Considering Bone Marrow Blasts From Nonerythroid Cellularity Improves the Prognostic Evaluation of Myelodysplastic Syndromes

2016 ◽  
Vol 34 (27) ◽  
pp. 3284-3292 ◽  
Author(s):  
Leonor Arenillas ◽  
Xavier Calvo ◽  
Elisa Luño ◽  
Leonor Senent ◽  
Esther Alonso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Who Classification ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Prognostic Assessment ◽  
Erythroid Hyperplasia ◽  
Risk Patients ◽  
Risk Categories

Purpose WHO classification of myeloid malignancies is based mainly on the percentage of bone marrow (BM) blasts. This is considered from total nucleated cells (TNCs), unless there is erythroid-hyperplasia (erythroblasts ≥ 50%), calculated from nonerythroid cells (NECs). In these instances, when BM blasts are ≥ 20%, the disorder is classified as erythroleukemia, and when BM blasts are < 20%, as myelodysplastic syndrome (MDS). In the latter, the percentage of blasts is considered from TNCs. Patients and Methods We assessed the percentage of BM blasts from TNCs and NECs in 3,692 patients with MDS from the Grupo Español de Síndromes Mielodisplásicos, 465 patients with erythroid hyperplasia (MDS-E) and 3,227 patients without erythroid hyperplasia. We evaluated the relevance of both quantifications on classification and prognostication. Results By enumerating blasts systematically from NECs, 22% of patients with MDS-E and 12% with MDS from the whole series diagnosed within WHO categories with < 5% BM blasts, were reclassified into higher-risk categories and showed a poorer overall survival than did those who remained in initial categories (P = .006 and P = .001, respectively). Following WHO recommendations, refractory anemia with excess blasts (RAEB)-2 diagnosis is not possible in MDS-E, as patients with 10% to < 20% BM blasts from TNCs fulfill erythroleukemia criteria; however, by considering blasts from NECs, 72 patients were recoded as RAEB-2 and showed an inferior overall survival than did patients with RAEB-1 without erythroid hyperplasia. Recalculating the International Prognostic Scoring System by enumerating blasts from NECs in MDS-E and in the overall MDS population reclassified approximately 9% of lower-risk patients into higher-risk categories, which indicated the survival expected for higher-risk patients. Conclusion Regardless of the presence of erythroid hyperplasia, calculating the percentage of BM blasts from NECs improves prognostic assessment of MDS. This fact should be considered in future WHO classification reviews.

Increased Bone Marrow Erythroid Precursors Is Associated with Shorter Survival in Low-Grade Myelodysplastic Syndromes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2371-2371
Author(s):  
Hesham M. Amin ◽  
Sherry A. Pierce ◽  
Hagop M. Kantarjian ◽  
Michael J. Keating ◽  
Emil J. Freireich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Prognostic Significance ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Low Grade ◽  
Nucleated Red Blood Cells ◽  
Erythroid Precursors ◽  
History Of

Abstract According to the FAB and WHO classifications, the diagnosis of acute erythroid leukemia is based on the numbers of nucleated red blood cells and myeloid blasts in the bone marrow. The WHO classification recognizes two types of acute erythroid leukemia; M6A with 51–80% erythroid precursors and with 20% or more of the non-erythroid precursors being myeloid blasts; and M6B with more than 80% of the nucleated cells in the bone marrow consisting of erythroid precursors, regardless of the percentage of the myeloid blasts. Previous studies have shown that many cases of acute erythroid leukemia arise in patients with a history of myelodysplastic syndrome and in other cases acute erythroid leukemia is associated with significant dysplastic features. The significance of the number of erythroid precursors is not well known in the myelodysplastic syndromes. In the present study, we included 617 consecutive patients with low-grade myelodysplasia (482 patients with refractory anemia [RA] and 135 patients with refractory anemia with ringed sideroblasts [RARS]). Among this group, 82 patients with 50% or more of erythroid precursors had shorter survival compared with 535 patients with less than 50% erythroid precursors (P &lt; .01; Figure 1). The shorter survival in those with 50% or more of erythroid precursors may reflect the tendency of these patients to have worse International Prognostic Scoring System (IPSS) scores. Thus, among the patients with less than 50% erythroid precursors and primary MDS, 35% were IPSS low, 52% IPSS intermediate 1, and 13% IPSS intermediate 2. For the patients with 50% or more of erythroid precursors, the corresponding proportions were 14%, 57%, and 29%, respectively (P &lt; .001). As a result of the association between IPSS and the percentage of erythroid precursors, the percentage of erythroid precursors had no effect on survival within individual IPSS groups. Similarly, the percentage of erythroid precursors had no prognostic significance in patients with refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML). Our findings demonstrate that in low-grade dysplasia (RA and RARS) the number of erythroid precursors may represent an important prognostic marker. These findings implicate that the percentage of erythroid precursors should be considered in the classification of the low-grade myelodysplastic syndromes. A multivariate analysis will be performed to ascertain the relative effects of IPSS score and the percentage of erythroid precursors on prognosis in patients with low-grade myelodysplasia. Figure Figure

