups were defined: Low (0-3 points) and high (4-7), with a significant difference in overall survival for AML (1 year: p = <0.00; 3 years: p = <0.00) and ALL (1 year: p = 0.04; 3 years: p = 0.01). In NHL 4 risk groups remain significantly different in regards to 1 and 3 years overall survival (1 year: p = 0.04; 3 years: p = 0.02). In patients with diagnosis of MDS EBMT was predictive of survival only significant at one year (p = 0.01). The EBMT score did to delineate risk groups patients with MM, LH, ASMO, or CML in this group. CONCLUSION EBMT score was validated in patients with hematologic malignancies transplanted in a center in Colombia, to our knowledge this is the first validation of this risk score in Latin America. Disclosures No relevant conflicts of interest to declare.

Prediction of Overall Survival in 520 Patients with Primary Myelofibrosis: Outcome Update of the Dynamic International Prognostic Scoring System (DIPSS) Patient Cohort

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1729-1729 ◽  
Author(s):  
Margherita Maffioli ◽  
Elisa Rumi ◽  
Francisco Cervantes ◽  
Alessandro M. Vannucchi ◽  
Enrica Morra ◽  
...  
Keyword(s):  
Median Time ◽  
Scoring System ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Outcome Data ◽  
International Prognostic Scoring System ◽  
Risk Category ◽  
Hematopoietic Stem

Abstract Abstract 1729 Background: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm whose survival at diagnosis is predicted by the International Prognostic Scoring System (IPSS), which is based on the presence of the following five risk factors: age greater than 65 years, presence of constitutional symptoms, hemoglobin level below 10 g/dL, leukocyte count greater than 25 ×109/L, and circulating blast cells 1% or greater (Cervantes et al, Blood 2009). To allow dynamic prognostication at any time during follow up, we further developed the Dynamic International Prognostic Scoring System (DIPSS), based on the same IPSS-factors, but with different score values (one point for each risk factor, two points for acquisition of anemia) and with a distinct score model (low risk, LR, 0 points; intermediate-1 risk, Int-1R, 1–2 points; intermediate-2 risk, Int-2R, 3–4 points; high risk, HR, 5–6 points) (Passamonti et al, Blood 2010). The DIPSS model was also efficient in the prediction of acute myeloid leukemia (AML) evolution (Passamonti et al, Blood 2010) and in the assessment of survival and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (Scott et al, Blood 2012). Aim: The aim of the present study is to update outcome data of PMF patients included in the original series used to generate the DIPSS model and to assess the DIPSS prediction of survival in PMF patients with a longer follow up. The Institutional Review Board approved the study, and the procedures followed were in accordance with the Declaration of Helsinki. Patients and methods: This study was performed on 520 of 525 regularly followed DIPSS-PMF patients, as five patients have been lost to follow up after the original publication. Results: Updated median follow up was of 4.1 years (range, 0.1–30.1). At the time of analysis 326 (63%) patients died, of whom 194 due to known causes: 69 AML, 16 non-AML disease progression, 21 bleeding, 17 thrombosis, 33 infections, 38 other. Median survival was 6 years (95% CI: 5.1–6.7). DIPSS stratification allowed different survivals in PMF patients even with a longer follow-up (Figure 1). Hence, to assess the time to DIPSS-category progression, we evaluated the median time spent within each risk group. This estimate revealed that the median time spent in each risk category was: 4.9 years in LR (range, 0–26.7), 2.1 years in Int-1R (range, 0–18.7), 1.7 years in Int-2R (range, 0–13.4), and 0.74 years in HR (range, 0–13.7). To investigate the prognostic role of the DIPSS score on survival, we analyzed the score as a categorical time-dependent covariate in a Cox survival regression model: the hazard ratio of shifting category from LR to Int-1R was 5.0 (95% CI: 2.4–10.6; P <0.001), it was 3.6 when shifting from Int-1R to Int-2R (95% CI: 2.6–4.9; P <0.001), and 2.7 (95% CI: 2.0–3.6; P <0.001) from Int-2R to HR. Conclusion: The updated analysis shows that the DIPSS model continues to predict survival in patients with PMF. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Marrow Blast Percentage Impact on High-Grade Myelodysplastic Syndrome By the Revised International Prognostic Scoring System

