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

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.

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Decisional Algorithm to Incorporate Hematopoietic Stem Cell Transplantation in the Management of Adult Patients with Acute Myeloid Leukaemia.

Blood ◽

10.1182/blood.v112.11.1519.1519 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1519-1519

Author(s):

Francesco Buccisano ◽

Luca Maurillo ◽

Maria Ilaria Del Principe ◽

Giovanni Del Poeta ◽

Paola Panetta ◽

...

Keyword(s):

Risk Assessment ◽

Stem Cell ◽

Adult Patients ◽

Cell Transplant ◽

Intermediate Risk ◽

Hematopoietic Stem ◽

Poor Risk ◽

Risk Categories ◽

Acute Myeloid

Abstract Implementation of transplant procedures and the availability of alternative sources of stem cells for patients without HLA identical siblings has made allogeneic stem cell transplant (ASCT) a suitable therapy for many patient affected by acute myeloid leukemia (AML); consequently, in AML patients transplant strategies must be carefully designed according to stringent risk/benefit analysis. To date, risk assessment relies on identification of baseline prognostic parameters such as karyotype, which has become critical in order to choose post-remissional therapy. Furthermore, there are strong evidences that the presence of specific gene abnormalities, such as mutations of FLT3, NPM and c-kit, allow to identify, within homogeneous cytogenetic groups, subsets of patients with distinct clinical outcome. We hypothesized that, in order to guide the post-remission decisional process, more robust informations may derive from the combined evaluation of conventional baseline and delayed prognosticators. Minimal residual disease (MRD) detection is potentially the most efficient tool to investigate the quality of remission and might represent the ideal parameter to be associated with baseline biological features for prognostic purposes. Therefore, we aimed to determine whether combined analysis of karyotype and MRD, using multiparametric flow-cytometry (MPFC), could help to refine risk assessment in adult patients with AML, allowing the most appropriate post-remissional strategy to be selected. We analyzed 132 patients with AML who had intensive chemotherapy with EORTC/GIMEMA protocols. According to MRC classification, 22 (17%), 104 (78%) and 6 (5%), respectively, had good, intermediate and poor risk karyotype. Thirteen of 107 (12%) carried a FLT3-ITD. Within good and intermediate risk categories, MRD positivity (≥ 3.5×10−4 residual leukemic cells at the post-consolidation time-point) was associated with a worse prognosis in terms relapse free (RFS) and overall survival (OS). In fact, we observed that: MRD negative good and intermediate risk categories shared the same favorable prognoses with RFS and OS of 80% vs. 69% and 84% vs 54%, respectively; MRD positive good and intermediate risk categories fared as worse as those with poorrisk karyotype or FLT3-ITD in terms of RFS (28% vs. 17% vs. 0%) and OS (42% vs. 21% vs. 17%). Using this approach the conventional cytogenetic classification that uses three categories is simplified into 2 prognostically defined groups: favorable, including MRD negative good and intermediate risk karyotype; unfavorable, including MRD positive good and intermediate risk karyotype, poor risk karyotype and FLT3-ITD positive cases (Fig. 1). Based on these observations, we believe that ASCT is recommended, not only for poor-risk karyotype or FLT3 positive AML, but also for good/intermediate risk categories not gaining MRD negativity, being this option able to provide a superior chance of prolonged RFS (Maurillo et al, JCO 2008). On the other hand, patients belonging to MRD negative good/intermediate risk categories, who can experience a 5-years survival higher than 60%, may have their life expectancy hampered by the choice of a therapeutic strategy with a disadvantageous risk/benefit ratio: for this category a standard intensification procedure (chemo and/or autologous transplant) is indicated. In conclusion, the combined assessment of baseline prognosticators (cytogenetics) and parameters inherent the quality of response (MRD), is useful to define discrete categories of risk within the respective karyotypic groups, allowing tailored therapeutic approaches to be applied according to the actual clinical risk and avoiding under or over treatments. Figure 1 Figure 1.

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Validation of the Revised International Prognostic Scoring System (R-IPSS) for Patients with Myelodysplastic Syndromes: Therapeutic Implications.