Clonal T Cell Expansion in High Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3435-3435
Author(s):  
Jeffrey S. Painter ◽  
Bai Fanqi ◽  
Alan Cantor ◽  
Alan F. List ◽  
P.K. Epling-Burnette
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Peripheral Blood ◽  
Cell Expansion ◽  
Who Classification ◽  
Refractory Anemia ◽  
Risk Patients ◽  
T Cell Expansion

Abstract Myelodysplastic Syndrome (MDS), a hematologic malignancy, is associated with cytogenetic and molecular abnormalities in maturing hematopoietic cells that occurs in 40–70% of cases. These abnormalities directly contribute to increased apoptosis and ineffective hematopoiesis of erythroid and myeloid progenitors while frequently sparing lymphoid subsets. In addition to these direct mechanisms of hematopoietic failure, failed hematopoiesis mediated indirectly by an autoimmune mechanism has been suggested to have importance in a subset of patients with the disease. Autoimmune-mediated bone marrow suppression is suggested by the positive outcome of several clinical trials using immunosuppressants. Depletion of autoreactive T cells with deleterious effects on bone marrow formation is considered the immunologic foundation for these therapeutic responses and bone marrow hypocellularity has been indicated as the best predictor of response. Antigen-driven expansion of immunodominant T cell clones can lead to overrepresentation of cells expressing individual T Cell Receptors (TCRs), which is known as TCR skewing. Treatment of hypocellular MDS patients with immunosuppressive therapies is associated with normalization of a skewed TCR- phenotype. The overall incidence of immunodominant T cell expansions has not been determined. The goal of our study was to assess the frequency of clonal T cell expansion in peripheral blood of MDS patients. Peripheral blood was analyzed from 52 patients for T cell CDR3-length skewing by genomic multi-plex PCR. All patients met the clinical criteria of MDS as defined by the WHO classification scheme. Patients with Refractory Anemia (RA) with and without Ringed Sideroblasts (RARS) represented 13% (n=7), Refractory Cytopenia with Multilineage Dysplasia (RCMD and RCMD-RS) represented 48% (n=25), and Refractory Anemia with Excess Blasts (RAEB1, RAEB2, and MDS that had progressed to AML) represented 38% (n=20). TCR-skewing occurred in 29 out of 52 patients with MDS (55%) compared to one out of 20 (5%) in age-matched normal controls. There was no difference in the frequency of clonal expansions based on the WHO classification. Based on the International Prognostic Scoring System (IPSS), we found that high risk patients (Int-2 and high) had a significantly higher incidence of clonal expansions than did patients with low risk disease (low and Int-1) (47% vs. 20%, respectively, p&lt;0.05). Indeed, patients with the highest incidence of having clonal T cell expansion were in the Int-2 risk category (86% by TCR-Vβ analysis, n=7). Of 47 patients with known bone marrow cellularity classification, we enrolled only eight (17%) that were classified as hypocellular, ten (21%) normal cellular, and 29 (62%) hypercellular. No patient with a hypocellular bone marrow in our analysis showed evidence of clonal T cell expansion (p&lt;0.05). These results suggest that clonal T cell expansion occurs prominately in high risk patients. We believe that cellular immunity in MDS could have both beneficial and deleterious effects. Antigen-specific cellular immune responses against pre-leukemic cells would be advantageous, while autoimmune destruction of normal bone marrow cells in the environment of an aggressive immune response would be deleterious. More information is needed about the role that clonal T cell expansion plays in high risk MDS.

