Revised-IPSS (IPSS-R) Is a Powerful Tool to Evaluate the Outcome of MDS Patient Treated with Azacitidine (AZA): The Groupe Francophone Des Myelodysplasies (GFM) Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 422-422 ◽  
Author(s):  
Lionel Ades ◽  
Mathilde Lamarque ◽  
Sophie Raynaud ◽  
Raphael Itzykson ◽  
Sylvain Thepot ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Scoring System ◽  
Prognostic Value ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Risk Groups ◽  
Predictive Score ◽  
Prognostic Impact ◽  
Very High

Abstract Abstract 422 Background: The IPSS published in 1997, based on cytogenetics, marrow blast % and the number of cytopenias, has played a major role in prognosis assessment in MDS. A provisional revised IPSS had been presented in 2011, which in our experience brought limited additional prognostic value for outcome of AZA treatment (Lamarque, ASH 2011). A final IPSS-R has now been published (Greenberg, Blood 2012), using the same parameters but 5 rather than 3 cytogenetic subgroups (Schanz et al, JCO, 2011), new cut off values for cytopenias and bone marrow blast % and different weighing of parameters. It appears to refine IPSS prognostic value but, like the original IPSS, was established in pts who had received no disease modifying drugs. We assessed the prognostic value of IPSS-R in 264 higher risk MDS treated with AZA, a drug with a survival impact in those pts. Methods: Between Sept 2004 and Jan 2009, before drug approval in EU, we enrolled 282 IPSS high and int 2 (higher) risk MDS in a compassionate patient named program of AZA and established in this cohort a prognostic scoring system (“AZA predictive score” based on Performance status (PS), cytogenetics, presence of circulating blasts, and RBC transfusion dependency) (Itzykson, Blood, 2011). We took advantage of this cohort to evaluate the prognostic impact of IPSS-R in higher risk MDS treated with AZA. Results: Median age was 71 years. WHO diagnosis: 4% RA, RARS or RCMD, 20% RAEB-1, 54%RAEB-2, 22% RAEB-t/AML. Cytogenetics could be reclassified using IPSS-R cytogenetic groups (Shanz, JCO 2011) in 265 pts, in: 1% very good, 37% good, 18% int, 12% poor and 32% very poor. 18%, 48% and 34% pts had Hb<8g/dl, between 8 and 10 and >10 g/dl, respectively. 43%, 32% and 25% had baseline platelet count <50 G/l between 50–100 and >100 G/L, respectively. ANC was <0.8 G/l in 45% pts. Marrow blast % was <=2%, 3–5%, 5–10%, >10 % in 2%, 3%, 18% and 77% pts. Overall IPSS-R could be calculated in 259 patients and was low (1 pt), Intermediate (28 pts, 11%), high (87 pt, 34%) and very high (143 pt, 55% pts). The only pt in the low group was excluded from further analysis. Using the “classical” IPSS, high and Int-2 patients treated with AZA had significantly different Response (37% vs 49%, p=0.05) and OS (median 9.4 vs 16 mo, respectively, p=0.004). Using the IPSS-R, 46%, 47% and 39% responded (CR, PR, or Hematological improvement- HI) to AZA in the int, poor and very poor groups, respectively (p=0.463). Individual IPSS-R parameters, including IPSS-R cytogenetic classification (p= 0.646), Hb level (p= 0.948), platelet count (p=0.10), ANC (p= 0.465) and marrow blast % stratified according to R-IPSS (p=0.287) had no significant impact on AZA response. According to IPSS-R cytogenetic classification, median OS was 21.8 mo, 12.3 mo, 15.1 mo and 7.1 mo in the good, int, poor and very poor risk groups respectively (overall p <10−4). Finally, According to IPSS-R, median OS was 30.7 mo, 17.6 mo, and 10 mo in the Intermediate, High and Very High risk groups, respectively (p <10−4, figure 1). I. The 55% patients with very high risk according to IPSS-R could be further subdivided by our AZA scoring system (Itzykson et al, Blood, 2011) in 3%, 67% and 30% low, int or high risk with a significant different OS across those groups (median not reached (NR), 12.7 and 5.9 mo, p <10−4). Similarly, The 34% patients with high risk according to IPSS-R could be further subdivided by the same AZA scoring system in 6%, 80% and 14% low, int or high risk with a significant different OS across those groups (median NR, 17.3 and 6.1 mo, p <10−4). Conclusion: Contrary to the provisional IPSS-R presented in 2011, the final IPSS-R (Greenberg, Blood 2012) has strong prognostic value for survival in MDS pts treated with AZA.Its prognosic value can be further improved by specific scoring systems established for AZA treatment, like the one published by our group (Itzykson, Blood, 2011). Disclosures: No relevant conflicts of interest to declare.

