Prognostic Impact of Monosomy 7 as a Single Anomaly In Primary MDS – Reclassification From Poor to Intermediate Prognosis

Abstract Abstract 1861 Introduction: Total or partial Monosomy 7 (-7/del(7q)) is one of the most frequent cytogenetic abnormalities in MDS, occurring in about 11% of abnormal cases in patients (pts) with primary MDS. The cytogenetic module of the IPSS defines any abnormality of chromosome 7 as unfavourable and classifies them, combined with complex abnormalities, into the poor risk cytogenetic subgroup. However, in previous publications from other groups, the prognosis of isolated -7/del(7q) was described as intermediate. The aim of the present study was to re-analyze the prognostic impact of -7/del(7q) as a single anomaly based on a large, international MDS database which was previously presented at the 2009 ASH-meeting (Schanz et al. abstract #2772). Materials and Method: Patients with -7/del(7q), derived from the international MDS database were examined. The large international data collection contains 2901 patients with MDS, originating from the German-Austrian (GA)-, the International MDS Risk Analysis Workshop (IMRAW)- and the Spanish Cytogenetic Working group (GCECGH) and the International Cytogenetics Working Group of the MDS Foundation (ICWG). Inclusion criteria for the study were defined as follows: Primary MDS, age >=16, and bone marrow blasts <=30%. Regarding therapy, patients with primary MDS who received supportive care, short courses of oral chemotherapy or hemopoietic growth factors were included. Univariate and multivariate analysis were performed for overall survival (OS) and risk of AML-transformation (AML-t). In multivariate analysis, site, age, gender, bone marrow blast count, date of first diagnosis and number of peripheral cytopenias were defined as co-variables. Results: In total, 60 patients (2.1% of all pts/4.4% of abnormal cases) with an isolated -7/del(7q) were detected. The median age of these pts was 66.1 years, which is significantly lower compared to pts without monosomy 7 (70.0 years; p<0.01; t-test, 2-sided). Regarding peripheral blood count, the mean hemoglobin in -7/del(7q) pts (9.2 g/dl) as well as ANC (1.7*103/ul) did not differ significantly as compared to pts without -7/del(7q) whereas the platelet count in pts with -7/del(7q) was significantly lower (82*103/ul vs. 125*103/ul; p<0.01). The median overall survival in -7/del(7q) pts was 16.0 (95% CI 14.0–21.4) months and the Hazard ratio (HR; as compared to a normal karyotype with a median survival of 47.4 (44.0-53.4) months as the reference category) was 1.6 (1.1-2.3; <0.01). Regarding the risk of AML-transformation, the median time to AML was 42.2 (14.4-not reached) months and the HR 1.7 (0.9-3.2; p<0.01). In comparison, this differed significantly from the median survival- (p<0.0001) and time to AML-transformation (p=0.027) for complex abnormalities, which are included with -7/del(7q) in the poor risk IPSS cytogenetic subgroup and were 5.7 (4.7-6.8) and 8.2 (6.4-14.0) months, respectively. The HR for complex abnormalities was 4.3 (3.4-5.4; p<0.01) for OS and 5.2 (3.8-7.5; p<0.01) for AML-transformation. Conclusions: The re-analysis of -7/del(7q), based on the largest MDS patient cohort yet published, confirms that the prognostic impact of an isolated total or partial monosomy 7 for overall survival as well as the risk of AML-transformation is intermediate, rather than poor. This finding is anticipated to be considered in the upcoming revision of the IPSS. Acknowledgments: The authors like to thank the MDS-Foundation for its support. Disclosures: Valent: Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Bennett:Johnson & Johnson: Consultancy.

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Multivariate Analysis of the Impact of Pre-Treatment Serum Ferritin Level On Response and Overall Survival in Patients with Myelodysplastic Syndromes Treated with Azacitidine

Blood ◽

10.1182/blood.v120.21.1710.1710 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1710-1710 ◽

Cited By ~ 1

Author(s):

Regina Garcia Delgado ◽

Dunia de Miguel ◽

Alicia Bailen ◽

José Ramón Gonzalez ◽

Joan Bargay ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Research Funding ◽