Clinical Features and Prognosis of Patients with Myelodysplastic/Myeloproliferative Syndrome-Unclassified (MDS/MPD-U): Refractory Anemia with Ringed Sideroblasts with Thrombocytosis (RARS-T) Is a Favorable Prognostic Subgroup.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2612-2612
Author(s):  
Ehab Atallah ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Sherry Pierce ◽  
Elihu Estey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Median Survival ◽  
Who Classification ◽  
Marrow Transplant ◽  
The Other ◽  
Biological Behavior ◽  
Refractory Anemia ◽  
Trisomy 8 ◽  
Female Ratio

Abstract MDS/MPD-U is a newly defined clinical entity in the WHO classification. It includes patients (pts) with features of both myelodysplasia and myeloproliferation that cannot be classified under any other WHO category. In addition it includes the provisional entity RARS-T. Recent reports found an increased incidence of JAK-2 mutation in pts with RARS-T, suggesting possibly a different biological behavior. The clinical outcome of MDS/MPD-U, and in particular RARS-T, pts have not been well described. We reviewed 142 patients in the MD Anderson Leukemia Department patient database with the diagnosis of MDS/MPD or MPD-U seen from September 1987 to July 2006, and identified 32 pts that fulfilled MDS/MPD-U criteria according to WHO classification. The median age was 64 years (range 21–82), with a male: female ratio of 3:1. Six pts had RARS-T (19%). Six pts had a previous malignancy (19%), of which 3 received radiation therapy; no chemotherapy was given. Twenty-five pts (73%) were symptomatic at presentation, including fatigue in 17 (53%), weight loss in 13 (41%), fever in 2 (6%), and night sweats in 7 (22%) pts. Fifteen (45%) pts were transfusion dependent. The median hemoglobin was 9.6 g/dl (range 4.8–15.3), white blood cell count 9x109/L (range 0.6–141), platelets 234x109/L (range 7–1687), and percentage of bone marrow blasts 3% (range 0–16). Fifteen pts (45%) had more than one lineage dysplasia and 22 pts (69%) had increased reticulin in the bone marrow. Cytogenetic analysis revealed diploid cytogenetics in 13, trisomy 8 (either alone or with other abnormalities) in 8, complex cytogenetics in 3, and others in 8 pts. Twenty-two pts were treated with multiple different therapies, including hypomethylating agent in 8, with no sustained responses to any therapy. Six pts received supportive care only and 4 are unknown. Two pts underwent bone marrow transplant; one is in remission for >4 years and the other died from acute graft versus host disease. Median follow up time for alive pts was 10.6 months (range 0.3–147). Median survival of the whole group was 19 months (95% CI; range 8–29). Of the 6 pts with RARS-T, 5 had diploid cytogenetics, two had prior malignancy and 5 were transfusion dependent at the time of diagnosis. Patients with RARS-T had a significantly better survival than the other pts (median survival not reached vs. 12 months; p=0.019; Figure 1). In conclusion, pts with MDS/MPD-U have a poor prognosis with a median survival of one year. However, RARS-T represents a subgroup of pts with better prognosis and long overall survival justifying their separate categorization. Overall Survival Overall Survival

Considering Bone Marrow Blasts from Nonerythroid Cellularity Improves the Prognostic Evaluation of MDS in the Context of IPSS-R and Permits a Better Risk Assessment of MDS Patients Classified into the Intermediate Risk Category

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3185-3185
Author(s):  
Xavier Calvo ◽  
Leonor Arenillas ◽  
Elisa Luño ◽  
Leonor Senent ◽  
Esther Alonso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lower Risk ◽  
Risk Group ◽  
Intermediate Risk ◽  
Leukemic Transformation ◽  
Prognostic Evaluation ◽  
Prognostic Assessment ◽  
Risk Patients ◽  
Very High ◽  
Risk Categories