Impact of the Provisional Revised-IPSS (R-IPSS) in 265 MDS Patients Treated with Azacitidine (AZA): The Groupe Francophone Des Myelodysplasies (GFM) Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 972-972 ◽  
Author(s):  
Mathilde Lamarque ◽  
Sophie Raynaud ◽  
Raphael Itzykson ◽  
Sylvain Thepot ◽  
Bruno Quesnel ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Risk Groups ◽  
Low Risk ◽  
Predictive Score ◽  
Prognostic Impact ◽  
Disease Modifying Drugs ◽  
Poor Risk ◽  
Disease Modifying

Abstract Abstract 972 Background: The IPSS published in 1997, based on cytogenetics, marrow blast % and the number of cytopenias, has played a major role in prognosis assessment in MDS. A recently presented (Greenberg, International MDS Workshop, Edinburgh 2011) IPSS provisional update (IPSS-R), using the same parameters but 5 rather than 3 cytogenetic subgroups (Schanz et al, EHA 2010), a new cut off for ANC (0.8 G/L) and different weighing of parameters, appears to refine IPSS prognostic value but, like the original IPSS, was established in pts who had received no disease modifying drugs. We assessed the prognostic value of IPSS-R in 265 higher risk MDS treated with AZA, a drug with a survival impact in those pts (Lancet Oncol, 2009). Methods: Between Sept 2004 and Jan 2009, before drug approval in EU, we enrolled 282 IPSS high and int 2 (higher) risk MDS in a compassionate patient named program of AZA and established in this cohort a prognostic scoring system (“AZA predictive score” based on Performance status (PS), cytogenetics, presence of circulating blasts, and RBC transfusion dependency) (Itzykson, Blood, 2011). We analyzed in this cohort the prognostic impact of IPSS-R in higher risk MDS treated with AZA. Results: Median age was 71 years. WHO diagnosis: 4% RA, RA RARS or RCMD, 20% RAEB-1, 54%RAEB-2, 22% RAEB-t (AML 20–30% blasts). Cytogenetics could be reclassified using new IPSS-R cytogenetic groups in 265 pts, in: 1% very good, 37% good, 18% int, 12% poor and 32% very poor. 66% pts had Hb<10g/dl, 74% had Platelets <100 G/L and 45% had ANC<0.8 G/l. Marrow blast % was <5%, 5–10%, 11–20%, 21–30% in 6%, 22%, 54% and 18% pts. Overall R-IPSS in the 265 patients was very good (no pt), Good (2 pts, <1%), intermediate (int 9.5%) poor (23%) and very poor (67% pts). The 2 pts of the Good group were excluded from further analysis. 56%, 55% and 38% had a response (CR, PR, or Hematological improvement- HI) to AZA in the int, poor and very poor R-IPSS groups, respectively (p=0.029). However, individual IPSS-R parameters, including IPSS-R cytogenetic classification (p=0.39), Hb level (p=0.42), platelet count (p=0.10), ANC (p=0.25) and marrow blast % (p= 0.129) stratified according to R-IPSS had no significant impact on AZA response. According to IPSS-R cytogenetic classification, median OS was 22.6 mo, 12.3 mo, 15.1 mo and 7.1 mo in the good, int, poor and very poor risk groups respectively (overall p <10−4, Int vs poor: p=0.85, figure 1). According to IPSS-R, median OS was 30.7 mo, 23.1 mo and 10 mo in the int, poor and very poor R-IPSS groups respectively (Int vs poor: p=0.7; poor vs very poor: p<10−3), figure 2). Thus, there was no OS difference between patients with Int and Poor R-IPSS, who represented 32% of the patients. Among those 85 patients, however, 5%, 70% and 25% respectively could be assigned to the high, intermediate and low risk groups of our AZA predictive score (Itzykson, Blood 2011) with significant differences in OS between the 3 groups (median 6.1 mo, 21 mo and not reached, respectively, p= 0.0001). Our AZA predictive score was also valid in the Very Poor R-IPSS group, with a median survival of 5.9 mo, 12.3 mo and not reached (p<10−4) in the high, int, low risk respectively. Using the “classical” IPSS, high and Int-2 patients treated with AZA had significantly different Response (37% vs 49%, p=0.05) and OS (median 9.4 vs 16 mo, respectively, p=0.004). Conclusion: In high and int 2 risk MDS (with current IPSS) treated with AZA, the R-IPSS could predict response to AZA but found no different OS between intermediate and Poor risk patients, who represented one third of the population. Thus, refined prognostic systems established in untreated patients may have to be complemented by more specific scores when using disease-modifying drugs, like our AZA predictive score in AZA treated patients. Disclosures: No relevant conflicts of interest to declare.

