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Does Bone Marrow Cellularity (BMC) Have a Role in Predicting Prognosis and Survival in Myelodysplastic Syndromes (MDS)?
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
S142
247 DOES BONE MARROW CELLULARITY (BMC) HAVE A ROLE IN PREDICTING PROGNOSIS AND SURVIVAL IN MYELODYSPLASTIC SYNDROMES (MDS)? U. Greenbaum1, E. Joffe2, H.S. Oster3, I. Kirgner3, I. Levi1, P. Raanani2, I. Avivi4, M. Mittelman3 1 Department of Hematology, Soroka University Medical center, Beer Sheva, Israel; 2Department of Hematology, Rabin Medical Center, Petah-Tikva, Israel; 3Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 4Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Background: The significance of BMC is unclear. Since BM blast% is related to BMC, we hypothesized their combination might improve prognostication. “Blast Index” was defined as: BI = BMC(%) X blast (%)/100. A retrospective analysis of BI’s prognostic value at diagnosis is reported. Patients and Methods: Four MDS cohorts were reviewed. To identify BI subgroups predicting overall survival (OS), conditional inference trees and exploratory plots with p minimization were used. Multivariable Cox proportional hazard models using IPSS-R were compared to models replacing blast% by BI. Model fit was evaluated using akaike information criterion (AIC). Model prognostic power was evaluated using Harrell’s C-index. Results: 355 MDS patients were evaluated (median age 74, FU 79m). Prognostic cutoffs were: BI = 0; 0.1–3; 3.1–6; BI >6 (Figure 1). When staging according to BI, 46 patients were “upstaged” from blast<2% to the low/int BI (0.1–3), 17 were “upstaged” from blast 5– 10% to BI >6. OS was 156 m (95% CI 87–NA) vs 117 (95% CI 87–NA), for the low BI vs low blast% groups; and 10 m (95% CI 9–39, 31 patients) vs 10 m (95% CI 4–NA, 15 patients), for the high BI vs bl >10% groups (Table 1). BI based univariable prediction models were slightly better, with an AIC difference of 5, but not significantly better per C-index (0.63 both). High BI levels were associated with worse cytopenias and cytogenetics. Replacing blast% by BI in the IPSSR was very similar to the original IPSSR (an AIC advantage of 5 point, C-index 0.71 vs. 0.69). However, some patients were reallocated to a different risk group (Table 2). This did not improve the IPSSR prognostic power. Conclusion: This large real-life study shows that although a minority of patients do re-stage when using BI, most would not benefit from incorporation of BM cellularity into the IPSSR. Table 1: Overall survival – IPSSR-BI Patients
Events
33 126 42 18 11
10 61 23 18 9
IPSSR-BI Very low Low Intermediate High Very high
Median Survival
Survival at 60 months
136 [85;NA] 87 [74;149] 39 [26;NA] 8 [5;23] 10 [4;NA]
0.86 [0.74;1] 0.66 [0.57;0.75] 0.41 [0.27;0.62] 0.06 [0.01;0.37]
HR
p value
1.0 1.76 [0.9:3.44] 3.24 [1.54:6.84] 12.38 [5.66:27.07] 18.6 [7.21:47.95]
1.0 0.1 <0.0001 <0.0001 <0.000
Table 2: Patients re-allocated using IPSSR-BI instead of IPSSR
Very low Low Intermediate High Very high
Decrease
Increase
0 0 3 0 0
9 5 4 1 0
No change 33 114 37 14 10
Fig. 1. Overall survival by BI
248 MUTATIONAL PROFILE OF HYPOPLASTIC VERSUS HYPERPLASTIC MYELODYSPLASTIC SYNDROMES WHO-2016 CLASSIFICATION F.M. Hernández Mohedo1, P. Montes Ramos2, M. Bernal Sánchez1, L. Hermosín Ramos3, M. Exposito. Ruiz4, F. Ruiz Cabello2, M. Jurado Chacón1 1 Hematology, Complejo Hospitalario Universitario de Granada, Granada, Spain; 2Inmunology, Complejo Hospitalario Universitario de Granada, Granada, Spain; 3Hematology, Complejo Hospitalario de Jerez, Jerez, Spain; 43Department of Investigation FIBAO, Complejo Hospitalario Universitario de Granada, Granada, Spain Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies. Although most MDS patients have normal or increased cellularity (Hyper-MDS), approximately 