Blood ◽

10.1182/blood.v120.21.2816.2816 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2816-2816 ◽

Cited By ~ 2

Author(s):

Asmita Mishra ◽

Najla H Al Ali ◽

Maria Corrales-Yepez ◽

Eric Padron ◽

Ling Zhang ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Scoring System ◽

Prognostic Value ◽

Risk Model ◽

Risk Group ◽

International Prognostic Scoring System ◽

Cell Transplant ◽

Kaplan Meier ◽

Very High

Abstract Abstract 2816 Background: The International Prognostic Scoring System (IPSS) was recently revised under the auspices of MDS foundation as a collaborative international effort. The proposed R-IPSS is suggested to refine the prognostic value of the IPSS. Instead of the 4 original IPSS categories, 5 categories are proposed by R-IPSS. To validate this prognostic model and examine its utility for therapy decisions, we tested the new risk model in a large external single institution patient cohort. Methods: Data were collected retrospectively from the Moffitt Cancer Center (MCC) MDS database and chart review. The primary objective was to validate the new risk model. The R-IPSS score was calculated as reported. Patients were divided into 5 prognostic categories (very low, low, intermediate, high and very high risk). The Kaplan–Meier method was used to estimate median overall survival. Log rank test was used to compare Kaplan–Meier survival estimates between the groups. Results: The MCC MDS database captured 1157 patients. Complete data was available for 1029 patients to calculate the R-IPSS score. Median age was 68 years, and the most common WHO subtype was RCMD (29%). Two thirds of patients were low/int-1 IPSS risk, and 44% were int-2 or high risk MDAS. (Table-1). Among those, 729 patients (77%) were RBC transfusion dependent (TD), and 264 (26%) had serum ferritin >1000 ng/l. Six hundred eighteen patients (60%) received hypomethylating agent (HMA). The median duration of follow up was 68 months (mo). Median OS according to IPSS risk score was 90 mo (95%CI 75–105), 44 mo (95%CI 39–46), 18 mo (95%CI 15–21), and 14 mo (95%CI 11–17), for low, int-1, int-2, and high risk categories, respectively (p < 0.005). According to MD Anderson risk Score, the median OS was 108 mo (95%CI 91–126), 55 mo (95%CI 50–60), 25 mo (95%CI 22–28), and 14 mo (95%CI 12–16), for low, int-1, int-2, and high risk respectively (p < 0.005). Using the R-IPSS, 106 (10%), 311 (30%), 247 (24%), 201 (20%), and 164 (16%) were classified as very low, low, int, high, and very high risk. The median OS was 82 mo (95% CI 64–100), 57 mo (95% CI 46–68), 41 mo (95% CI 33–49), 24 mo (95% CI 20–28), and 14 mo (95% CI12–16) for each of the corresponding R-IPSS groups (p <0.005). Table-2 summarizes reclassification of each IPSS risk group by R-IPSS and expected OS accordingly. Among those patients who received HMA, the median OS from time of diagnosis was 76 mo, 55 mo, 42 mo, 25 mo, and 16 mo for very low, low, int, high, and very high risk respectively (p < 0.005). A survival benefit for HMA therapy was only statistically significant in patients with very high risk R-IPSS, with a corresponding median OS of 16 mo with HMA versus 7 mo with no HMA (p< 0.005). OS in patients with very high or high R-IPSS who underwent Allogeneic Stem cell transplant (ASCT) was improved compared to corresponding patients who received non-ASCT management. Patients who had very low, low, and int risk R-IPSS had no apparent OS benefit with ASCT. (Table-3). Conclusion: Our data validates the prognostic value of the proposed R-IPSS, but refines prognostic discrimination only for intermediate risk group of IPSS. Both the R-IPSS and IPSS were valid prognostic models for patients treated with HMA. The benefit of ASCT was restricted to patients with high and very high R-IPSS groups. The utility of the R-IPSS as a tool for therapeutic decisions should be further examined before wide adaptation. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.5217.5217 ◽

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.

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

Blood ◽

10.1182/blood.v126.23.2874.2874 ◽

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.