Validation of Updated Cytogenetic Risk Classification in Patients with Myelodysplastic Syndrome: Retrospective Study at Single Institution.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4837-4837
Author(s):  
Jina Yun ◽  
Jee Hyun Kong ◽  
Jung A. Kim ◽  
Dong Hwan Dennis Kim ◽  
Jun Ho Jang ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Medical Center ◽  
High Risk Group ◽  
Risk Classification ◽  
International Prognostic Scoring System ◽  
Prognostic Impact ◽  
Very High

Abstract Abstract 4837 Introduction The International Prognostic Scoring System (IPSS) or the WHO Classification-Based Prognostic Scoring System (WPSS) are considered as gold standard to evaluate the patients with MDS in terms of their clinical courses. Recently, a new prognostic cytogenetic risk classification, defined as favorable (5q-, 12p-, 20q-, +21, -Y, 11q-, t(11)(q23), normal, 2 abnormalities including 5q-), intermediate-1 (+1q, 3q21/q26-abnormalities, +8, t(7q), +19, -21, any other single, any other double), intermediate-2 (-X, -7/7q-, 2 abnormalities incl. -7/7q-, complex = 3 abnormalities) or unfavorable risk group (Complex >3 abnormalities), has been reported through 3 large, well-characterized international investigations (German-Austrian (GA), Spanish MDS-registry, IMRAW). This new cytogenetic classification system showed better discrimination of patients according to their prognosis with respect to overall survival and leukemic transformation. The current study attempted to evaluate the new prognostic cytogenetic risk classification in patients with MDS, retrospectively. Patients and methods Between 1996 and 2007, 180 patients with MDS, who were diagnosed and treated at the Samsung medical center, Seoul, Korea, were enrolled into the study. One hundred seventy one patients were analyzed, 115 patients receiving best supportive care were included in the present analysis. Clinical characteristics were as follows; age 59 years (median, range 16-83), male 72%; 3 patients (pts) has 5q-; 1 patient (pt), 12p-; 3 pts, 20q-; 5 pts, -Y; 1 pt, 11q-; 1 pt, t(11)(q23); 80 pts, normal; 2 pts, 2 abnormalities including 5q-; 1 pt, +1q; 1 pt, 3q21/q26-abnormalities; 18 pt, +8; 16 pts, any other single; 19 pts, any other double; 2 pts, -7/7q-; 6 pts, complex = 3 abnormalities; 12 pts, complex >3 abnormalities. Results According to IPSS, 10 patients (9%) were at low risk, 77 patients (67%) at intermediate-1 (Int-1) risk, 22 patients (19%) at intermediate-2 (Int-2) risk and 6 patients (5%) at high risk. According to WPSS, 10 patients (9%) were at very low, 25 patients (22%) at low, 36 patients (31%) at intermediate, 31 patients(27%) at high and 13 patients(11%) at very high risk group. According to new cytogenetic risk classification, 66 patients (57%) were at favorable, 34 patients (30%) at intermediate-1 (Int-1), 9 patients (8%) at intermediate-2 (Int-2) and 6 patients (5%) at unfavorable subgroup. The median OS in overall population was 23.2 months. According to the IPSS, median OS in the Low, Int-1, Int-2 and High subgroup was 37.8, 27.5, 14.8 and 11.6 months, respectively (p<0.001). According to the WPSS, median OS in the subgroup of Very low, Low, Intermediate, High and Very high risk was 54.6, 43.1, 27.5, 16.5 and 11.9 months, respectively (p<0.001). By the new cytogenetic risk classification, median OS in the Favorable, Int-1, Int-2 and Unfavorable subgroup was 23.8, 24.1, 13.0 and 9.1 months (p=0.035). Sixteen cases (13.9%) showed documented leukemic evolutions with median 9.2 months of onset. It was difficult to analyze of leukemic evolution risk due to small number of sample size. Discussion In the present study, the new cytogenetic risk classification does not seem to be validated retrospective series of patients, we couldn't validate that the new cytogenetic subgroups are powerful predictor of prognosis as good as IPSS or WPSS. To warrant availability of the new cytogenetic risk classification, large data sets should be necessary. Also, we should be consider review about the prognostic impact of the karyotype in MDS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Validation of Kantarjian (2010) Model for Intensive Chemotherapy in Older Adults with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5258-5258
Author(s):  
Shawn Tahata ◽  
Annie Im ◽  
Michael Boyiadzis ◽  
Daniel Normolle
Keyword(s):  
Older Adults ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Historical Data ◽  
Performance Status ◽  
Risk Groups ◽  
Intensive Chemotherapy ◽  
Ecog Performance Status ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) carries a poor prognosis in older adults. Limited clinical trial data exist to support the use of conventional cytarabine-based regimens in this population, and practice standards have been extrapolated from studies in younger patients. Intensive chemotherapy in older adults is associated with high rates of treatment-related mortality and poor overall survival. In 2010, Kantarjian and colleagues developed a risk model for 8-week mortality using adverse prognostic risk factors, including age ≥80 years, complex karyotype (≥3 abnormalities), poor performance status (ECOG score ≥2), and serum creatinine >1.3 mg/dL. This study validates the Kantarjian model for progression-free survival (PFS) and overall survival (OS) in older patients with AML treated with intensive chemotherapy. Methods: Adults aged ≥70 years with AML (≥20% blasts in bone marrow or peripheral blood) who received intensive chemotherapy at UPMC Hillman Cancer Center between 2000 and 2011 were evaluated. Patients were stratified into low, intermediate, and high-risk groups according to the Kantarjian (2010) model and analyzed for PFS and OS using the Kaplan-Meier method. Differences in PFS and OS between risk groups were assessed with the log-rank test. ECOG performance status was estimated using historical data at the time of diagnosis. Additional variables, including AML type (primary vs. secondary), percent blasts at diagnosis, percent CD34-positive blasts, hemoglobin, leukocytes, platelets, LDH, AST, ALT, total bilirubin, albumin, and Charlson comorbidity index (CCI) were tested for added prognostic value when incorporated into the model, using Cox proportional-hazards regression for PFS and OS. Results: Clinical data were collected for 68 patients. Of these, 26 patients, all of whom were diagnosed prior to 2003, were excluded from the final analysis due to insufficient electronic health records. The remaining 42 patients were used for the validation study. Median age at diagnosis was 73 years (range: 70-87). Twenty-seven patients (64%) had primary AML, whereas 10 (24%) had AML evolving from another hematologic disorder and 5 (12%) developed AML after radiation or chemotherapy for another malignancy. Eleven (26%) patients had ≥3 karyotypic abnormalities and the remaining 31 (74%) had fewer than 3. Thirty-three (79%) patients had an ECOG performance status of 0 or 1, and the remaining 9 (21%) did not have sufficient historical data to estimate ECOG score and were given a score of 0. In total, there were 23, 16, and 3 patients categorized into the low, intermediate, and high-risk groups, respectively. These groups had non-overlapping PFS and OS curves (p <0.001 for both endpoints). The low, intermediate, and high-risk groups had median PFS of 9.6, 5.1, and 2.1 months and median OS of 14.0, 6.3, and 2.1 months, respectively. None of the additional variables were found to add significant prognostic value to the existing model. Discussion: The Kantarjian (2010) model is a valid method of risk-stratifying older adults with respect to PFS and OS, and may be useful when weighing the risks and benefits of intensive chemotherapy in these patients. In this study, we did not identify other disease characteristics or measures of organ function that significantly improved the model, although our analysis is limited by small sample size. We note that all patients in our study had an ECOG score of 0 or 1, implying selection of healthier patients for induction chemotherapy at our institution. Our results suggest that patients in the intermediate and high-risk groups may not derive significant PFS and OS benefit from intensive chemotherapy when the risks of morbidity and mortality from treatment are considered. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2816-2816 ◽  
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.