15% of them have hypocellular bone marrow (Hypo-MDS). The reports concerning the differences in genetic alterations between Hypo and Hyper-MDS are limited, but HypoMDS seems to be a different molecular profile, with lower incidences of somatic driver mutations in the splicing machinery and lower incidence of high risk mutation. This data may support the hypothesis of a different clonal architecture. Methods: We performed a prospective analysis of 32 patients with MDS and MDS/MPN disease 2016 WHO classification, from January to December 2016. The molecular profile was analyzed by next generation sequencing NGS technology. We analyze the number of driver mutations by molecular pathway (Splicing, Metylation, Transcription, Chromatin modification, Receptors Kinases, Cohesin and RAS) and we cathegorize them as High molecular score (>2 driver mutations), High risk mutations (TP53, RUNX1, EZH2 and ETV6), and High variant allele frequency (VAF > 20%) between Hypo and Hyper/MDS, analyzed with statistical software SPSS.19. Results: We have analyzed a total of 32 cases MDS and MDS/MPN, subdivided according to the 2016 WHO classification: 26 as HyperMDS and 6 as Hypo-MDS. The number of somatic driver mutations was 77 (14 for Hypo and 63 Hyper-MDS). Median molecular score was 2.25 and median VAF 32.90%. In the Hypo-MDS, the frequency of High variant allele frequency was inferior (57.1% vs 70.2%; p = 0.359), the frequency of High molecular score was lower (16.7% vs 44.0%; p = 0.363) and the frequency of high risk mutations (TP53, RUNX1, EZH2 and ETV6), was lower than in Hyper-MDS (16.7% vs 57.7%; p = 0.172). The analysis of molecular pathway by variant show than mutations in the splicing machinery were less frequent in Hypo-MDS than Hiper-MDS (7.1% vs 17.5%; OR 0.362; p = 0.353) and in contrast was higher, in DNA methylation (42.9% vs 22.8%; OR 2.358, p = 0.136), transcription (28.6% vs 19.3%; OR 1.673; p = 0.449) and Receptor-Kinases (7.1% vs 3.5%; OR 2.115; p = 0.353), but statistical significance was not achieved.
S142
247 DOES BONE MARROW CELLULARITY (BMC) HAVE A ROLE IN PREDICTING PROGNOSIS AND SURVIVAL IN MYELODYSPLASTIC SYNDROMES (MDS)? U. Greenbaum1, E. Joffe2, H.S. Oster3, I. Kirgner3, I. Levi1, P. Raanani2, I. Avivi4, M. Mittelman3 1 Department of Hematology, Soroka University Medical center, Beer Sheva, Israel; 2Department of Hematology, Rabin Medical Center, Petah-Tikva, Israel; 3Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 4Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Background: The significance of BMC is unclear. Since BM blast% is related to BMC, we hypothesized their combination might improve prognostication. “Blast Index” was defined as: BI = BMC(%) X blast (%)/100. A retrospective analysis of BI’s prognostic value at diagnosis is reported. Patients and Methods: Four MDS cohorts were reviewed. To identify BI subgroups predicting overall survival (OS), conditional inference trees and exploratory plots with p minimization were used. Multivariable Cox proportional hazard models using IPSS-R were compared to models replacing blast% by BI. Model fit was evaluated using akaike information criterion (AIC). Model prognostic power was evaluated using Harrell’s C-index. Results: 355 MDS patients were evaluated (median age 74, FU 79m). Prognostic cutoffs were: BI = 0; 0.1–3; 3.1–6; BI >6 (Figure 1). When staging according to BI, 46 patients were “upstaged” from blast<2% to the low/int BI (0.1–3), 17 were “upstaged” from blast 5– 10% to BI >6. OS was 156 m (95% CI 87–NA) vs 117 (95% CI 87–NA), for the low BI vs low blast% groups; and 10 m (95% CI 9–39, 31 patients) vs 10 m (95% CI 4–NA, 15 patients), for the high BI vs bl >10% groups (Table 1). BI based univariable prediction models were slightly better, with an AIC difference of 5, but not significantly better per C-index (0.63 both). High BI levels were associated with worse cytopenias and cytogenetics. Replacing blast% by BI in the IPSSR was very similar to the original IPSSR (an AIC advantage of 5 point, C-index 0.71 vs. 0.69). However, some patients were reallocated to a different risk group (Table 2). This did not improve the IPSSR prognostic power. Conclusion: This large real-life study shows that although a minority of patients do re-stage when using BI, most would not benefit from incorporation of BM cellularity into the IPSSR. Table 1: Overall survival – IPSSR-BI Patients