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

Blood ◽

10.1182/blood.v120.21.1729.1729 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1729-1729 ◽

Cited By ~ 1

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.

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Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma

Acta Haematologica ◽

10.1159/000501298 ◽

2019 ◽

Vol 143 (2) ◽

pp. 146-154

Author(s):

Leona A. Holmberg ◽

Damian Green ◽

Edward Libby ◽

P.S. Becker

Keyword(s):

Multiple Myeloma ◽

Randomized Study ◽

Single Agent ◽

Survival Rates ◽

High Dose ◽

Cell Transplant ◽

Hematopoietic Stem ◽

High Dose Melphalan ◽

Additional Therapy

Background: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. Patients and Methods: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. Results: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12–9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. Conclusions: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.

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A Novel Prognostic Model in Heavily Treated Patients with Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v124.21.168.168 ◽

2014 ◽

Vol 124 (21) ◽

pp. 168-168

Author(s):

Aziz Nazha ◽

David J. Seastone ◽

Tomas Radivoyevitch ◽

Aaron T. Gerds ◽

Sudipto Mukherjee ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Prognostic Model ◽

Cox Model ◽

Single Agent ◽

Gene Mutations ◽

Cell Transplant ◽

Secondary Mds ◽

Very High

Abstract Background The Revised International Prognostic Scoring System (IPSS-R) was developed to risk stratify untreated patients (pts) with MDS. It has since been validated in pts treated with a single line of drug therapy, and has been modified in untreated pts to include mutational data; however, these approaches do not reflect typical MDS pts who receive different types of treatment in different sequences. We propose a prognostic model that incorporates mutational data and predicts outcome in pts with primary and secondary MDS regardless of their initial or subsequent treatments. Methods Clinical and mutational data of 333 pts with newly diagnosed MDS who were treated at out institution between 1/2000-1/2012 were analyzed. The IPSS-R was calculated at diagnosis. Survival was calculated from the date of diagnosis to last follow up or death. A panel of 62 gene mutations obtained by next generation targeted deep sequencing selected based on the frequency observed in a separate cohort of MDS patients analyzed by whole exome sequencing (WES). A Cox proportional multivariate analysis including age, IPSS-R score and mutations that are present in >/= 10 pts was used to select independent prognostic factors. The fit of the proposed model to the data was assessed by using the Akaike information criterion (AIC). Results Pt clinical characteristics are summarized in Table 1. Median age was 68 years (range, 20-87); 214 pts (64%) had de novo MDS, 39 (12%) had prior antecedentl hematologic disorders, 37 (11%) secondary MDS, and 43 (13%) had chronic myelomonocytic