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5510-5510
Author(s):  
Omar Alkharabsheh ◽  
Mrinal M. Patnaik ◽  
Naseema Gangat ◽  
Kebede H. Begna ◽  
Hassan B. Alkhateeb ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Scoring System ◽  
International Prognostic Scoring System ◽  
High Grade ◽  
Survival Difference ◽  
Significant Difference ◽  
Risk Of Progression ◽  
Very High

Abstract Introduction: The revised international prognostic scoring system (IPSS-R) for myelodysplastic syndrome (MDS) is widely accepted and has been validated in multiple studies. Patients with adverse cytogenetics do poorly and that is reflected in this scoring system by having the highest score for cytogenetics; 2 for intermediate, 3 for poor and 4 for very poor. Little is known about the effect of marrow blasts in adverse cytogenetic in the high-grade MDS defined by IPSS-R intermediate (>3), high (>4.5) and very high (>5). The goal is to examine the effect of marrow blast percentage on outcome in patients with adverse cytogenetics that is present in the high-grade MDS. Methods: We performed data collection from the Mayo clinic records for patients with confirmed MDS after obtaining appropriate IRB approval. Patients were divided based on their total IPSS-R score and we extracted high-grade MDS cases with intermediate, high and very-high IPSS-R only. Cytogenetics and baseline CBC were available for analysis. We calculated the survival difference in patients with blasts <5% and patient with blasts of 5% to 19% for every group. Survival estimates were calculated by Kaplan-Meier method and compared by log-rank testing using JMP v.13. Results: Our database had 1300 patients with confirmed MDS, 41% (N=536) are high-grade MDS. From those, the median age was 70 and 70% were males. Median bone marrow blast was 6% (0-19). Baseline hemoglobin is 9.2 g/dL, WBC 2.7, ANC 1.05, and platelets 69. Their cytogenetics were 1% very good, 31% good, 23% intermediate, 16% poor and 29% very poor. The total IPSS-R groups were 39%,31%, and 30% for the intermediate, high, and very-high groups respectively. The overall survival (OS) for the high-grade MDS with marrow blast <5% was 12.3 months and for patients with marrow blasts ≥5% 11.4 months (P=.4). At each high-grade MDS; intermediate, high and very high, there were no statistically significant differences for patients with marrow blasts below or above 5%. In term of risk of progression to AML, patients with blasts ≥5% were at higher risk of progression compared with <5% (25% vs 10% , P<.001), with no statistically significant difference in term of time-to-AML progression. Conclusion: The percentages of bone marrow blasts had no impact on overall survival among patients with high grade MDS. However, patients with ≥5% marrow blasts are at a higher risk for progression to AML. Disclosures Al-Kali: Novartis: Research Funding.

Complex Karyotype Predicts Outcome Better Than Monosomal Karyotype In Patients with MDS/Secondary Acute Leukemia Treated with Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): a Retrospective Survey on Behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 578-578 ◽  
Author(s):  
Angelique .M. Brands-Nijenhuis ◽  
Michel van Gelder ◽  
Theo M. de Witte ◽  
Johannes Schetelig ◽  
Anja van Biezen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Chromosome 7 ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Significant Difference ◽  
Monosomal Karyotype ◽  
Better Than