Events
33 126 42 18 11
10 61 23 18 9
IPSSR-BI Very low Low Intermediate High Very high
Median Survival
Survival at 60 months
136 [85;NA] 87 [74;149] 39 [26;NA] 8 [5;23] 10 [4;NA]
0.86 [0.74;1] 0.66 [0.57;0.75] 0.41 [0.27;0.62] 0.06 [0.01;0.37]
HR
p value
1.0 1.76 [0.9:3.44] 3.24 [1.54:6.84] 12.38 [5.66:27.07] 18.6 [7.21:47.95]
1.0 0.1 <0.0001 <0.0001 <0.000
Table 2: Patients re-allocated using IPSSR-BI instead of IPSSR
Very low Low Intermediate High Very high
Decrease
Increase
0 0 3 0 0
9 5 4 1 0
No change 33 114 37 14 10
Fig. 1. Overall survival by BI
248 MUTATIONAL PROFILE OF HYPOPLASTIC VERSUS HYPERPLASTIC MYELODYSPLASTIC SYNDROMES WHO-2016 CLASSIFICATION F.M. Hernández Mohedo1, P. Montes Ramos2, M. Bernal Sánchez1, L. Hermosín Ramos3, M. Exposito. Ruiz4, F. Ruiz Cabello2, M. Jurado Chacón1 1 Hematology, Complejo Hospitalario Universitario de Granada, Granada, Spain; 2Inmunology, Complejo Hospitalario Universitario de Granada, Granada, Spain; 3Hematology, Complejo Hospitalario de Jerez, Jerez, Spain; 43Department of Investigation FIBAO, Complejo Hospitalario Universitario de Granada, Granada, Spain Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies. Although most MDS patients have normal or increased cellularity (Hyper-MDS), approximately 15% of them have hypocellular bone marrow (Hypo-MDS). The reports concerning the differences in genetic alterations between Hypo and Hyper-MDS are limited, but HypoMDS seems to be a different molecular profile, with lower incidences of somatic driver mutations in the splicing machinery and lower incidence of high risk mutation. This data may support the hypothesis of a different clonal architecture. Methods: We performed a prospective analysis of 32 patients with MDS and MDS/MPN disease 2016 WHO classification, from January to December 2016. The molecular profile was analyzed by next generation sequencing NGS technology. We analyze the number of driver mutations by molecular pathway (Splicing, Metylation, Transcription, Chromatin modification, Receptors Kinases, Cohesin and RAS) and we cathegorize them as High molecular score (>2 driver mutations), High risk mutations (TP53, RUNX1, EZH2 and ETV6), and High variant allele frequency (VAF > 20%) between Hypo and Hyper/MDS, analyzed with statistical software SPSS.19. Results: We have analyzed a total of 32 cases MDS and MDS/MPN, subdivided according to the 2016 WHO classification: 26 as HyperMDS and 6 as Hypo-MDS. The number of somatic driver mutations was 77 (14 for Hypo and 63 Hyper-MDS). Median molecular score was 2.25 and median VAF 32.90%. In the Hypo-MDS, the frequency of High variant allele frequency was inferior (57.1% vs 70.2%; p = 0.359), the frequency of High molecular score was lower (16.7% vs 44.0%; p = 0.363) and the frequency of high risk mutations (TP53, RUNX1, EZH2 and ETV6), was lower than in Hyper-MDS (16.7% vs 57.7%; p = 0.172). The analysis of molecular pathway by variant show than mutations in the splicing machinery were less frequent in Hypo-MDS than Hiper-MDS (7.1% vs 17.5%; OR 0.362; p = 0.353) and in contrast was higher, in DNA methylation (42.9% vs 22.8%; OR 2.358, p = 0.136), transcription (28.6% vs 19.3%; OR 1.673; p = 0.449) and Receptor-Kinases (7.1% vs 3.5%; OR 2.115; p = 0.353), but statistical significance was not achieved.