Minimal Residual Diease Evaluation By Flow Cytometry Is a Complementary Tool To Cytogenetics For Treatment Decision In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2576-2576
Author(s):  
María-Belén Vidriales ◽  
Estefania Perez-Lopez ◽  
Carlota Pegenaute ◽  
Marta Castellanos ◽  
Jose Juan Perez ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Prognostic Value ◽  
Cox Regression ◽  
Autologous Transplantation ◽  
Risk Groups ◽  
Allogeneic Transplantation ◽  
Induction Treatment ◽  
Prognostic Impact ◽  
Grey Zone

Abstract The two main criteria for risk-adapted treatment in AML are the presence of adverse cytogenetic or molecular features, and the response to induction treatment assessed by morphology, in which only failure to respond is truly informative. Therefore, more sensitive techniques are needed to evaluate the response. However, the potential value of MRD detection within different cytogenetic subgroups in AML has not yet been defined. This raises the question of whether a negative MRD result could counterbalance the adverse effect of poor-risk cytogenetics, or whether high MRD levels after induction modify the outcome of patients with otherwise favourable feature. In addition, it is not known whether the modality of intensification therapy modifies the influence of the level of MRD assessed after induction therapy. We analyzed the prognostic impact of MRD level on the BM at CR after induction therapy using MFC in 306 non-APL AML patients. First, we have validated the prognostic value of MRD thresholds we had previously proposed (≥0.1%; ≥0.01-0.1%; and <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p=0.002). The second aim was to investigate if MRD is independent of cytogenetics. Intermediate risk cytogenetics represent a grey zone for risk stratification, and our data show that MRD evaluation by MFC discriminate three prognostic subgroups, with a 5-year RFS of 38%, 50% and 70% for patients with high (n = 86), intermediate (n = 83), and low MRD levels (n = 18) (p = 0.03). In addition, MRD assessments yielded relevant information on favourable (poor prognosis for high MRD levels) and adverse (undetectable MRD overcomes adverse prognosis) cytogenetic groups. Regarding the role of different intensification approaches, we have observed that MRD levels (evaluated at the time of mCR) allowed the identification of three risk groups among the 118 patients who underwent autologous transplantation (p = 0.02), with 5-year RFS of 40%, 57% and 83% for patients with high, intermediate and low MRD, respectively. In patients intensified with allogeneic transplantation (n = 83), MRD levels also discriminated three subgroups with 5-year RFS of 53%, 62%, and 75% for cases with high, intermediate and low MRD levels (not statistically significant differences). In patients intensified with chemotherapy alone (n = 105), only cases that achieved low MRD had an acceptable outcome, with a 5-year RFS of 65%, whereas those with intermediate or high MRD levels had a very poor outcome (5-year RFS of 11% and 28%; p = 0.020). In addition, considering patients with intermediate or high risk MRD levels (n=169), intensification with transplant improved the outcome as compared with intensification with chemotherapy (p < 0.001), with a 5-year RFS of 75%, 43% and 20% for allogeneic transplanted patients, autologous transplantation, and chemotherapy treated patients, respectively. When only patients with high MRD levels (n = 86) were considered, those receiving autologous transplantation and chemotherapy had similarly very poor results (5-year RFS of 35% and 30%), and only allogeneic transplantation offered a favourable outcome for these patients, with a 5-year RFS of 66% (p = 0.06). By contrast, the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis (Cox regression) revealed an independent prognostic value for flow-MRD levels at the time of mCR, whether considered as a continuous (p=0.03) or categorical variable (p < 0.001), together with the cytogenetic classification (p = 0.001), and patient age (p = 0.002). A scoring system, easy to apply in clinical practice, was generated based on MRD level and cytogenetics, assigning 0 points if the variable fell in the low-risk category, 1 point for intermediate levels of MRD or medium-risk cytogenetics, and 2 points for high MRD levels or high-risk cytogenetics. Based on these scores, five significantly different AML risk groups could be defined for scores of 0 to 4. These groups had 5-year RFS of 100% (n = 4), 70% (n = 30), 54% (n = 102), 35% (n = 103) and 19% (n = 19), respectively (p < 0.001). We conclude that immunophenotypic evaluation of MRD is a useful prognostic factor that could be used together with cytogenetics for the prognostic stratification of AML patients. Moreover, allogeneic transplant is the preferable option for patients with high MRD levels after induction therapy independently of the cytogenetic signature. Disclosures: Hernandez: Roche Diagnostics: Research Support Other.

Prognostic Impact Of Body Mass Index (BMI) In Acute Myeloid Leukemia (AML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2658-2658
Author(s):  
Emmanuelle Kempf ◽  
Pierre Hirsch ◽  
Myriam Labopin ◽  
Christophe Marzac ◽  
Jean-Yves Perrot ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Remission Rate ◽  
Performance Status ◽  
Univariate Analysis ◽  
White Blood Cells ◽  
Dose Calculation ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Chemotherapy Dose