Abstract Abstract 578 Introduction Monosomal Karyotype (MK) has been shown to be associated with a very poor prognosis in AML patients. Last year at ASH, we presented data from the EBMT on patients diagnosed with MDS and chromosome 7 abnormalities, showing that MK predicts better than complex karyotype (CK) for a dismal outcome after allogeneic HSCT (abstract #293). We now performed a retrospective analysis on data from the registry in the complete cohort of patients with MDS and secondary AL (sAL) to determine the effect of MK on outcome after allogeneic HSCT. Methods A total of 1689 patients from 172 centres in 23 countries with diagnosis MDS or secondary acute leukemia (sAL) with known cytogenetic abnormalities (karyotype only) at diagnosis or later in the disease course were assessed. 1437 were included in the analysis; 226 were excluded because of insufficient data. Kaplan-Meier survival curves were used and log rank test to determine statistical significance. Results 1041 patients were diagnosed with MDS and 396 with sAL. Median follow up for sAL patients was 7.5 months (range 0–253) and MDS 8.0 months (range 0–276). 201 patients fulfilled criteria for MK and 279 patients for complex karyotype (CK). MK outcome was worse than no MK: overall survival 32 months versus 97 months (p=0.002). CK outcome was worse than no CK: overall survival 26 months versus 100 months (p&lt;0.0001). No difference in outcome between MK and CK existed: overall survival of 32 months and 26 months respectively (p= 0.274). There was considerable overlap between MK and CK (i.e. patients fulfilling criteria both for MK and CK). To see how we could further differentiate, we analyzed three subgroups: MK but not CK (43 patients; MK+CK−), no MK but CK (98 patients; MK−CK+) and MK and CK (150 patients; MK+CK+). The survival of patients in each of these groups was compared with the group having no MK and no CK (n=1050). Overall survival was not different for patients with MK+CK− (median 13 vs 19 months, p=0.983), but for patients with MK-CK+ or MK+CK+ a significant difference in survival was observed with a median of 8 months (p=0.008) and 7 months (p&lt; 0.0001) respectively. MK−CK+ and MK+CK+ did not differ statistically (p=0.42) from each other. See figure. These results differ from the results presented at ASH last year. Since this cohort consists of patients with and without chromosome 7 abnormalities, we suspect that presence of this specific chromosomal aberration is the main reason for the observed difference. Multivariate analysis will be performed the coming months. Conclusion These results indicate that CK is a better predictor for poor outcome than MK after allogeneic HSCT in this cohort of MDS and sAL patients with and without chromosome 7 abnormalities. Disclosures: No relevant conflicts of interest to declare.

Application Of The Revised International Prognostic Scoring System In Korean Patients With MDS and Clinical Significance Of Clonal Evolution

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5217-5217
Author(s):  
Jae Hyeon Park ◽  
Si Nae Park ◽  
Jiseok Kwon ◽  
Kyongok Im ◽  
Jung Ah Kim ◽  
...  
Keyword(s):  
Scoring System ◽  
Conflicts Of Interest ◽  
Clonal Evolution ◽  
Prognostic Score ◽  
Supportive Therapy ◽  
International Prognostic Scoring System ◽  
Korean Patients ◽  
System 2 ◽  
Very High