Abstract Introduction: Proportion of bone marrow (BM) blasts is a major prognostic factor for outcome in patients with myelodysplastic syndromes (MDS) and is included in the most applied prognostic scoring systems: IPSS and IPSS-R. IPSS-R stratifies patients in five risk categories: very low (VL), low (L), intermediate (I), high (H) and very high (VH). Some concerns exist about the real prognostic significance of intermediate risk group, as these patients showed around 30 months of median overall survival (OS) in different studies. The Spanish Group of myelodysplastic syndromes considers as high-risk patients those with an expected median OS inferior to 30 months. As showed in a recent study of our group, considering BM blasts from nonerythroid cellularity improves the prognostic evaluation of MDS (Arenillas et al, J Clin Oncol 2016) when applying IPSS and WHO classification. Aims: 1) To assess OS and leukemia-free survival (LFS) prediction by IPSS-R by counting BM blast percentage from nonerythroid cells (NECs). 2) To evaluate whether considering BM blasts from NECs rather than from total nucleated cells (TNCs) improves the prognostic assessment of patients classified into the intermediate risk group. 3) To establish which of these methods present the best prediction capacity for survival and leukemic transformation. Methods: We retrospectively analyzed 3,924 denovo MDS diagnosed according to WHO 2008 from the MDS spanish registry. Percentage of BM blasts from NECs was calculated as follows: [%BM blasts from TNCs/(100 - %BM erythroblasts) x 100]. Survival curves were constructed by using the Kaplan-Meier (K-M) method and compared using the log-rank test. C-index was implemented to assess the method with the best predictive value for survival and leukemic transformation. Results: Median age at diagnosis was 75y (16-101y) and 59% were males. Estimated median follow-up, as calculated by reverse K-M method, was 46.5 months (95% CI, 43.9-49) and median OS was 56.97 months. We assessed OS predicted by IPSS-R by considering BM blasts from TNCs and from NECs (recoded IPSS-R) Fig 1A and 1B. As depicted, five groups with significant differences in OS were observed by using both methods. Interestingly, median OS of intermediate risk group patients changed from 32.3 to 40.4 months by considering blasts from NECs instead of TNCs, whereas patients classified in high and very high risk categories showed almost the same survival even though the higher-risk categories were increased in 25.7%. Of 3,285 patients, 164 (5%) classified in the lower-risk IPSS-R categories (VL, L, I) were reclassified into higher-risk categories (H, VH) when BM blasts were enumerated from NECs. OS and LFS of these upgraded patients was significantly shorter to those observed in patients who remained in the initial categories (median OS, 28.2 vs 71.7 months, P<0.001; median LFS, 63 vs N.R. months, P<0.001) Fig 2A and 2B. In the same way, 24% of patients classified into the intermediate IPSS-R risk group were reclassified into higher-risk categories and showed a significantly shorter OS and LFS (median OS, 24 vs 34.3 months, P=0.012; median LFS, 56.8 vs 164.7 months, P=0.005). Thus, by counting BM blasts from NECs we were able to detect a group of patients labeled at present as having lower-risk disease but who presented an outcome much closer to that of higher-risk patients. The worse outcome observed in these reclassified patients was mainly influenced by the difference in the weight of blasts when assessed from NECs, as other prognostic factors that could explain this difference in outcome, as cytogenetics and degree of cytopenias, were adjusted by using the IPSS-R. Finally, C-index was calculated at 2 and 5 years and the recoded IPSS-R showed a slightly higher value for the prediction of survival and leukemic transformation [(survival, recoded IPSS-R vs IPSS-R: 2y, 0.731 vs 0.728; 5y, 0.696 vs 0.695) (leukemic transformation, recoded IPSS-R vs IPSS-R: 2y, 0.731 vs 0.730; 5y, 0.719 vs 0.716)]. Conclusions: calculating the percentage of BM blasts from NECs improves prognostic assessment of MDS in the context of IPSS-R. By using this method, a more comprehensive distribution of patients was observed, as patients now included in the intermediate risk group presented an outcome much closer to that expected in lower-risk patients. This approach could help clinicians in risk-adapted therapeutic decisions by allowing a better definition of this controversial group. Figure Figure. Figure Figure. Disclosures No relevant conflicts of interest to declare.