Abstract Background Obesity is an increasing matter of concern worldwide. A few studies suggested that BMI might be a risk factor for outcome in different malignancies including AML. However, not all studies could confirm the prognostic value of BMI in AML. Also, capping chemotherapy dose calculation at 2m² of Body Surface Area (BSA) is widely used, but there is no strong evidence-based rationale for this. With this background, this single centre report aimed to assess whether BMI and chemotherapy dose capping could be correlated with outcome in AML patients receiving intensive induction and consolidation chemotherapy. Patients and Methods Between 2003 and 2012, all consecutive AML patients referred to our centre were prospectively included in this analysis. Eligible patients were those treated with intensive induction chemotherapy (consisting in cytosine arabinoside and anthracyclines). Acute promyelocytic leukemia cases were excluded. Anthropomorphic, patients, cytogenetic and molecular AML characteristics were collected and analyzed to assess their impact on Overall Survival (OS), Leukemia-Free Survival (LFS) and Complete Remission Rate (CR1). Analyses were performed using the logistic regression method. For every patient, BSA was capped at 2m² for chemotherapy dose calculation. Results In all, data were available for 233 patients: median age was 56 (range, 16-80) years; 60% were men; median weight was 69 kg (range, 40-158); median height 169 cm (range, 146-207); BSA > 2m² was observed in 15% of cases; underweight was seen in 7% of cases, while overweight represented 33%, and truly obese patients 10%. 64% had a Performance Status (PS) of 0 or 1. In terms of AML characteristics, secondary AML was diagnosed in 16% of cases. The good, intermediate, and poor cytogenetic risk groups represented 9%, 67%, and 24%, respectively. FLT3-ITD was observed in 17% of cases; (bi allelic) CEBPα mutation in 6% and NPM1 mutation in 23%. 27% of patients could proceed to allogeneic stem cell transplantation. With a median follow-up of 40.2 (range, 0.69-107.7) months, CR1 was achieved in 71% of cases. Overall median OS was 51±4 months, and median LFS was 45±4 months. In multivariate analysis including all relevant factors from the univariate analysis, and after adjustment for gender, BMI did not prove to be significantly associated with OS (p=0.98; HR=1.0;95%CI [0.951-1.052]), nor with LFS (p=0.88;HR=1.0;95%CI [0.957-1.05]). Also, obesity was not associated with CR1 achievement (p=0.70;HR=1.3;95%CI [0.360-4.56]). Factors significantly associated with OS were age under 60 years (p<0.0001;HR=2.6;95%CI [1.7-4.1]), good versus intermediate (p<0.026;HR=5.0;95%CI [1.2-20.8]) and good versus poor cytogenetic risk group (p<0.0001;HR13;95%CI [3.2-58.3]), presence of FLT3-ITD (p=0.058;HR=1.6;95%CI [1.0-2.7]), and initial White Blood Cells Count (p=0.008;HR=1.8;95%CI [1.2-2.8]). Finally, outcome of patients with BSA >2 m² (who underwent chemotherapy capping) was not different from other patients: BSA > 2 m² did not impact OS (p=0.65;HR=0.84;95%CI [0.39-1.8]), or LFS (p=0.6;HR=0.82;95%CI [0.38-1.75]), or CR1 (p=0.5;HR=0.63;CI [0.162-2.432]). Conclusion BMI doesn’t seem to be a prognostic factor in intensively treated AML patients. Chemotherapy dose calculation capping at 2m² of BSA is not associated with a poorer outcome in this population. Disclosures: No relevant conflicts of interest to declare.

The Significance of Serum Albumin Level and Platelet Count in Patients with Diffuse Large B-Cell Lymphoma in the Context of an Enhanced International Prognostic Index (NCCN-IPI)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1463-1463 ◽  
Author(s):  
Yotaro Ochi ◽  
Yusuke Koba ◽  
Yoshimitsu Shimomura ◽  
Yuichiro Ono ◽  
Nobuhiro Hiramoto ◽  
...  
Keyword(s):  
Platelet Count ◽  
Performance Status ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
The Elderly ◽  
Prognostic Impact ◽  
Five Factors ◽  
Group 2