Complete Response ◽

The Other ◽

Prognostic Impact ◽

Transfusion Dependency ◽

Baseline Characteristics ◽

Pre Treatment ◽

The Impact

Abstract Abstract 1710 Introduction: Red blood cell (RBC) transfusion dependency independently predicted inferior overall survival (OS) (Itzykson R, et al. Blood. 2011;117:403-11). Transfusion dependency appears to have a major negative prognostic impact in patients with myelodysplastic syndromes (MDS) (Malcovati L, et al. J Clin Oncol. 2005;23:7594-603). The independent prognostic value of development of iron overload on OS and acute myeloid leukemia (AML) risk in MDS has been demonstrated (Sanz G, et al. Blood. 2008;112:abstract 640). Serum ferritin (SF) concentration predicts morbidity and mortality after hematopoietic cell transplantation (Sorror ML, et al. Blood. 2009;114:abstract 651). The prognostic impact of SF on overall response (OR) and OS in patients with MDS treated with azacitidine (AZA) remains unknown. Aim: To analyze the impact of pre-treatment SF levels on response and OS in patients with World Health Organization-defined MDS or AML with 20–30% bone marrow (BM) blasts who received AZA through a compassionate-use program in Spain. Methods: We report a retrospective multivariate analysis of the impact of SF level on OR and OS in patients treated with AZA. Hematologic response was assessed according to International Working Group 2003 (AML) and 2006 (MDS) criteria. SF levels were selected based on median SF value, dividing in two the first half for a better discrimination of the effect (< 500 ng/mL, 500–1000 ng/mL, and > 1000 ng/mL). Comparison of baseline characteristics between SF level groups was performed using Chi-Squared, Fisher's exact, or Likelihood Ratio Chi-Square test for qualitative variables; and analysis of variance, Mann-Whitney and Wilcoxon, or Kruskal-Wallis test for quantitative variables. A logistic regression model was used to evaluate the effect of pre-treatment variables (ie, SF levels, sex, age, French-American-British classification, BM blast count, time since diagnosis, hemoglobin [Hb] level, International Prognostic Scoring System [IPSS] risk, and thrombocytopenia) on best OR (marrow complete response [mCR] + complete response [CR] + partial response [PR] + hematologic improvement [HI]). A Cox proportional hazards model was used to evaluate the effect of the mentioned variables on OS. All analyses were done using SAS System® version 9.2. Results: Of 240 patients enrolled, pre-AZA SF levels were available for 190 patients. The median pre-treatment SF level was 1001 ng/mL (range 21–5548). Baseline characteristics according to SF levels (< 500 ng/mL [n = 49], 500–1000 ng/mL [n = 46], and > 1000 ng/mL [n = 95]) are summarized in Table 1. OR rates were higher and OS was increased in patients with pre-AZA SF levels of ≤ 1000 ng/mL (Table 2 and Fig). In multivariate analysis, pre-treatment SF levels were predictive of best OR (P = 0.0001). Patients with SF levels > 1000 ng/mL had a reduced likelihood of OR (P < 0.0001 vs SF levels < 500 ng/mL). Baseline SF levels were also predictive of OS (P = 0.0002); patients with SF levels > 1000 ng/mL had the lowest likelihood of OS (P = 0.0012 vs SF < 500 ng/mL; and P = 0.0023 vs SF 500–1000 ng/mL). None of the other variables analyzed had a significant impact on OR or OS. Conclusion: Patients with pre-AZA SF levels > 1000 ng/mL had lower OR rates and inferior OS compared with patients with SF levels ≤ 1000 ng/mL. None of the other patient baseline characteristics analyzed had an impact on these outcomes. Our results suggest that higher OR rates and increased OS are obtained with AZA treatment in MDS patients with SF levels ≤ 1000 ng/mL, compared with patients with SF levels > 1000 ng/mL. This may advocate for early initiation of therapy before increasing SF level; however, prospective controlled clinical trials are needed to confirm this hypothesis. Acknowledgments: Regina Garcia Delgado, Dunia de Miguel, Alicia Bailen, José Ramón González, Joan Bargay, Jose F. Falantes, Rafael Andreu, Fernando Ramos, Mar Tormo, Rafael F. Duarte, Ma José Jiménez Lorenzo, Salut Brunet, Benet Nomdedeu, Antonio Figueredo, Javier Casaño, Llorenç Badiella, and Antonio Fernández Jurado submitted this abstract on behalf of the Asociación Andaluza de Hematología y Hemoterapia, Spain. Disclosures: Garcia Delgado: Celgene Corporation: Research Funding. de Miguel:Celgene Corporation: Speakers Bureau. Bargay:Celgene Corporation: Research Funding. Ramos:Celgene Corporation: Speakers Bureau. Sanz:Celgene Corporation: Speakers Bureau.

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Prognostic Impact of Bone Marrow Fibrosis in Primary Myelofibrosis: A Study of Agimm Group on 540 Patients

Blood ◽

10.1182/blood.v126.23.351.351 ◽

2015 ◽

Vol 126 (23) ◽

pp. 351-351 ◽

Cited By ~ 1

Author(s):

Paola Guglielmelli ◽

Giada Rotunno ◽

Annalisa Pacilli ◽

Elisa Rumi ◽

Vittorio Rosti ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Primary Myelofibrosis ◽