leukemia (CMML). Pts received between 0-7 lines of therapy: 15% did not receive any treatment, 85% received at least one treatment, 40% received >/=2 treatments, 20% received >/= 3 treatments and 14% of pts eventually underwent hematopoietic cell transplant (HCT). First line therapies included: growth factors (30%), azacitidine +/- combination (32%), decitabine +/- combination (7%), single agent lenalidomide (5%), investigational agents (5%), induction chemotherapy with cytarabine and an anthracycline (7+3, 2%), and immunosuppressive therapy (4%). With a median follow-up of 38 months (mo) (range, 0.4-128.5), 70 pts (21%) progressed to AML and the median OS was 35.1 mo (range, 0.4-128.5). Per IPSS-R risk groups, median OS for very low was 35 mo, low 35 mo, intermediate 22 mo, high 19 mo, and very high 12 mo, Figure 1. Among the 62 gene mutations, 25 were present in >/= 10 pts: TET2 (17%), ASXL1 (15%), SF3B1 (14%), STAG2 (11%), DNMT3A (11%), RUNX1 (10%), U2AF1 (9%), GPR98 (8%), ZRSR2 (7%), BCOR (6%), TP53 (5%), NF1 (5%), EZH2 (5%), APC (5%), SUZ12 (5%), BCORL1 (4%), CBL (4%), PRPF8 (4%), NRAS (3%), CUX1 (3%), DDX54 (3%), IDH2 (3%), KDM6A (3%), PHF6 (3%), and SETBP1 (3%). A Cox proportional hazard analysis including age, IPSS-R score, and the 25 genes mutations listed above identified the following as independent prognostic factors: age, IPSS-R, ASXL1, BCOR, BCORL1, EZH2, IDH2, SF3B1,TP53. The linear predictive Cox model score obtained using the fitted coefficients of each prognostic factor was: ASXL1 X 0.65+BCOR X 0.92+BCORL1 X (-1.65)+EZH2 X 0.71+IDH2 X (-1.0)+SF3B1 X (-0.59)+TP53 X 1.24+Age X 0.04+IPSS-R score X 0.43. Four prognostic groups were proposed: low (score 0-3.4, 80 pts, median OS 47.3 mo), intermediate-1 (score 3.5-4, 69 pts, median OS 30.2 mo), intermediate-2 (score 4.1-5.4, 131 pts, median OS 19.9 mo), and high (score >/= 5.5, 53 pts, median OS 12.2 mo), p < 0.001, Figure 2. The new model demonstrated a markedly better fit, reflected in an AIC of 2026, compared to 2058 for the IPSS-R. Conclusion We propose a new mathematical model that incorporates age, IPSS-R score and several gene mutations that can accurately predict OS in pts with primary and secondary MDS as well as CMML regardless of initial or subsequent treatments, including HCT. This model also highlights the importance of mutational data along with clinical data for risk stratification in MDS. Figure 1 Overall survival by IPSS-R Figure 1. Overall survival by IPSS-R Figure 2 Overall survival by the new prognostic model Figure 2. Overall survival by the new prognostic model Table 1 Patient characteristics No. (%) / [Range] Total 333 Median age, years 68 [20-87] Male 205 (62) Female 128 (38) Median white blood cell (WBC) X 109/L 3.8 [0.69-125.9] Median absolute neutrophil count (ANC) X 109/L 1.62 [0.02-170] Median hemoglobin,g/dl 9.6 [3.9-14.6] Median platelets X 109/L 93 [4-776] Median bone marrow blasts % 2 [0-19] IPSS-R Very low 50 (15) Low 128 (38) Intermediate 59 (18) High 60 (18) Very high 36 (11) Disclosures No relevant conflicts of interest to declare.