Abstract Introduction The International Prognostic Index (IPI) is used to predict survival in patients with diffuse large B-cell lymphoma (DLBCL). The IPI includes five factors: age, stage, LDH, performance status, and extranodal sites. However, studies suggest that certain blood markers not included in the IPI, such as CRP, albumin, absolute lymphocyte count (ALC), and platelet count, predict survival. Recently, an enhanced IPI (NCCN-IPI) was proposed and showed excellent prognostic performance. It uses the same factors as the IPI, but refines the impact of age and LDH and the definition of extranodal disease. Few studies have assessed the prognostic impact of blood markers other than the five factors of the IPI in the context of the NCCN-IPI. Here, we analyzed the prognostic role of simple blood markers in the NCCN-IPI. Patients and Methods Data from consecutive DLBCL patients diagnosed between January 2004 and June 2014 were retrospectively analyzed. Patients receiving rituximab and anthracycline-based chemotherapy were included in the analysis. Values considered positive were CRP >1 mg/dl, albumin <3.5 g/dl, ALC <1,000/µl, or platelets <100,000/µl. The primary endpoint was overall survival (OS), assessed using the Kaplan-Meier method. The log-rank test and Cox regression analysis were used to assess the prognostic value of each variable. Results A total of 398 patients (median age, 69 years (range, 21-104)) were included. Of these, 124 (31.2%) had an ECOG performance status >1, 221 (55.5%) had advanced stage disease, and 223 (56.1%) had a high or high-intermediate NCCN-IPI score (>3). Pretreatment CRP, albumin, ALC, and platelet count values were positive in 215 (54%), 127 (31.9%), 144 (36.2%), and 31 (7.8%), respectively. The median follow-up was 34.8 months (range, 0.5-134) and the 5-year OS of the entire cohort was 68.8%. Univariate analysis identified CRP [hazard ratio (HR) 3.15; 95% confidence interval (CI) 2.07-4.80, p<0.001), albumin (HR 4.46; 95% CI 2.96-6.7, p<0.001), ALC (HR 2.40; 95% CI 1.62-3.54, p<0.001), platelet count (HR 4.69; 95% CI 2.87-7.67, p<0.001), and NCCN-IPI score >3 (HR 5.05; 95% CI 3.00-8.51, p<0.001) as significant for OS. NCCN-IPI, albumin, and platelet count remained significant in multivariate analysis (NCCN-IPI: HR 3.14; 95% CI 1.77-5.60, p<0.001; albumin: HR 2.41; 95% CI 1.36-4.27, p=0.002; platelets: HR 2.77; 95% CI 1.66-4.61, p<0.001), whereas CRP and ALC did not (CRP: HR 0.91; 95% CI 0.51-1.66, p=0.78; ALC: HR 1.33; 95% CI 0.87-2.03, p=0.18). Based on albumin and platelet count values, patients were divided into three risk groups for OS: group 1 included albumin- and platelet-negative patients (n=247); group 2 included either albumin- or platelet-positive patients (n=128); and group 3 included both albumin- and platelet-positive patients (n=23) (82.6%, 50.2% and 12.9%, respectively; p<0.001) (Figure 1A). The association of these risk groups with OS independently of the NCCN-IPI was evaluated. For patients with low or low-intermediate NCCN-IPI, the 5-year OS for group 1 (n=151), group 2 (n=22), and group 3 (n=2) was 89.2%, 76.8%, and 0%, respectively (p<0.001) (Figure 1B). For patients with high or high-intermediate NCCN-IPI, the 5-year OS for groups 1 (n=96), 2 (n=106), and 3 (n=21) was 72.6%, 44.3%, and 14.6%, respectively (p<0.001) (Figure 1C). Assessment of the prognostic impact of albumin and platelet count in the elderly led to the exclusion of the low risk category (score 0-1) among those older than 60 years (n=291) because of their age score points (>1 points) in the NCCN-IPI; thus, the ability of NCCN-IPI to differentiate risk groups might be diminished in the elderly. For low-intermediate (n=97), high-intermediate (n=118), and high (n=76) NCCN-IPI patients, the 5-year OS for the elderly according to the NCCN-IPI was 80.3%, 64.8% and 42.5%, respectively (p<0.001) (Figure 2A). The combination of albumin and platelet count also predicted survival in the elderly: the 5-year OS for groups 1 (n=169), 2 (n=103), and 3 (n=19) was 77.7%, 50.1%, and 0%, respectively (p< 0.001) (Figure 2B). Conclusion Despite the improved performance of the NCCN-IPI, albumin and platelet count were independent prognostic factors and predicted survival even in the elderly. Considering albumin and platelets may improve the accuracy of recently established prognostic models. Prospective studies should evaluate the prognostic impact of albumin and platelets. Disclosures No relevant conflicts of interest to declare.