Abstract Introduction The International Prognostic Scoring System (IPSS) was recently revised (IPSS-R). IPSS-R was developed using a large cohort of patients received supportive therapy, so we validated the new prognostic score system in Korean patients. IPSS-R emphasizes initial cytogenetic abnormalities, but the risk of clonal evolution is not well identified in follow up of MDS patients. Methods Data of 88 MDS patients were collected retrospectively and verified by chart review. And we also collected cytogenetic analysis results performed with bone marrow study. Results By IPSS-R cytogenetic scoring system, 2 (2.3%), 41 (46.6%), 22 (25.0%), 5 (5.7%), and 18 (20.5%) patients were classified as very good, good, intermediate, poor, and very poor, respectively. According IPSS, 5 (5.7%), 50 (56.8%), 19 (21.6%), and 14 (15.9%) patients were classified as low, intermediate-1, intermediate-2, and high, respectively. According to IPSS-R, 2 (2.3%), 13 (14.8%), 28 (31.8%), 25(28.4%), and 20 (22.7%) patients were reclassified as very low, low, intermediate, high, and very high, respectively. Median 3 years overall survival of patients intermediate, high and very high IPSS-R are 36 (95%CI 34-39), 32 (95%CI 8 – 56), and 13 (95%CI 6-21), respectively (P = 0.004). Clonal evolutions were occurred in 22 patients and they were classified by IPSS-R cytogenetic scoring system: 11 (50.0%) good, 8 (36.4%) intermediate, 1 (4.5%) poor, 2 (9.1%) very poor. Prior clonal evolution was considered as except concurrent occurrence of clonal evolution and acute myeloid leukemia (AML) transformation. These 17 patients have significant correlation with AML transformation (P = 0.010) and mortality (P = 0.021). Conclusion IPSS-R gives more refined prognostic discrimination and can be applicable in Korean MDS patients. In addition, the clonal evolution occurring during follow up should be considered as a risk factor of AML transformation and mortality. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Hemoglobin Level As a Continuous Variable in Calculating Prognosis in MDS: Incorporation into LSC4 and IPSS-R

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Faezeh Darbaniyan ◽  
Guillermo Montalban Bravo ◽  
Yue Wei ◽  
Rashmi Kanagal-Shamanna ◽  
Koji Sasaki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Scoring System ◽  
Research Funding ◽  
Continuous Variable ◽  
Classification Performance ◽  
International Prognostic Scoring System ◽  
Data Set ◽  
Hematopoietic Stem ◽  
Survival Status ◽  
Cd34 Cells

INTRODUCTION: Myelodysplastic syndromes (MDS) are a group of hematopoietic stem-cell disorders, with heterogenous prognosis. The Revised International Prognostic Scoring System (IPSS-R) (Greenberg et al., Blood, 2012) is the standard prognostic scoring system that uses several clinical and cytogenetic criteria as categorical parameters to predict prognosis of patients with newly diagnosed MDS. A recent study compared the performance of IPSS-R with a panel comprised of 4 stemness-related genes: LAPTM4B, NGFRAP1, EMP1, and CPXM1 (LSC4) and showed a significant improvement of survival classification performance when focusing on gene expression panel (Wang et al., Blood Advances, 2020). Despite the recent upgrade, the performance of none of these markers is sufficient enough and there is still need for improvement. METHODS: In order to evaluate the predictive power of the LSC4 and develop novel models integrating RNA-sequencing data with clinical variables, we evaluated bone marrow samples from 56 independent MDS patients prior to any therapy. Patient samples were collected using institutional guidelines. BM mononuclear cells (MNCs) were enriched by Ficoll (GE Healthcare, Chicago, IL) protocol, following manufacture's guidance. BM CD34+ cells were enriched using magnetic cell separation (MACS) and CD34+ magnetic beads (Miltenyi Biotech, Germany). RNA from sorted BM CD34+ cells was isolated using the TRIzol RNA isolation kit (Fisher Scientific, Waltham, MA) followed by RNA-Seq library construction. FASTQ files were processed in TopHat2 using the default options. We implemented cox proportional hazard model to create the survival panel and time dependent AUCs was used in order to evaluate the performance of the model. We divided the patients into high versus low groups using optimum cutoff method and used Kaplan-Meier estimator to show the survival behavior in each group. RESULTS: In this work we first validated the LSC4 panel and compared it with the IPSS-R on our data set. Furthermore, in order to improve the classifier performance, we calculated the correlation of clinical features with survival status. We observed that Hemoglobin (Hgb), as a continuous variable, has a significant effect on predicting the overall survival and it can significantly improve the survival classification performance when combined with the IPSS-R or LSC4 scores (HR = 0.63, 95% CI 0.44 - 0.89, P &lt;0.001 when Hgb combines with IPSS-R and HR = 0.67, 95% CI 0.48 - 0.93, P&lt;0.001 when Hgb combines with LSC4). Our proposed models show an enhanced time AUC performance when focusing on survival status beyond 20 months of follow up compare to IPSS-R and LSC4 scores (Figure 1a). We have also observed that combining Hgb with LSC4 or IPSS-R significantly improves the confidence interval for long term survivals (Figure 1b). In fact, in these panels, unlike the IPSS-R panel, we treat Hgb as a continuous variable and we believe factorial consideration of Hgb can underestimates the true effect of this feature on survival. We also showed a distinct separation between two survival curves when we used new proposed panels amongst all patients (Figures 1c and 1d). CONCLUSIONS: In this work, while providing further validation for LSC4 model, we showed that Hemoglobin, as a continuous variable, has a significant prognostic effect when integrated with either IPSS-R or LSC4. Hereby, we observed that increasing Hgb even by a single unit can improve patient's overall survival. Figure 1 Disclosures Sasaki: Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy; Otsuka: Honoraria. Garcia-Manero:H3 Biomedicine: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding.