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Validation Of The Revised International Prognostic Scoring System (IPSS-R) In 1000 Newly Diagnosed MDS Patients With Low- and Intermediate-1 Risk MDS In The European Leukemianet MDS (EUMDS) Registry

Blood ◽

10.1182/blood.v122.21.2770.2770 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2770-2770 ◽

Cited By ~ 2

Author(s):

Louise de Swart ◽

Alex Smith ◽

Tom Johnston ◽

Detlef Haase ◽

Jackie Droste ◽

...

Keyword(s):

High Risk ◽

Mortality Rate ◽

Risk Score ◽

Scoring System ◽

Scoring Systems ◽

International Prognostic Scoring System ◽

Newly Diagnosed ◽

High Age ◽

Very High

Abstract Background The EUMDS registry was initiated to provide an overview of the real-world demographics, diagnostics and disease-management of MDS. The first patient was registered in December 2007 and today 16 countries and 131 centers are participating. In 1997 the International Prognostic Scoring System (IPSS) was developed to predict clinical outcomes for patients with MDS and is still the most widely used prognostic scoring system. Recently, the IPSS has been revised (IPSS-R). Objective To validate the prognostic discrimination of the IPSS and IPSS-R in the first 1000 newly diagnosed lower risk MDS patients. Results The median age of the population at diagnosis was 75 years (range 19-95). WHO 2001 classification was RCMD (35%), RARS (18%), RA (18%), RAEB-1 (12%), RCMD-RS (7%), 5q- syndrome (6%), MDS-U (3%) and RAEB-2 (0.4%). Within the first two years of follow-up 57% of the patients received MDS specific treatment: 48% received erythropoiesis stimulating agents (ESA), 11% granulocyte colony-stimulating factor (G-CSF), 51% received at least one red blood cell transfusion and 8% iron chelation therapy. IPSS risk score was Low in 49%, Intermediate-1 in 45% (0.5=32%, 1=13%) and unknown in 6% (no cytogenetic analysis) of the patients. IPSS-R risk score was Very Low in 25%, Low in 44%, Intermediate in 16%, High/Very high in 4% of the patients, and 10% unknown (Figure 1; Table 1). 77% of IPSS karyotypes were Good, 15% Intermediate, 1% Poor and unknown in 6%. 7% of the IPSS-R cytogenetic groups were Very good, 72% Good, 11% Intermediate, 1% were each Poor or Very poor and 8% unknown. Overall survival (OS) and disease progression (DP) (high risk MDS/Leukaemia) were both evaluated. Median follow-up time was 2.1 years (range 0 - 4.9 years). The mortality rate in patients with IPSS Low was 23% and 38% among those with an Intermediate IPSS (HR 2.09, 95%CI: 1.64-2.66; Figure 2A). The mortality rate in patients according to the IPSS-R was Very Low (21%; HR 0.77, 95%CI: 0.55-1.07), Low (26%; HR 1), Intermediate (51%; HR 2.53, 95%CI: 1.90-3.38) and High/Very high (65%; HR 4.47, 95%CI: 2.94-6.78) (Figure 2B). The prognostic discrimination of the scoring systems was assessed using the Akaike Information Criterion (AIC) from univariate proportional hazards models; the lower the AIC value the more informative the prognostic scoring system. The AIC of the IPSS and IPSS-R models were 3198.77 and 3154.48, respectively for OS and 1323.16 and 1274.19, respectively for DP (Table 1). A similar assessment of the components of the IPSS and IPSS-R scores revealed comparable fits to both OS and DP, regardless of which component was considered (Table 2). Conclusion IPSS and IPSS-R both predict OS and DP very well. IPSS-R was slightly superior in evaluating the clinical outcome, but it identified a subgroup (4.5% of all patients) of High and Very High-risk patients with a very poor prognosis, and another subgroup of good prognosis patients (IPSS-R Very Low) within the IPSS INT-1 cohort (13.6% of IPSS INT-1). Both scoring systems appear to be more strongly associated with predicting the risk of developing DP than OS. This observation may be due to the average high age at diagnosis of MDS reflecting the effect of competing causes of death associated with high age. Disclosures: Guerci-Bresler: Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

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Next Generation Myelofibrosis Risk Analysis in the Electronic Health Record

Blood ◽

10.1182/blood-2018-99-113692 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3038-3038

Author(s):

Andrew Sochacki ◽

Cosmin Adrian Bejan ◽

Shilin Zhao ◽

Travis Spaulding ◽

Thomas Stricker ◽

...

Keyword(s):