Improved Outcome in High Risk and Very High Risk ALL by Risk Adapted SCT and in Standard Risk ALL by Intensive Chemotherapy in 713 Adult ALL Patients Treated According to the Prospective GMALL Study 07/2003.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 12-12 ◽  
Author(s):  
Nicola Gökbuget ◽  
Renate Arnold ◽  
Angelika Böhme ◽  
Rainer Fietkau ◽  
Mathias Freund ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Residual Disease ◽  
Univariate Analysis ◽  
Early Death ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Standard Risk ◽  
Very High ◽  
Improved Outcome

Abstract In 2003 the German Multicenter ALL Study Group (GMALL) initiated the trial GMALL 07/2003. Major aims were improvement of outcome by shortened, intensified induction, intensified consolidation, risk adapted and extended SCT indication and minimal residual disease (MRD) based treatment stratification. 8drug-induction was followed by uniform 1st consolidation based on HDARAC and HDMTX. Further treatment was stratified according to the following risk factors (RF): WBC > 30.000 in B-prec. ALL, late CR (>3wks), proB-, earlyT and mature T-ALL, Ph/BCR-ABL and t(4;11)/ALL1-AF4. The risk groups were defined as follows: standard risk (SR, no RF), high risk (HR,>= 1RF) and very high risk (VHR,Ph/BCR-ABL). HR and VHR pts were scheduled for SCT in CR1 with the following priorities: allo sibling, allo matched unrelated and autologous. VHR pts mostly received Imatinib according to different schedules. SR pts received 5 consolidation cycles (HDMTX/ASPx3, VP16/ARAC, CYCLO/ARAC) and reinduction. SR pts with high MRD after consolidation I were allocated to SCT. In the remaining SR pts decision on maintenance therapy was based on MRD. Between 04/03-12/06 713 evaluable (15–55 yrs) pts were included. The median age was 34 yrs. The CR rate after induction was 89% with 5% early death and 6% failure. 50%, 33% and 17% were allocated to SR (N=353), HR (N=235) and VHR (N=117) with similar CR rates of 92%, 88% and 85%. CR rate was not different in pts < vs > 35 yrs (90% vs 89%). 5 year overall survival (OS) was 54% and survival of CR (S-CR) pts was 59%. HR and VHR pts obtained 55% and 49% S-CR at 3 yrs resp. HR subgroups showed different S-CR for early T (58%), mature T (70%), pro B (66%) and other B-lineage ALL (37%). 68% and 71% of HR and VHR pts received SCT in CR1 as scheduled which thus contributed substantially to improved outcome. In SR- ALL S-CR was 69% (68% c/preB, 66% thymicT). The CCR probability was 52% at 3 yrs. CNS prophylaxis was very effective since only 2% of the CR pts had CNS involvement at relapse. Univariate analysis confirmed a significant prognostic impact of immunphenotype, WBC in B-lin ALL, time to CR and Ph/BCR-ABL. WBC was no prognostic factor in T-lin-ALL. Age was highly significant for survival with 64% survival < 35 yrs vs 48% above 35 yrs. In adolescents below 25 years the most favourable survival of 67% was achieved. In standard risk pts below 35 yrs the survival was 73% without SCT in CR1. Overall the study yielded improved CR rates (89%) and survival (54%). Risk adapted SCT indication was feasible (realised in 70% of HR/VHR pts) and lead to improved survival particularly in early/mature T-ALL and pro B-ALL. In standard risk (SR) the survival is favourable, even above 70% in young pts; however, the relapse rate is still high. Further intensification of therapy during the first year seems required. By definition of new risk factors additional SR patients could be allocated to SCT in CR1. There is however no intention to transfer all SR patients to SCT. Future improvement will be attempted by further inclusion of subtype specific and targeted therapies.