Driver Mutations ◽

Prognostic Impact ◽

Advisory Committees ◽

The Impact

Abstract Background. The prognostic significance of bone marrow (BM) fibrosis grade in pts with primary myelofibrosis (PMF) is debated. A fibrosis grade greater than 1 was associated with a 2-fold higher risk of death compared with pts with early/prefibrotic MF (grade 0) [Thiele J, Ann Hematol 2006]. Recent data suggest that more accurate prediction of survival is achieved when fibrosis grade is added to IPSS [Verner C, Blood 2008; Giannelli U, Mod Pathol 2012]. Aim. To analyze the prognostic impact of fibrosis in diagnostic BM samples of 540 WHO-2008 diagnosed PMF pts with extensive clinical and molecular information collected in 6 Italian centers belonging to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). Methods. The clinical variables assessed were those previously identified as prognostically relevant in the IPSS score. Published methods were used to screen mutations of JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. European consensus scoring system was used to grade fibrosis (on a scale of MF-0 to MF-3). The prognostic value of fibrosis with regard to overall survival (OS) was estimated by Kaplan-Meier method and Cox regression. Results. Pts' median age was 61y; median follow-up 3.7y; median OS 10.5y; 184 pts (34.1%) died. IPSS risk category: low 33.7%, Int-1 27.7%, Int-2 19.1%, High-risk 19.5%. Mutational rate: JAK2 V617F 62.6%, CALR 20.7% (type-1/1-like 77.7%, type2/2-like-2 21.4%), MPL W515 5.9%; 62 (11.5%) were triple negative (TN). 171 pts (31.7%) were High-Molecular Risk (HMR) category (Vannucchi AM, Leukemia 2013); mutation rate: EZH2 7.2%, ASXL1 22.2%, IDH1-2 2.4%, SRSF2 8.3%. According to fibrosis grading, 50 pts were MF-0 (9.3%), 180 MF-1 (33.3%), 196 MF-2 (36.3%), 114 MF-3 (21.1%). Compared with both MF-0 and MF-1, MF-2 and MF-3 pts presented more frequently constitutional symptoms (P<.0001), larger splenomegaly (P<.0001), greater risk of developing anemia (P<.0001) or thrombocytopenia (P=.003). We found a significant association (P<.0001) between IPSS higher/Int-2 risk categories and MF-2 and -3 (20.5% and 37.8%, respectively, vs 14.8% and 6.0% for MF-0 and -1). There was no correlation between fibrosis grade and phenotypic driver mutations; in particular, TN pts were equally distributed among MF fibrosis grades (10%, 10.6%, 14.3% and 8.8% from MF-0 to -3, respectively). Conversely, the frequency of HMR pts increased progressively according to fibrosis grade: 8 pts MF-0 (16%), 46 MF-1 (25.6%), 66 MF-2 (33.7%) and 51 MF-3 (44.7%) (P<.0001). In particular, we found a significant association between fibrosis grade and ASXL1 (12%, 15%, 23.5% and 36% from MF-0 to -3; P<.0001) and EZH2 (2%, 3.9%, 8.2%, 13.2%; P=.01) mutations. Also, pts with 2 or more HMR mutated genes were preferentially MF-2 or -3 ( 0%, 4.4% 10.2% and 10.5% from MF-0 to -3; P=.001). Median OS was significantly shorter in pts with MF-2 (OS 6.7y, HR 7.3, IC95% 2.7-20.0; P<.0001) and MF-3 (OS 7.2y, HR 8.7, IC95% 3.1-24.2; P<.0001) compared with MF-1 (14.7y; HR 3.9, IC95% 1.4-10.9, P=.008) and MF-0 (P<.0001) used as reference group (OS not reached) (Figure). Excluding MF-0, MF-2 and -3 maintained negative prognostic impact with HR 1.9 (1.3-2.6; P=.001) and 2.2 (1.5-3.3; P<.0001) respectively vs MF-1. The impact of fibrosis on OS was maintained when analysis was restricted to younger (≤65y) pts. In multivariate analysis using the individual IPSS variables, grade MF-2 and -3 were independently predictive of survival (HR 3.9 (1.4-10.8), and HR 4.2 (1.5-12.0), respectively, P=.008 for both). The negative impact on survival of MF-2/-3 was maintained regardless of IPSS category, HMR status, number of HMR mutated genes and driver mutations, included as covariates (Table). In low, Int-1 and Int-2, but not high-risk IPSS categories, MF-2/-3 associated with reduced survival (P<.03). Conclusions. Overall, these results indicate that higher grades (MF-2 and MF-3) of fibrosis correlate with defined clinical and molecular variables and independently negatively impact on OS in PMF, suggesting the opportunity to explore its value in the setting of clinical and molecular prognostic scores for PMF. Table. Multivariate Analysis Variables HR 95% CI P value HMR status 2.4 1.5-3.7 <.0001 HMR≥2mutations 4.3 2.8-6.4 .009 IPSS scoring Int1 2.9 1.6-5.1 <.0001 Int2 10.0 5.6-17.7 <.0001 High 9.7 5.5-17.2 <.0001 Driver mutations CALR type2 3.4 1.3-8.6 .010 JAK2/MPL 2.4 1.4-4.3 .003 TN 4.5 2.3-8.8 <.0001 Fibrosis MF-2/MF-3 3.8 1.4-10.6 .010 Figure 1. Figure 1. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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The 2016 Revised World Health Organization Classification of 'Myelodysplastic Syndrome with Isolated Del(5q)'; Prognostic Implications of Single Versus Double Cytogenetic Abnormalities

Blood ◽

10.1182/blood.v128.22.5542.5542 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5542-5542

Author(s):

Mark Gurney ◽

Mrinal M Patnaik ◽

Curtis A. Hanson ◽

Mark R. Litzow ◽

Aref Al-Kali ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Research Funding ◽