2008 WHO Classification of Pediatric AML.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1044-1044
Author(s):  
Kara L. Davis ◽  
Amy Heerema-McKenney ◽  
Lisa Ma ◽  
Daniel A. Arber ◽  
Gary V Dahl
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Who Classification ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Similar Frequency ◽  
Molecular Features ◽  
Genetic Abnormalities ◽  
Pediatric Aml

Abstract Abstract 1044 Background: Acute myeloid leukemia (AML) represents approximately 15% of cases of childhood leukemia. In children, overall survival rates have improved to 65% but early relapse and poor response to induction therapy are significant reasons for failure. The classification of AML has evolved from the FAB system based on morphology, to the more prognostically useful 2008 WHO Classification based upon morphology, cytogenetics and molecular features (Vardiman JW et al, Blood. 114 p.937 (2009)). As the classification relied heavily on data from adults, the epidemiology and prognostic significance of these categories in children remains to be fully explored. In the current study we review 106 consecutive cases of AML diagnosed between 1993–2010 at Lucile Packard ChildrenÕs Hospital and classify them according to the 2008 WHO AML categories. Methods: A retrospective chart review was performed. Data on karyotype, treatment, remission status or death was recorded. Bone marrow morphology was reviewed for all cases lacking a recurrent genetic abnormality and DNA was recovered from archived bone marrow aspirate smears for PCR analysis of NPM1, CEBPA and FLT-3 ITD. Results: Our cohort consisted of 54 (51%) females and 52 (49%) males. Overall survival at 4 years was 58.3% (Figure 1). The breakdown of subgroups according to the WHO 2008 Classification is outlined in Table 1. Discussion: Our results vary from the adult literature, reflecting the increased prevalence of AML with recurrent genetic abnormalities, with some categories occurring almost exclusively in children, such as t (1;22) and t(9;11). Data from cases without one of the seven recurrent cytogenetic abnormalities shows a similar frequency to that seen other pediatric series (Manola. Euro J Haematol 83 p.391 (2009)). Twelve cases (11%) fall under the diagnosis of AML with myelodysplasia related changes, the majority of which share an MDS-related karyotype. This category was previously considered rare in children. Two cases of AML with mutated NPM1 also met diagnostic criteria for the AML-MRC category, including one with multilineage dysplasia, and one with a history of prior MDS. Cases of AML with variant 11q23 were nearly as common as those with the t(9;11). Cases of biphenotypic leukemia were rare (less than 1%), reflecting the more stringent criteria now utilized. Ten percent of cases are therapy-related AML, three times higher than the adult cohort at Stanford (Weinberg et al. Blood 113 p. 1906(2009)). This highlights a serious issue facing pediatric oncologists and their patients. Conclusions: Our pediatric retrospective cohort highlights that important differences exist between adult and pediatric AML. When compared with adults, recurrent genetic abnormalities are more frequently represented as well as treatment related AML. The data also indicate that morphology with myelodysplastic changes is much more frequent than previously thought. KLD and AHM contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Clinical and Biological Effects of Expression of Dedicator of Cytokinesis 1 (DOCK1) in Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5517-5517
Author(s):  
Sze Hwei Lee ◽  
Wen-Chien Chou
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Lower Risk ◽  
Who Classification ◽  
Clinical Genetic ◽  
Leukemic Transformation ◽  
Expression Levels ◽  
Lower Expression