MT1-MMP Plays a Critical Role In the Modulation of Hematopoiesis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3851-3851
Author(s):  
Chiemi Nishida ◽  
Beate Heissig ◽  
Yoshihiko Tashiro ◽  
Motoharu Seiki ◽  
Hiromitsu Nakauchi ◽  
...  
Keyword(s):  
Stromal Cell ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Cancer Drug ◽  
Hematopoietic Stem ◽  
Kit Ligand ◽  
Significant Difference ◽  
Stromal Cell Derived Factor

Abstract Abstract 3851 Specific niches, in which hematopoietic stem cells (HSCs) reside control the balance between HSC quiescence and self-renewal, yet little is known about the extrinsic signals provided by the niche and how these niche signals regulate such a balance. In the recent study, activation of the fibrinolytic pathway via matrix metalloproteinases (MMPs) including MMP-9 resulted in the release of kit ligand (KitL) in the BM niche. Membrane type 1-MMP (MT1-MMP) can activate MMP-9 in the process of mutual activation of MMP. It has already known that BM myeloablation with irradiation or anti-cancer drug induces MT1-MMP expression, but the role of MT1-MMP in hematopoiesis is not well-understood. We examined MT1-MMP deficient mice (MT1-MMP-/-) 12 days after birth. MT1-MMP-/- were suffering from pancytopenia, and are reduced numbers of bone marrow mononuclear cells (BMMCs), splenocytes and number of hematopoietic progenitor cells in the BM although the number of HSCs in BM showed no significant difference. BM cytospins from MT1-MMP-/- mice showed mild erythropoietic disturbance and severer impairment of myelopoiesis. Interestingly, a powerful hematopoietic factor, Kit-ligand (KitL) levels were significantly lower in MT1-MMP-/- mice than wild type. MT1-MMP knockdown by shRNA or/and siRNA impaired KitL expression and secretion in transfected stroma cells compared to Mock controls, demonstrating that reduced KitL plasma levels were due to impaired release/production and not due to reduced numbers of stromal cells in MT1-MMP-/-. Similarly, impaired proliferation and differentiation of MT1-MMP-/- BMMCs in vitro could be restored by exogenous sKitL. Others and we reported that BM ablation induces the production of stromal cell-derived factor-1 (SDF-1; CXCL12), which plays a key role in stem cell homing and B-cell lymphopoiesis. Reduced SDF-1 expression was observed in BMMCs of MT1-MMP-/- mice and genetic knockdown of MT1-MMP resulted in lower SDF-1 expression both on a transcriptional and protein level. BMMCs of MT1-MMP-/- showed a decrease in the percentage of mature B cells compare to controls. Knocking down of MT1-MMP in stromal cell reduced the number of adherent hematopoietic cells, but addition of rec. SDF-1 could reverse the phenotype. These results suggested stromal-derived MT1-MMP was functionally important to maintain HSC function in long-term cultures of WT HSCs. Thus, MT1-MMP is a critical modulator of hematopoiesis, as it alters the growth factor output of niche cells. Disclosures: No relevant conflicts of interest to declare.