Cytogenetic Abnormality ◽

World Health ◽

Monosomy 7 ◽

Cytogenetic Abnormalities ◽

Who Criteria ◽

Significant Difference ◽

Health Organization

Abstract Background: 'Myelodysplastic syndrome (MDS) with isolated del(5q),' as defined by the World Health Organization (WHO) criteria (SwederlowSH, et al, 2008) is a unique pathological entity with favorable outcomes. The 2016 revision to the classification expands this entity to include cases that have an additional cytogenetic abnormality, with the exception of monosomy 7 or del(7q) (Arber DA, et al, Blood 2016). The objective of our study was to evaluate the prognostic impact of an additional cytogenetic abnormality, other than monosomy 7 or del(7q), in patients with 'MDS with isolated del(5q)'. Methods: After due IRB approval, the Mayo Clinic MDS database (n=1067) was utilized for this study. All patients had bone marrow (BM) biopsies and cytogenetic studies performed at diagnosis. The International Society for Cytogenetic Nomenclature guidelines were used for cytogenetic nomenclature, while the 2008 and 2016 WHO criteria were used for morphological diagnosis. Results: Patient Characteristics: 72 patients (7.2%) met the 2016 WHO criteria for 'MDS with isolated del(5q)' of which 60% were female and median age was 74 years (28-90). In 61 (85%) cases del(5q) was the only cytogenetic abnormality, while in 11 (15%), del(5q) was present with an 'additional cytogenetic abnormality' (ACA). One additional case within the database had del(5q) accompanied with monosomy 7, which was not included in the analysis. Risk stratification by IPSS-R was as follows; 24 (29%) 'very low', 44 (64%) 'low' and 4 (6%) 'Intermediate' risk, with no patient classified as 'high' or 'very high' risk. At a median follow up of 43 months, 55 (76%) deaths and 5 (7%) leukemic transformations were documented. del(5q) versus del(5q) with an additional cytogenetic abnormality- phenotypic correlates: In the 'del(5q) with ACA' group, the additional abnormalities included trisomy 8 (n=4), del(20q) (n=3), der(9;18) (n=1), inv(3)(p25,q21)(n=1), -Y (n=1), and i(Xp) (n=1) (Table 1). There was no significant difference between the 'del(5q)' and 'del(5q) with ACA' groups in terms of age, gender, hemoglobin, platelet count, white cell count, absolute neutrophil count, bone marrow blast percentage or transfusion requirement. A greater proportion of the 'del(5q) with ACA' group (27%) had IPSS-R risk in the 'intermediate' category compared to the 'del(5q)' group (2%) (p=0.01). 18 of 42 cases diagnosed after 2004 (43%) were treated with lenalidomide, with no difference in the proportions treated between the two groups (p=1.00). del(5q) versus del(5q) with an additional cytogenetic abnormality- impact on overall survival (OS) and leukemia-free survival (LFS): The median survival of the cohort was 54 months. Survival was not significantly different between the 'del(5q)' group (median 55 months) and the 'del(5q) with ACA' group (median 38 months) (p=.75, Figure 1). This finding was consistent when analysis was restricted to patients in both groups treated with lenalidomide (p=0.29). The incidence of leukemic transformation in the del(5q) group was 5%, compared with 18% for the 'del(5q) with ACA' group (p=0.16), however there was no significant difference in LFS between the two groups (p=0.57). Conclusion : In our cohort of primary MDS patients meeting the 2016 WHO definition of 'MDS with isolated del(5q)', we confirm no significant survival difference between cases with del(5q) as the sole cytogenetic abnormality versus cases where del(5q) was accompanied by an additional cytogenetic abnormality. Table 1 Additional Cytogenetic Abnormalities with del(5q): Table 1. Additional Cytogenetic Abnormalities with del(5q): Figure 1 del(5q) vs del(5q) with an additional abnormality (ACA): Overall Survival Figure 1. del(5q) vs del(5q) with an additional abnormality (ACA): Overall Survival Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

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Cytogenetic Risk Features in MDS-Update and Present State.

Blood ◽

10.1182/blood.v114.22.2772.2772 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2772-2772 ◽

Cited By ~ 2

Author(s):

Julie Schanz ◽

Heinz Tuechler ◽

Francesc Solé ◽

Mar Mallo ◽

Barbara Hildebrandt ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Survival Data ◽

Working Group ◽

Scoring System ◽

Conflicts Of Interest ◽

Observation Time ◽

Prognostic Impact ◽

Inclusion Criteria ◽

Data Set

Abstract Abstract 2772 Poster Board II-748 Introduction: The IPSS-Score, published by Greenberg et al. (1997), defines the gold standard in risk stratification of patients with MDS. Since its implementation in 1997 based on 816 patients with primary MDS, the knowledge concerning the prognostic impact of distinct abnormalities increased extensively. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 3803 patients, originating from the German-Austrian (GA)-, the International Risk analysis workshop (IMRAW)- and the Spanish Cytogenetics working group (GCECGH). Additionally, 53 cases of rare abnormalities were contributed by the International Cytogenetics Working Group of the MDS Foundation (ICWG), resulting in total number of 3856 pts. As compared to our previous reports, the data set was substantially enlarged by adding the GCECGH cases and data quality was improved by updating the clinical and survival data; allowing the analysis of the prognostic impact for isolated abnormalities exclusively to assure a maximum accurateness. Furthermore, multivariate analysis was refined by including peripheral cytopenias. Materials and Methods: Inclusion criteria were defined as follows: Primary MDS, age >=16, and bone marrow blasts <=30%. Regarding therapy, exclusively patients with primary MDS and supportive care, only allowing short courses of oral chemotherapy or hemopoietic growth factors were included. Based on these criteria, 958 pts. were excluded resulting in 2901 pts. available for final analysis. Univariate and multivariate analysis concerning overall survival (OS) and 25% AML-transformation (AML-t) was performed. In multivariate analysis, age, gender, bone marrow blast count and number of peripheral cytopenias were defined as co-variables. OS and AML-t in distinct cytogenetic abnormalities was only calculated when the abnormality occurred as an isolated aberration with a minimal frequency of n=10. Median observation time was 19.0 months. Clinical follow-up was performed until April 2009. Results: In total, 20 cytogenetic subgroups matching the inclusion criteria were detected. Abnormalities were grouped as normal (n=1522, 52.5% of all cases), single (1 abnormality), double (2 abnormalities) or complex (>=3 abnormalities). Single abnormalities found were: del(5q) (176, 6.1%); -7/7q- (59, 2.0%); +8 (130, 4.5%); del(20q) (48, 1.7%), -Y (46, 2.1%); der(1;7)(q10;p10)/t(1;7)(var;var) (10, 0.3%); der(3)(q21)/der(3)(q26) (10, 0.3%); del(11q) (19, 0.7%); del(12p) (17, 0.6%); i(17)(q10) (11, 0.4%); +19 (10, 0.3%), +21 (10, 0.3%) and any other single (150, 5.2%). Double abnormalities were stratified into 3 subgroups: double including del(5q) (45, 1.6%); double including -7/7q- (31; 1.1%) and any other double (98, 3.4%). As reported (Haase et al. Blood 2008), complex karyotypes were sub-divided into 2 groups: Karyotypes with 3 abnormalities (59, 2.0%) vs. >3 abnormalities (188, 6.5%). Finally, 20 pts. (0.7%) displayed cytogenetically unrelated clones. According to OS and AML-t, abnormalities were classified to 4 prognostic subgroups: good (normal, del(5q), double incl. del(5q), der(1;7)(q10;p10)/t(1;7)(var;var), del(11q), del(12p), +19, del(20q), -Y); int-1 (any other double, +8, i(17)(q10), +21, any other single, independent clones); int-2 (double incl. -7/7q-, der(3)(q21)/der(3)(q26), -7/7q-, complex 3 abnormalities) and poor (complex >3 abnormalities). Median survival was 50.6 months for good (n=1936), 25.7 months for int-1 (n=451), 16.0 months for int-2 (n=177) and 5.7 months for poor (n=188) and AML-t was 71.9 months for good (n=1681), 14.7 months for int-1 (n=384), 9.8 months for int-2 (n=148) and 3.4 months for poor (n=159). Differences in OS and AML-t were highly significant (p<0.0001). Multivariate analysis resulted in a Hazard Ratio of 1.0 for good (reference category), 1.8 for int-1, 2.1 for int-2 and 4.8 for poor concerning OS. Regarding AML-t, HR was 1.0 for good, 2.6 for int-1, 3.1 for int-2 and 5.2 for poor (all p <0.0001 for OS and AML-t). Conclusions: In summary, we were able to generate a solid database for a revised cytogenetic scoring system, which can serve as the cytogenetic model for the upcoming revision of the IPSS. Acknowledgments: The authors like to thank the MDS-Foundation for its support. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Impact of Additional Chromosomal Aberrations (ACA) to 5q- in Patients with primary Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v112.11.1649.1649 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1649-1649