High Risk ◽

Median Survival ◽

Scoring System ◽

Low Risk ◽

International Prognostic Scoring System ◽

Proportional Hazard ◽

Next Generation ◽

Advisory Committees ◽

Cox Proportional Hazard

Abstract Background: Myelofibrosis (MF) is a devastating myeloproliferative neoplasm that is hallmarked by marrow fibrosis, symptomatic extramedullary hematopoiesis, and risk of leukemic transformation, most commonly driven by janus kinase 2 (JAK2) pathway mutations. MF risk classification systems guide prognosis, decisions regarding allogeneic stem cell transplantation, and disease modifying agents. Key systems include the Dynamic International Prognostic Scoring System (DIPSS) 2009, DIPSS plus 2010, Genetics-Based Prognostic Scoring System (GPSS) 2014, and Mutation-Enhanced International Prognostic Scoring System (MIPSS) 2014. System contributions include dynamic scoring (DIPSS), cytogenetics (DIPSS Plus), and high risk molecular mutations (GPSS and MIPSS). To power the next generation of MF risk prognostication, and ascertain new prognostic factors, large scale electronic health record (EHR) and genomic data will need integration. As a proof of concept, we leveraged our de-identified research EHR (2.9 million records) and linked genomic biobank (288,000 patients) to develop an all-inclusive phenotype-genotype-prognostic system for MF and recapitulate DIPSS, DIPSS Plus, GPSS and MIPSS. Methods: Our previously described methods (Bejan et al. AACR 2018) utilized natural language processing to algorithmically identify 306 MF patients. A subset (N=125) had available DNA for genotyping. We automatically extracted: age greater than 65, leukocyte count (WBC) greater than 25x109/L, hemoglobin (Hgb) less than 10g/dL, platelets (PLT) less than 100 x 109/L, circulating myeloid blasts ≥ 1%, and 10% weight loss compared to baseline as a proxy for constitutional symptoms. Transfusion data was not included. Karyotype data was manually reviewed. Next generation sequencing (NGS) was performed on biobanked peripheral blood DNA with the Trusight Myeloid Panel (Illumina®). Genotyped samples were restricted to dates after MF diagnosis. Multivariate Cox proportional hazard analysis was performed on all clinical and genomic variables. DIPSS plus was calculated without adjustment but lacked transfusion data. DIPSS, GPSS and MIPSS scores were calculated by published methods. Results: Multivariate Cox proportional hazard regression identified Hgb (HR=6.4; P=0.006), myeloid blasts (HR=3.8; P=0.03), and ASXL1 (HR=5.2; P=0.02) as significant in our cohort with regard to overall survival (OS). We noted a strong trend for high risk karyotype (HR=5.6; P=0.07). Our DIPSS model median survival (N=120) for each subgroup; low risk (median survival not met), intermediate-1 (108 months), intermediate-2 (47 months) and high risk (6 months) P=0.0002 (Figure 1a). DIPSS Plus (N=122) integrated karyotype data and PLT count with similar survival with the exception of high risk (4 months) P=0.00003 (Figure 1b). The percentage of patients with driver mutations in JAK2V617F (57%), CALR (3%) and MPLW515 (7.2%); JAK2WT, CALRWT and MPLWT triple negative (34%); high molecular risk ASXL1 (15%), EZH2 (6%), IDH1/2 (7%), SRFS2 (17%); other variants of interest TET2 (9.6%), TP53 (29%) and DNMT3A (16.8%). MIPSS (N=125; 48 months follow up) noted low risk, intermediate-1, and intermediate-2 (median survival not met) and high risk (32 months) P=0.0001 (Figure 1c). GPSS (N=125; 48 months follow up) did not demonstrate statistical separation among groups (Figure 1d). Discussion: This proof of concept transformed raw EHR records into clinical risk scores for MF. The addition of retrospective DNA analysis via NGS opens the possibility of multi-institutional EHR-biobank studies to most accurately create a system to define MF risk. Our sample size limited the significance of age, PLTs, poor risk mutations and other variables previously shown to impact OS. Likewise, we lacked the capacity to track transfusion dependence, previously shown to have prognostic relevance. Still, prognostication via the EHR mimics common scoring systems in MF and supports correct MF case selection, accurate laboratory extraction and reproducible genotyping of biobanked samples. Similar to the original GPSS report, our low risk cohort was small (N=2) and will benefit from expansion of genotyping underway. Finally, this phenotype-genotype-prognostic paradigm represents a technical advance and a unique opportunity to deploy patient specific comorbidities from lifetime EHR records to further refine risk across all myeloid disease. Disclosures Savona: Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Incorporation of Molecular Data into the Current Prognostic Models in Treated Patients with Myelodysplastic Syndromes: Which Model Is the Best

Blood ◽

10.1182/blood.v128.22.50.50 ◽

2016 ◽

Vol 128 (22) ◽

pp. 50-50 ◽

Cited By ~ 2

Author(s):

Karam Al-Issa ◽

Ahmad Zarzour ◽

Tomas Radivoyevitch ◽

Matt Kalaycio ◽

Betty K. Hamilton ◽

...