The Revised International Prognostic Scoring System (IPSS-R) Is Not Predictive Of Survival In Patients With Secondary Myelodysplastic Syndromes (MDS)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1524-1524
Author(s):  
Aziz Nazha ◽  
Sudipto Mukherjee ◽  
Ramon V. Tiu ◽  
Yogen Saunthararajah ◽  
Michael K. Keng ◽  
...  
Keyword(s):  
Scoring System ◽  
Single Agent ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Poor Risk ◽  
Very High ◽  
Risk Categories

Abstract Background The International Prognostic Scoring System (IPSS) has been the most widely used risk assessment tool to predict clinical outcome in MDS. Recently, the revised IPSS (IPSS-R) was introduced to allow a greater discriminating capacity in assessing cytogenetic abnormalities and cytopenias and further refines prognostication. However, like the IPSS, the IPSS-R was developed in pts with primary MDS and its utility in pts with secondary (s)MDS is unclear. Material and Methods We conducted an IRB-approved analysis of 765 pts diagnosed with MDS (per 2008 WHO criteria) and evaluated at the Cleveland Clinic between 9/1998 and 1/2013. IPSS-R was calculated as described previously (Greenberg et al, Blood 2012). Cytogenetic risk subgroups were per IPSS-R. Overall survival (OS) was measured from the time of diagnosis to time of death or last follow up. Time-to-event analyses were performed by the Kaplan-Meier method, and curves were compared with the 2-tailed log rank test. Differences among variables were evaluated by the chi-square test and Mann-Whitney U test for categorical and continuous variables, respectively. Results We identified 56 pts (7%) with sMDS: 14 (25%) pts had prior antecedent hematologic disorder, 32 (57%) had prior radiation therapy, and 10 (18%) received prior chemotherapies. Eleven pts (20%) were untreated and 45 pts (80%) received treatment: 17 (30%) with single agent 5-azacitidine, 12 (21%) with supportive measures, 9 (16%) with hematopoietic stem cell transplant (HSCT), and 7 (11%) with other therapies. For all pts, the median age was 66 years (range, 24-81). Median white blood cell count at diagnosis was 3.8 k/mL (range, 0.9-179.7), median absolute neutrophil count (ANC) was 2.2 k/mL (range, 0.1-145.6), median hemoglobin was 9.6 g/dL (range, 0.4-14), median platelet count was 65 X 103/mL (range, 4-460), and median bone marrow blasts was 5% (range, 0-26). The distribution of cytogenetic categories based on IPSS-R criteria was similar in pts with sMDS [2 (4%) very good, 28 (50%) good, 8 (14%) intermediate, 10 (18%) poor and 8 (14%) very poor] compared to primary MDS [28 (4%) very good, 351 (50%) good, 109 (15%) intermediate, 84 (12%) poor and 137 (19%) very poor]. IPSS-R risk categories in pts with sMDS [3 (5%) very low, 15 (27%) low, 11 (20%) intermediate, 15 (27%) high, and 12 (21%) very high] compared to primary MDS [75 (11%) very low (P = 0.15), 221 (31%) low (P = 0.3), 162 (23%) intermediate (P = 0.3), 145 (20%) high (P = 0.1), and 106 (15%) very high (P = 0.1)] were also similar. With a median follow up of 18.4 months (m, range, 1.8-104.6), the median OS for sMDS pts was not reached for very low risk pts, 31.6 m for low risk, 13.7 m for intermediate risk, 27.3 m for