Author(s):

Maria del Mar Mallo ◽

José Cervera ◽

Julie Schanz ◽

Blanca Espinet ◽

Esperanza Such ◽

...

Keyword(s):

Median Survival ◽

Chromosomal Abnormality ◽

Working Group ◽

Chromosomal Abnormalities ◽

Trisomy 13 ◽

Chromosome 17 ◽

Study Group ◽

Prognostic Impact ◽

Monosomy 7 ◽

Group B

Abstract Deletion of the long arm of chromosome 5 is the most frequent chromosomal abnormality in MDS (10–15% of MDS cases). Patients with del(5q), particularly those with the ‘5q-syndrome’ have a much better prognosis than other MDS subtypes. Although the presence of additional chromosome abnormalities (ACA), apart from 5q-, has been suggested to negatively influence this favourable outcome, the exact prognostic impact of ACA remains unknown. The aim of the present study was to analyse the prognostic value of ACA in a large series of patients with MDS with 5q- abnormality, treated with supportive care. Three-hundred and five MDS patients with del(5q) were selected from a 3128 cases database that included 1004 patients from the Spanish Haematological Cytogenetics Working Group (GCECGH) (Solé et al., 2005) and 2124 patients from the German-Austrian MDS Study Group (Haase et al., 2007). Patients were separated into two groups: group A (n=204), all del(5q) cases as a single anomaly and group B (n=101) with additional cytogenetic anomalies. Patients in Group B were subdivided according to: the number of additional anomalies (1 to 3 5 anomalies); and the type of additional cytogenetic aberrations: chromosomes 1 and 3, monosomy 7, 7q-, trisomy 8, trisomy 11, trisomy 13, 12p-, involvement of chromosome 17, -18/18q-, 20q-, trisomy 21, loss of X/Y chromosome, and unrelated clones. The series includes 90 males (29.5%) and 215 females (70.5%) with a median age of 66 years (range: 3–92 yr). Using FAB criteria (n=294): 52% had RA, 9% RARS, 30% RAEB, 8% RAEB-t and 1% CMML. WHO classification was available for 217 patients: 52% had ‘5q- syndrome’, 1% RA, 0% RARS, 2% RCMD, 2% RSCMD, 13% RAEB-1, 20% RAEB-2, 1% CMML, 8% AML and 1% were unclassifiable. Overall, 204 (67%) of the patients presented 5q- isolated, 52 (17%) 5q- with one additional abnormality, 10 (3%), 6 (2%), 7 (2%) and 26 (9%) with 2, 3, 4 and 5 or more additional abnormalities, respectively. Follow-up data were available for 273 patients (89.5%). Median survival was 48 months for all. Median survival for patients with isolated del(5q), with one additional abnormality and with two or more additional abnormalities (complex karyotypes) was 69, 55 and 8 months, respectively (P<0.0001). However, no statistical differences were found between patients with isolated del(5q) and patients with only one additional abnormality (P=0.35). Complex karyotypes showed a very adverse outcome. None of the single additional anomalies analysed showed a particular better or worse prognosis. Preliminary results of a multivariate analysis (n=76) showed a highest predictive survival time value for cytogenetics complexity followed by the number of cytopenias and the age. In conclusion, patients with 5q- associated with two or more additional chromosomal abnormalities have a significantly worse overall survival than patients with isolated 5q- or with only one additional anomaly. Our results do not support the exclusion of patients with one single additional chromosomal abnormality and typical bone marrow features from the ‘5q- syndrome’ WHO category. This work is presented on behalf of the Grupo Cooperativo Español de Citogenética Hematológica (GCECGH), German-Austrian MDS Study Group (GASMSG), International Working Group on MDS Cytogenetics of the MDS Foundation.