Keyword(s):

Scoring System ◽

Research Funding ◽

Predictive Power ◽

Molecular Data ◽

Low Risk ◽

World Health ◽

Prognostic Models ◽

International Prognostic Scoring System ◽

Cell Transplant ◽

Training Cohort

Abstract Background Several prognostic models have been developed to risk stratify patients (pts) with MDS including: the International Prognostic Scoring System (IPSS), Revised IPSS (IPSS-R), World Health Organization classification-based Prognostic Scoring System (WPSS), and MD Anderson Prognostic Scoring System (MDPSS). All except for the MDPSS were developed in treatment-naive pts and, if validated in treated pts, were done so primarily in those receiving one line of therapy. Incorporation of molecular data into the IPSS-R improves its predictive power, and adding molecular data to the IPSS can upstage or downstage some pts. In this study, we compared the prognostic utility of each prognostic model, after adding molecular data, in treated MDS pts. Method Clinical and mutational data from MDS pts diagnosed between 1/2000-1/2013 were analyzed. A panel of 60 gene mutations that were described as commonly mutated in myeloid malignancies was included. Patients who underwent hematopoietic cell transplant (HCT) were censored at the time of transplant. Univariable and multivariable analyses on the training cohort were performed by applying Cox proportional hazards regression analyses that included age, model score, and molecular mutations with an outcome of overall survival (OS). All molecular models were then applied to the validation cohort. The fit of the proposed models to the data was assessed by using Akaike's information criterion (AIC, lower values imply better fit) and concordance (c-) index. Results A total of 610 pts were included and divided into two cohorts, training (404 pts), and validation (206 pts). Median age of the training cohort was 67 years (range, 19-88); 83 pts (20%) had MDS/MPN including chronic myelomonocytic leukemia (CMML). Pts received a median of 2 lines of therapies (range, 0-7) and 15% of pts underwent HCT. First line therapies included: supportive care (22%), growth factors (22%), azacitidine +/- combinations (30%), decitabine +/- combinations (6%), lenalidomide (5%), induction chemotherapy (3%), immunosuppressive therapy (3%), and other therapies /clinical trials (9%). The median OS in the training and validation cohorts per scoring system (SS), i.e. IPSS, WPSS, MDPSS, and IPSS-R, is summarized in Table 1. The most common mutations in the training cohort were: TET2 (19%), ASXL1 (16%), SF3B1 (13%), DNMT3A (9%), STAG2 (9%), RUNX1 (8%), and U2AF1 (7%). In univariate analyses, mutations in EZH2 (HR1.8, p = .02), TP53 (HR2.3, p < .001), RUNX1 (HR 1.5, p = .05), and NPM1 (HR1.49, p = .001) had a negative impact on OS while SF3B1 (HR .34, p < .001) mutations were associated with favorable outcome. In multivariate analyses that included SS, mutations (from the list above), and age (except for the MDPSS, which already includes age), the following independent prognostic factors for OS were identified: age, EZH2, SF3B1, TP53, and each SS. Based on the fitted coefficients of each prognostic factor, a molecular version of each model including IPSSm, WPSSm, MDPSSm, and IPSS-Rm was proposed with median OS in the training and validation cohorts as summarized in Table 1. The addition of molecular data improved (reduced) the AIC and (raised) the C-index for the IPSS (2332.6, .69 vs. 2365.8, .64), WPSS (2322.3, .68 vs. 2356.2, .65), MDPSS (2308.4, .71 vs. 2323.4, .69), and IPSS-R (2305.2, .70 vs. 2330.5, .66), respectively. Further, the addition of molecular data to the IPSS upstaged 37% of pts from lower- to higher-risk disease and downstaged 5% of intermediate-1 to low risk disease. In the WPSS, it upstaged 21% of pts and downstaged 24%; in the MDPSS it upstaged 19% and dowstaged 22% of pts from intermediate-1 to low risk; and in the IPSS-R it upstaged 26% to higher-risk disease and 59% of pts with intermediate risk to a higher risk category. Conclusions The addition of molecular data to established MDS prognostic models can improve their predictive power, even in treated MDS patients. More importantly, adding molecular information can upstage or downstage pts into different risk categories. This study highlights the importance of incorporating molecular data into clinical prognostic systems. Disclosures Mukherjee: Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

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