poor risk and 39 m for very poor risk (P = 0.15, Figure 1). Conclusion Although pts with sMDS had similar cytogenetic and IPSS-R risk categories compared to those with primary MDS, the IPSS-R did not predict for OS in sMDS pts. The lack of predictability of IPSS-R could be because that most of our pts with sMDS received therapy including HSCT. A new prognostic module to predict the outcome of pts with sMDS who are receiving treatment is needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Comparison Study Between Allogeneic and Autologous Hematopoietic Stem Cell Transplant for High-Risk Peripheral T-Cell Lymphomas (PTCL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5845-5845 ◽  
Author(s):  
Haiwen Huang ◽  
Qiangli Wang ◽  
Zhengming Jin ◽  
XiaoWen Tang ◽  
Huiying Qiu ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cell Transplant ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Objective: To evaluate the efficacy of auto-HSCT and allo-HSCT in the treatment of high risk peripheral T cell lymphoma (PTCL). Methods: From July 2007 to July 2014, 60 cases of high risk PTCL were analyzed retrospectively. Results: All 60 patients were at high risk group (carried with IPI≥3), with a median age of 31 (13-55) years old. Of the 60 cases, 22 were PTCL-not otherwise specified (PTCL-NOS), 22 with ALK negative anaplastic large cell lymphoma (ALK-negative ALCL) and 16 with angioimmunoblastic T-cell lymphoma (AITL). Twenty-one (21/60) received allo-HSCT and thirty-nine patients (39/60) received auto-HSCT. Before receiving transplantation, 40/60 patients were in complete remission (CR), 2/60 patients were partial remission (PR) and 18/60 patients were not remission (NR). In the 40 CR patients before transplant, 10 patients received allo-HSCT and 30 patients received auto-HSCT. In the 20 PR/NR patients before transplant, 11 patients received allo-HSCT and 9 patients received auto-HSCT. After a median follow-up of 39 (range 1-96) months, the K-M analysis showed that the 5-year PFS for auto-HSCT and allo-HSCT were 61% and 60% (P = 0.724). The 5-year OS for auto-HSCT and allo-HSCT were 62% and 61% (P = 0.724). There were no statistically significant differences between the auto-HSCT and allo-HSCT. And the cumulative TRM of allo-HSCT and auto-HSCT were 16.5% and 0 (P=0.250) within 5-years after transplantation. At the end of the last follow-up, 7 patients relapsed in auto-HSCT group and 2 patients relapsed in allo-HSCT group, the 5-year cumulative recurrence rates of auto-HSCT and allo-HSCT transplantation were 37.2% and 10.1% (P=0.298), respectively. Conclusion: There was no significant difference in the long-term survival between auto-HSCT and allo-HSCT for high risk PTCL patients. The effect of allo-HSCT may be better for NR patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Successful Result of 113 Patients for Refractory/Recurrent Leukemia By Allogeneic Hematopoietic Cell Transplantation and Prophylactic Immunotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5856-5856
Author(s):  
Jingbo Wang ◽  
Xiaojun Huang ◽  
Ying Hu ◽  
Song Xue ◽  
Haoyu Cheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Prolymphocytic Leukemia ◽  
Significant Difference