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Increased Bone Marrow Iron at Diagnosis Is Associated with Inferior Prognosis in Patients with Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-152402 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3700-3700

Author(s):

Annika Kasprzak ◽

Sandra Becker ◽

Martina Rudelius ◽

Corinna Strupp ◽

Kathrin Nachtkamp ◽

...

Keyword(s):

Bone Marrow ◽

Iron Overload ◽

Median Survival ◽

Myelodysplastic Syndromes ◽

Iron Uptake ◽

Research Funding ◽

Blue Staining ◽

Prognostic Impact ◽

Iron Stores ◽

Bone Marrow Iron

Abstract Introduction: Iron storage in patients (pts) with myelodysplastic syndromes at the time of diagnosis may vary from normal to iron overload. Even before the first blood transfusion, storage iron can be increased due to down-regulation of hepcidin and subsequent increase in duodenal iron uptake. Iron overload is known to worsen the prognosis of MDS patients, partly due to iron-related organ damage after long-term transfusion therapy, and partly due to an increased risk of infections. However, it is unclear whether increased storage iron at the time of diagnosis already has a prognostic influence. We assessed bone marrow iron stores at the time of MDS diagnosis and correlated them with clinical outcome. Methods: In a retrospective analysis of 3762 adult MDS patients from the Düsseldorf MDS Registry, Prussian blue staining of marrow smears was performed in our cytology lab to assess iron stores according to the following categories: normal or decreased iron stores versus increased iron stores versus iron overload. Patients were followed up for survival and AML evolution until June 2021. Median time of follow-up was 20 months. 67.4% of the patients died during the course of the disease. Results: The study included 3.762 adult patients who received their initial diagnosis of MDS between 1970 and 2021. 58% were diagnosed as non-blastic MDS ( MDS SLD (RS) (n=240), MDS MLD (RS) (n=350), MDSdel(5q) (n=107), and MDS-U (n=25). Iron stores were decreased in 8% of the patients, normal in 44%, increased in 41%, and strongly increased in 7% (massive iron overload). In 282 cases, histologic assessment of storage iron was available. When comparing cytologic and histologic assessment, we found a strong correlation (p<0.0005), since 87% of the patients with increased iron on cytomorphology also showed increased iron as assessed by histopathology. However, 37% of the patients who cytologically showed normal iron stores, were reported to have slightly increased iron as assessed by histopathology. Median and mean serum ferritin values of patients with normal or decreased iron stores were 295 and 629 µg/l, respectively, as compared to 548 and 902 µg/l, respectively, in patients with increased iron stores. The cumulative risk of AML evolution was not associated with the results of iron staining. Regarding survival, we found that patients with decreased or normal storage iron had a median survival of 31 months, whereas those with increased iron had a median survival of 28 months (p=0.007). Focusing on patients with non-blastic MDS, the difference was not significant (46 vs 44 ms). However, patients who presented as EB I (n=435), EBII (n=510), AML MRC (n=264), CMML I (n=254), or CMML II (n=77), showed a prognostic impact of storage iron; patients with increased iron had a median survival of 11 months, as compared to 16 months in patients with normal or decreased iron (p<0.0005). Conclusion: Increased tissue iron in the bone marrow at the time of diagnosis is associated with inferior survival in patients with MDS, primarily in patients with higher risk MDS. At diagnosis, patients are not yet transfusion-dependent. This suggests that increased iron reflects a prolonged period of increased duodenal iron uptake as a consequence of ineffective erythropoiesis. Therefore, increased marrow iron at the time of MDS diagnosis seems to be a surrogate parameter of hematopoietic insufficiency, which is the real cause of inferior prognosis. Disclosures Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Gattermann: Novartis: Honoraria; Takeda: Research Funding; Celgene: Honoraria. Germing: Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding.

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SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia

Blood ◽

10.1182/blood-2009-06-227363 ◽

2010 ◽

Vol 115 (3) ◽

pp. 615-625 ◽

Cited By ~ 100

Author(s):

Ion Cristóbal ◽

Francisco J. Blanco ◽

Laura Garcia-Orti ◽

Nerea Marcotegui ◽

Carmen Vicente ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Genetic Alterations ◽

Leukemic Cells ◽

Prognostic Impact ◽

Hematopoietic Stem ◽

Monosomy 7 ◽

Protease Cleavage ◽

Prognostic Group ◽

Acute Myeloid

Abstract Acute myeloid leukemias (AMLs) result from multiple genetic alterations in hematopoietic stem cells. We describe a novel t(12;18)(p13;q12) involving ETV6 in a patient with AML. The translocation resulted in overexpression of SETBP1 (18q12), located close to the breakpoint. Overexpression of SETBP1 through retroviral insertion has been reported to confer growth advantage in hematopoietic progenitor cells. We show that SETBP1 overexpression protects SET from protease cleavage, increasing the amount of full-length SET protein and leading to the formation of a SETBP1–SET-PP2A complex that results in PP2A inhibition, promoting proliferation of the leukemic cells. The prevalence of SETBP1 overexpression in AML at diagnosis (n = 192) was 27.6% and was associated with unfavorable cytogenetic prognostic group, monosomy 7, and EVI1 overexpression (P < .01). Patients with SETBP1 overexpression had a significantly shorter overall survival, and the prognosis impact was remarkably poor in patients older than 60 years in both overall survival (P = .015) and event-free survival (P = .015). In summary, our data show a novel leukemogenic mechanism through SETBP1 overexpression; moreover, multivariate analysis confirms the negative prognostic impact of SETBP1 overexpression in AML, especially in elderly patients, where it could be used as a predictive factor in any future clinical trials with PP2A activators.