Abstract Background: DOCK1 is an archetype member of the CDM (CED-5, Dock180, Myoblast city) superfamily of guanine nucleotide exchange factors and functions as an RAC activator. DOCK1 is involved in diverse biological processes including cytoskeleton rearrangement, cell motility and phagocytosis. Expression of DOCK1 is ubiquitous except in hematopoietic cells. Several studies highlighted the functional implications of DOCK1 in migratory and invasive properties of cancer cells, yet the roles of DOCK1 in hematological malignancies are not known. Materials and Methods: In this study, we focused on myelodysplastic syndrome (MDS) according to the diagnostic criteria of 2008 WHO classification, a clinically heterogeneous myeloid cancer whose pathogenesis remains enigmatic. We employed Affymetrix Human Transcriptome Array 2.0 to quantify the global expression patterns of the marrow mononuclear cells (MNC) in 243 newly diagnosed MDS patient recruited in the National Taiwan University Hospital (NTUH). We specifically analyzed the clinical, genetic, and prognostic significance of DOCK1 expression in various stages of MDS. Results: Our data showed that higher expression of DOCK1 conferred an unfavorable prognosis in MDS patients. Increased expression levels of DOCK1 was associated with higher-risk MDS defined by either revised international scoring system (IPSS-R) or WHO classification. Notably, DOCK1 expression levels in lower-risk MDS such as RA, RARS, RCMD, RCMD-RS, in which the marrow blast percentages were not increased, were still significantly higher than normal marrow (Figure 1), implying that the higher DOCK1 expression was independent of blast numbers in the samples, at least in these subgroups of patients. Among the 51 patients documented with leukemic transformation, 36 patients (70.6%) had higher DOCK1 expression compared with 70 out of 168 patients (41.7%) without transformation (P < 0.001). Regarding the genetic alterations, mutations in RUNX1, EZH2, SETBP1, ZRSR2, ASXL1 and TP53 were more frequently seen in the patients with higher DOCK1 expression, whilst SF3B1 mutation showed the contrary pattern. Remarkably, we demonstrated step-wise decreasing DOCK1 expression in the marrow MNC from higher-risk MDS, lower-risk MDS, to normal marrow, suggesting an impact of DOCK1 in pathogenesis in MDS. With a median follow up of 37.4 months, higher expression of DOCK1 was associated with shorter overall survival (OS) (median 13.7 months vs. 69.9 months) and shorter interval to leukemic transformation (median 23.6 months vs. not reached) after a follow up of 20.0 months (both P < 0.001) (Figure 3A and 3B). Independent analysis of DOCK1 expression showed higher level in the very poor cytogenetic subgroup in MDS (P < 0.001). In the multivariate analysis, higher DOCK1 expression proved to be a strong unfavorable prognostic factor for OS and leukemic transformation (P = 0.005 and P = 0.001, respectively) independent of other unfavorable factors including age, karyotype, and mutations of ASXL1, RUNX1, EZH2 and TP53. Conclusion: To our knowledge, our study is the first to show the clinical, genetic, prognostic, and biological association of DOCK1 expression in MDS patients. The step-wise increasing expression levels of DOCK1 in MNC from normal marrow, lower-risk MDS to higher-risk MDS patients highlight the hitherto unappreciated role of DOCK1 in the pathogenesis of MDS. Further studies on large and prospective cohorts are necessary to confirm our observations. Animal studies are needed to elucidate the in vivo roles of DOCK1 in MDS. Figure 1 Boxplots of DOCK1 expression levels in bone marrow MNC according to IPSS-R score Figure 1. Boxplots of DOCK1 expression levels in bone marrow MNC according to IPSS-R score Figure 2 Boxplots of DOCK1 expression levels in bone marrow MNC according to 2008 WHO classification of MDS subgroups Figure 2. Boxplots of DOCK1 expression levels in bone marrow MNC according to 2008 WHO classification of MDS subgroups Figure 3 Overall survival (A) and leukemic transformation (B) of 228 MDS patient with higher expression versus lower expression of DOCK1 Figure 3. Overall survival (A) and leukemic transformation (B) of 228 MDS patient with higher expression versus lower expression of DOCK1 Disclosures No relevant conflicts of interest to declare.

Final Phase I/II Results of Rigosertib (ON 01910.Na) Hematological Effects in Patients with Myelodysplastic Syndrome and Correlation with Overall Survival,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3822-3822 ◽  
Author(s):  
Azra Raza ◽  
Peter L. Greenberg ◽  
Matthew J. Olnes ◽  
Lewis R. Silverman ◽  
Francois Wilhelm
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Who Classification ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Phase Iii ◽  
Refractory Anemia ◽  
Blast Response