Abstract Objective: To retrospectively evaluate the results of allogeneic hematopoietic stem cell transplantation for Refractory/Recurrent leukemia. Methods: From July 2012 to May 2016, total 113 patients with Refractory/Recurrent leukemia were enrolled, including 31 cases of ALL, 73 cases of AML and 8 cases of CML-BP, 1 case of Prolymphocytic leukemia. The average leukemia burden was 51% (10-99) in bone marrow before conditioning. Myeloablative conditioning regimens consisted of 13 cases of BuCy, 47 cases of TBI/FLAG, 28 cases of TBI/Cy, and 16 cases of FLAG that followed by reduced-intensified BUCY, 9 cases of CLAG/BuCy. Transplant types included sibling HLA-identical allo-HSCT (n=22) and relative HLA-haploidentical HSCT (n=91). All patients received cyclosporine A, MMF and methotrexate for GVHD prophylaxis. Analyzed outcomes were hematological engraftment, incidence of acute and chronic GVHD, incidence of CMV/EBV infecton, incidence of relapse, and nonrelapse mortality (NRM), Overall survival (OS) and Disease-free survival (DFS). Results: The median mononuclear cells and CD34+ for transfusion were 8.83 (7.02-11.64) ×108/Kg and 2.91 (0.8-8.32) ×106/Kg. 111 patients achieved stable engraftment, 2 patients died of infection before engraftment. The median time of ANC≥0.5×109/L was 16 days(8-29) and the median time of platelet ≥20×109/L was 22 days (8-150). On day 28postallogeneic transplant, 110 patients were in complete remission of bone marrow, 1 patient was in hematologic relapse. Immunity residue were negative in 107 patients and positive in 4 patients. 62 patients developed acute GVHD, the accumulative incidence of aGVHD was (57.6±4.8)%, the accumulative incidence of II-IV grade aGVHD was (47.2±4.8)%, and the accumulative incidence of III-IV grade aGVHD was (25.2±4.1)%. 62 patients developed cGVHD (43 patients extensive, 19 patients limited), the accumulative incidence of cGVHD was (70.2±6.6)% and for extensive type, the accumulative incidence was (43.6±5.2)%. The accumulative incidence of CMV infection was (42.3±4.7)%, and the accumulative incidence of EBV infection was (4.5±2)%. 10 patients developed virus cystitis, and the accumulative incidence was (9.1±2.1)%. The median follow-up time post transplantation was 10 months (1-46), 35 patients occurred hematologic relapsed and the accumulative incidence of relapse was (39.7±5.9)%. For AML, ALL and CML-BP patients, the accumulative incidence of relapse were (33.8±6.9)%, (56.6±11.7)% and (25±15.3)%respectively (p>0.05). On median follow up (10 months), 49 patients died and 64 patients survived. The cause of death included relapse (28 cases), infection (6 cases), GVHD (11 cases) diffuse alveolar hemorrhage (2cases), radiation enteritis (1 case), and TMA (1 case).Among 64 survirors, two-year accumulative incidences of OS were (49.3±5.7)%, and two-year accumulative incidences of LFS were (45.1±5.4). The two-year accumulative incidences of OS for AML, ALL and CML-BP patients were ( 52.4±7.1)%, (28.1±9.7)%,and (87.5±11.7)%respectively (p>0.05). The two-year accumulative incidence of LFS for AML, ALL and CML-BP patients were (49.8±6.5)%, (24.7±9.1)%, and (70±18.2)%respectively (p>0.05). Incidence of relapse, OS and LFS were similar in different conditioning cohorts (p>0.05). There was no significant difference in the incidence of relapse, OS and LFS over two years among patients with C-Kit, FLT3, MLL and without such genes(p>0.05). There is significant difference in incidence of relapse, OS and LFS among patients with different leukemia burdens(p<0.01). Patients with leukemia burden at 10-19% has lower relapse rate but higher OS and LFS compared to patients with leukemia burden at 80%. Incidence of relapse, OS and LFS for the prophylactic immunotherapy cohort were 32.9%, 61.1% and 57.6% respectively, compared to 45.2%, 35.8% and 35% for non prophylactic immunotherapy cohort (p<0.01). Incidence of relapse , OS and LFS for the cGVHD cohort were 12.9%, 68.4% and 66.2% respectively, compared to 78.7%, 13.9% and 12.8% for non cGVHD(p<0.01). Incidence of relapse , OS and LFS for extensive cGVHD cohort were 12.3%, 62.1% and 61.8% respectively, compared to 58.8%, 31.4% and 31.2% for non extensive cGVHD(p<0.01) Conclusion: Our clinical results have shown that the salvaged HSCT is a promising modality for treatment of Refractory/Recurrent leukemia. Especially for Refractory/Recurrent AML and CML-BP. Disclosures No relevant conflicts of interest to declare.

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