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31. RADIATION NECROSIS IN STEREOTACTIC RADIOSURGERY AND CHECKPOINTS INHIBITORS FOR BRAIN METASTASES FROM LUNG ADENOCARCINOMA

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa073.019 ◽

2020 ◽

Vol 2 (Supplement_2) ◽

pp. ii5-ii5

Author(s):

James Jurica ◽

Shraddha Dalwadi ◽

David Baskin ◽

Eric Bernicker ◽

Brian Butler ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Brain Metastases ◽

Lung Adenocarcinoma ◽

Stereotactic Radiosurgery ◽

Median Survival ◽

Radiation Necrosis ◽

Concomitant Treatment ◽

Prognostic Assessment ◽

Graded Prognostic Assessment

Abstract PURPOSE Treatment with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) is increasingly common for brain metastases (BM) from lung adenocarcinoma. Rates of radiation necrosis (RN) with SRS in the setting of ICIs is an ongoing area of research. We investigated rates of RN in patients with BM from lung adenocarcinoma treated with SRS with or without concurrent ICIs. METHODS We identified 39 patients at a single institution who underwent SRS treatment for BM from lung adenocarcinoma. Of these, 19 (49%) received SRS without ICIs and 20 (51%) patients received ICIs within a month of SRS. The rate of RN, defined by MRI features and histology when available, was compared between each group using multivariate analysis. Kaplan Meier survival estimates were calculated based on overall survival and compared to median survival predicted by the graded prognostic assessment. RESULTS Overall survival for all patients from diagnosis of brain metastases was 16.6 months (range 3.6–45.9) and median survival predicted by the graded prognostic assessment was 13.7 months (range 6.9–26.5). In total 11 (28%) patients developed MRI and/or histologic evidence for RN during the follow-up period; 5 of 20 (25%) from the SRS with ICI group and 6 of 19 (31%) from the SRS without ICI group. In multivariate analysis, ICI treatment had no significant impact on rates of RN between groups (OR 0.72 [95% CI: 0.17–2.93]; p=0.65) while bevacizumab treatment was associated with a decreased RN risk (OR 0.88 [95% CI: 0.43–0.99]; p=0.02). CONCLUSION Retrospective analysis of patients with BM from lung adenocarcinoma treated with SRS suggested that administration of ICIs does not increase risk for development of RN. Further, concomitant treatment with bevacizumab may decrease risk of RN. These findings suggest that patients with BM from lung adenocarcinoma can be treated with combination therapy without increased risk of neurologic toxicity.

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Acute Myeloid Leukemia (AML) Treated with Azacitidine: Survival Outcomes for Patients Who Complete More Than Six Cycles Are Similar to High-Risk Myelodysplastic Syndrome/Low Blast Count AML

Blood ◽

10.1182/blood-2019-122122 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5156-5156

Author(s):

Jill Fulcher ◽

Zahra Abdrabalamir Alshammasi ◽

Nathan Cantor ◽

Christopher Bredeson ◽

Grace Christou ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Median Survival ◽

Research Funding ◽

Survival Outcomes ◽

Advisory Committees ◽

Ottawa Hospital ◽

Funding Agencies ◽

Progression Of Disease ◽

Refractory Aml

INTRODUCTION: Despite accumulating evidence supporting the efficacy of hypomethylating agents in patients with AML and > 30% bone marrow blasts as well as in relapsed/refractory AML, this therapy is not yet funded by National Health Plans / Healthcare Funding Agencies in a number of countries including Canada. The assistance of an industry-sponsored compassionate program has enabled provision of azacitidine for this group of patients at The Ottawa Hospital. We report here our local "real-world" experience of azacitidine efficacy in this diverse group of AML patients and identify a sub-group whose outcomes are equivalent to that of patients with higher-risk Myelodysplastic Syndrome (MDS) and AML with 20-30% blasts for whom azacitidine therapy has funding approval in Canada. METHODS: All patients who received azacitidine at The Ottawa Hospital between 2009 and 2016 were included in this single-center, retrospective analysis. Azacitidine was administered at a dose of 75mg/m2 subcutaneously daily for 7 consecutive days every 28 days. Response was evaluated with a repeat bone marrow aspirate and trephine biopsy after the 6th cycle. In those patients confirmed to have stable or responsive disease, azacitidine was continued until progression of disease, intolerable side-effects of the drug or the patient chose to discontinue therapy. Overall survival curves were generated using the Kaplan-Meier method and log-rank tests were used to compare subgroups of patients. Actuarial median survival months were calculated with 95% confidence intervals (CI). P-values less than 0.05 were considered statistically significant. RESULTS: During the study period, 109 patients received azacitidine: 54 had MDS /AML with 20-30% blasts (the 'funded' group) and 55 had either AML with > 30 % blasts (n=23), AML relapsed post-intensive chemotherapy (n=14), AML relapsed post-allogeneic stem cell transplant (n=10) or primary refractory AML (n=8) (the 'unfunded' group). Median survival of the 'funded' group was 12.2 months while median survival of the 'unfunded' group was 5.6 months (95% CI 3.3-7.7; p=0.0058). Of the AML patients in the 'unfunded' group, 24% completed more than 6 cycles of azacitidine compared to 52% of patients in the 'funded' group. In both the 'funded' and 'unfunded' groups, patients who completed more than 6 cycles of azacitidine had similar survival outcomes (p=0.7277): the 'funded' group had a median survival of 19 months (95% CI 14.4-25.3) while the median survival of this sub-population of the 'unfunded' AML group was 22 months (95% CI 11.7-24.9). Patients in both groups who failed to complete more than 6 cycles of azacitidine also had a similar outcome (p=0.39), with a median survival of 5.7 months (95% CI 4.0-6.3) for patients with MDS/AML 20-30% blasts and 3.6 months (95% CI 2.2-5.1) for AML patients with > 30% blasts or relapsed/refractory disease. Reasons for patients not completing at least 6 cycles of azacitidine included progression of disease (25%), bacterial infections most commonly pneumonia (53%) and patient preference (7%). CONCLUSION: A significant sub-population of AML patients with > 30% blasts or refractory/relapsed AML can achieve a meaningful survival benefit with the hypomethylating agent, azacitidine. A higher proportion of this AML patient population discontinued azacitidine as a result of infective complications. The provision of routine prophylactic antibiotics may enable more patients with AML to receive an adequate amount of azacitidine to achieve therapeutic benefit and warrants further investigation. Our results add to the growing body of 'real-world' evidence that supports healthcare funding agencies to provide coverage of azacitidine for patients with AML who in some countries at present do not fulfill government funding criteria. Disclosures Bredeson: Otsuka: Research Funding. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding.