Abstract Abstract 3822 Rigosertib is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and blasts, while being non-toxic to normal cells. We analyzed bone marrow (BM) response and overall survival (OS) in 60 patients (pts) with myelodysplastic syndrome (MDS), including 51 patients with refractory anemia and excess blasts (RAEB) and 9 patients with refractory cytopenia and multilineage dysplasia (RCMD) enrolled in 4 independent phase 1/2 clinical trials. These pts were treated with rigosertib administered as a continuous intravenous infusion (CIV) from 2 to 6 days weekly or every other week with BM response initially assessed per protocol by week 4 or 8 and every 8 weeks thereafter. Overall survival (OS) analyses were performed by the method of Kaplan-Meier. OS was related (p=0.04) to FAB/WHO classification (see Table 1) in all MDS pts. Eight pts had hematological improvements. OS was also related to IPSS scoring (p=0.02; Table 2) and to BM blastic response (Table 3; p=0.008) in the 51 RAEB-1,-2,-t pts and in a subset of 38 RAEB-1,-2,-t pts refractory or relapsing after treatment with hypomethylating agents (azacitidine/decitabine) (Table 4; p=0.001). A 49-week OS was found in 15 patients in this last group treated with 3-day rigosertib infusions (1800 mg/day) every other week. Rigosertib infusions were well tolerated without evidence of bone marrow myelotoxicity. These results and the predictive value of BM response to rigosertib for estimating OS survival have led to the initiation of a randomized Phase III survival trial of rigosertib 3-day CIV infusions vs best supportive care in RAEB -1, -2 and-t pts who failed or progressed after receiving hypomethylating agents.Table 1.Overall Survival by FAB/WHO Classification in 60 MDS ptsFAB/WHO ClassificationRCMDRAEB-1RAEB-2RAEB-tP valueN pts9172113Median OS (weeks)988235210.04Table 2.Overall Survival by IPSS Scoring in 51 RAEB-1, -2, -t ptsIPSS ScoringIntermediate-1Intermediate-2High RiskP valueN pts101427Median OS (weeks)Not Reached37280.02Table 3.Overall Survival by BM Blast Response in 51 RAEB-1, -2, -t ptsBM Blast Response≥ 50% Blast DecreaseStable BM ResponseProgressive DiseaseNot AssessedP valueN pts1620510Median OS (weeks)513715110.008Table 4.Overall Survival by BM Blast Response in 38 RAEB-1, -2, -t pts Refractory or Relapsing After Azacitidine/Decitabine TreatmentBM Blast Response≥ 50% Blast DecreaseStable BM ResponseProgressive DiseaseNot AssessedP valueN pts1312310Median OS (weeks)444915100.001 Disclosures: Raza: Onconova Therapeutics Inc: Research Funding. Greenberg:Onconova Therapeutics Inc: Research Funding. Olnes:Onconova Therapeutics Inc: Onconova Therapeutics Inc provided study drug. Silverman:Onconova Therapeutics Inc: Research Funding. Wilhelm:Onconova Therapeutics Inc: Employment, Equity Ownership.

scholarly journals Panobinostat and decitabine prior to donor lymphocyte infusion in allogeneic stem cell transplantation

2020 ◽  
Vol 4 (18) ◽  
pp. 4430-4437
Author(s):  
Burak Kalin ◽  
Yvette van Norden ◽  
Michel van Gelder ◽  
Dimitri Breems ◽  
Johan Maertens ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Donor Lymphocyte Infusion ◽  
Refractory Anemia ◽  
Epigenetic Therapy ◽  
International Prognostic Scoring System ◽  
Hematopoietic Stem ◽  
Poor Risk ◽  
Risk Patients

Abstract Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post–allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.

Marrow Fibrosis in Myelodysplastic Syndromes - Its Significance in the Context of the WHO Classification of Disease and the International Prognostic Scoring System.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1446-1446
Author(s):  
Guntram Buesche ◽  
Arnold Ganser ◽  
Ludwig Wilkens ◽  
Brigitte Schlegelberger ◽  
Hartmut Hecker ◽  
...  
Keyword(s):  
Survival Time ◽  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Who Classification ◽  
World Health ◽  
International Prognostic Scoring System ◽  
Bone Marrow Biopsies ◽  
Health Organization ◽  
Marrow Fibrosis

Abstract Marrow fibrosis (MF) is rarely considered in myelodysplastic syndromes (MDS) although the frequency of this complication ranges from 10 to 50 % in the few reports on this issue, and there are no data on occurrence and significance of this complication in the context of the International Prognostic Scoring System (IPSS) and the World Health Organization (WHO) classification of disease. In a retrospective study, diagnostic bone marrow biopsies from a total of 936 patients with MDS were examined for MF and its relevance to the course of disease. Frequency of MF varied markedly between different types of MDS ranging from 3 % (RARS) to 37 % (MDS, therapy-related; WHO classification, P < 0.000005). Risk of MF furthermore correlated with multilineage dysplasia (P < 0.000005). However, there was no obvious correlation to the IPSS or to karyotype abnormalities. The survival time of patients was significantly reduced by about 50 % from 11 (RAEB-1/-2) - 55 (RARS, RCMD-RS) down to 6 (RAEB-1/-2) - 33 months (RARS, RCMD-RS) in median when MF was detected independently of the IPSS and the classification of disease (FAB, WHO; P = 0.0001). We conclude that MF is an unfavorable complication of MDS significantly shortening the survival time of patients independently of the IPSS and the classification of disease.

Sign in / Sign up

Export Citation Format

Share Document