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Targeted Intravenous Busulfan and Fludarabine Allogeneic Transplantation Conditioning in Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.2290.2290 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2290-2290

Author(s):

Joseph A. Pidala ◽

Jongphil Kim ◽

Claudio Anasetti ◽

Melissa Alsina ◽

Ernesto Ayala ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Large Series ◽

Myelogenous Leukemia ◽

Secondary Aml ◽

Relapsed Disease ◽

Acute Myeloid

Abstract Abstract 2290 Poster Board II-267 Reduced and intermediate intensity conditioning with allogeneic hematopoietic cell transplantation (HCT) offers promise to effectively control hematologic malignancies, while limiting treatment related toxicity and mortality (TRM). We aimed to examine the efficacy of IV targeted Busulfan and Fludarabine (IV-Bu/Flu) in a large series of adults with exclusively acute myelogenous leukemia (AML). One hundred adults (median age 48) with AML (CR1 49, CR2 25, REL1 8, REL2 1, PIF 16, untreated 1) were treated with Busulfan 130-145 mg/m2/day for four days with pharmacokinetic targeting on the final two days to achieve an area under the curve (AUC) of 5300 (+/-10%) μmol*min/L/day and Fludarabine 40mg/m2/day for 4 days, followed by transplantation of G-CSF mobilized peripheral blood stem cells (PBSC) (N=98) or unstimulated bone marrow (BM) (N=2) from allogeneic donors (MRD 38, MUD 38, MMUD 24). Acute GVHD prophylaxis consisted of tacrolimus/methotrexate (N = 77), tacrolimus/mycophenolate mofetil (N = 22), or tacrolimus/sirolimus (N = 1). Median time to neutrophil and platelet engraftment was 16 and 12 days, respectively. Non-relapse mortality was 3% at 100 days, and 15% by 1 year. The cumulative incidence of relapse was 41%. Overall survival (OS) was 59% (95% CI: 48.1 – 67.5) at 1 year, and 42% (95% CI: 30.8-53.3) at 4 years. OS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 52.9%, 40.1%, 41.2%, and 57.5% respectively; none with relapsed disease survived to 4 years (log-rank p = 0.0014). Progression-free survival (PFS) was 53% (95% CI: 42.8 – 62.2) at 1 year, and 32.3% (95% CI: 21.8 – 43.2) at 4 years. PFS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 44.1%, 33.4%, 33.9%, and 33.1%, respectively, while none with relapsed disease at transplant reached this endpoint (p = 0.0264). On multivariable modeling, remission status at HCT (relapsed disease HR 14.85 (95% CI: 2.12 - 104.2), p = 0.007), moderate/severe cGVHD (HR 0.281, 95% CI: 0.10 - 0.76; p = 0.013), and day 90 bone marrow (BM) chimerism ≥ 90% (HR 0.245, 95% CI: 0.08 - 0.79; p = 0.018) predicted overall survival, and day 90 BM chimerism ≥ 90% (HR of 0.18 (95% CI: 0.08 - 0.45), p = 0.0002) predicted PFS. The following were not significantly related with OS or PFS: age, cytogenetics, donor relation, number of induction cycles, aGVHD prophylaxis regimen, maximum aGVHD grade, WBC at diagnosis, time in first CR, or % BM blasts prior to transplant. Day 90 BM chimerism and cGVHD were significantly related with relapse. Maximum grade of aGVHD predicted non-relapse mortality. These data support the low TRM and efficacy of IV-Bu/Flu in a large series of exclusively AML patients, and demonstrate the impact of day 90 bone marrow chimerism as an important prognostic factor. Further efforts to mitigate relapse risk after HCT are warranted, particularly in those with advanced disease at time of transplant. Disclosures: Off Label Use: IV busulfan and fludarabine for the treatment of acute myeloid leukemia. Alsina:Ortho Biotech: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau. Field:PDL BioPharma: Research Funding. Fernandez:Otsuka: Honoraria.

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