The Utility Of Newer Risk Models In Predicting Outcomes Of Patients (pts) With Higher-Risk (HR) Myelodysplastic Syndromes (MDS) Treated With Azactidine (aza)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2771-2771
Author(s):  
Amer M. Zeidan ◽  
Najla H Al Ali ◽  
Mohamed A. Kharfan-Dabaja ◽  
Eric Padron ◽  
Ling Zhang ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Research Funding ◽  
Goodness Of Fit ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Information Criteria ◽  
Prognostic Groups ◽  
Very High

Abstract Background While aza is the only drug shown to prolong survival in MDS, only half of aza-treated pts achieve objective responses (10-20% complete remission), and 4-6 months might be needed before a response is seen. Therefore the ability to select pts with high and low likelihoods of benefit from aza therapy is a clinical and a research priority. No clinical or laboratory parameter consistently predicts response or survival with aza therapy. A French prognostic scoring system (FPSS) was proposed to predict survival among aza-treated pts with HR-MDS. We sought to compare the relative prognostic discriminatory power of the FPSS with that of the revised IPSS (IPSS-R) and the global MD Anderson prognostic scoring system (MDAPSS) in a large cohort of aza-treated pts with IPSS HR-MDS. Methods The MDS database at Moffitt Cancer Center (MCC) was used to identify patients with HR-MDS (International Prognostic Scoring System [IPSS] intermediate-2 [INT-2] and high-risk) who received aza therapy. Kaplan-Meier curves were used to depict survivals, and the log-rank test was used to compare median overall survival (OS). Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models. Results We identified 259 patients HR-MDS (74.1% with INT-2 and 25.9% with high IPSS) treated with aza at the MCC. The median duration of follow up since diagnosis was 53 months (M) (95% confidence interval [CI], 49-59 M). The median number of aza cycles was 5 (range 1-72), with 75% of pts receiving 4 cycles of therapy or more. The median time from diagnosis to aza initiation was 1.5 M. The median OS for the entire cohort was 19 M (95%CI, 16-22 M), 64% of pts were males, 91% were white, 80% were older than 60 years, and 25% had therapy-related MDS. For the IPSS, the median OS was 23.5 M (CI, 18.4-28.6 M) for INT-2 and 15.9 M (CI, 13.6-18.2 M) for high-risk group (P=0.004). For the FPSS, the median OS was 29.5 M (CI, 14.1-44.9 M) for low risk (LR), 21.1 M (CI, 16.4-26.0 M) for intermediate risk (IR), and 14.1 M (CI, 8.7-19.5 M) for HR (P=0.001). For the MDAPSS the median OS was not reached (NR) for low, 53.5 M (CI, 37.5-69.4 M) for INT-1, 29.5 M (CI, 18.3-40.6 M) for INT-2, and 16.1 M (CI, 14.5-17.7 M) for high risk groups (P<0.0001). For the IPSS-R, the median OS 40.6 M (CI, 22.8-58.4 M) for low, 44.7 M (CI, 25.0-64.4 M) for INT, 23.5 M (CI, 20.3-26.8 M) for high, and 15.2 M (CI, 13.7-16.8 M) for very-high risk groups (P<0.0001). Scores generated using AIC to assess the relative goodness of fit (lower is better) were 1453 (IPSS-R), 1480 (MDAPSS), 1512 (FPSS), and 1522 (IPSS). The IPSS could not refine any of the other models. All three newer models refined IPSS INT-2 but not IPSS high-risk. The IPSS did not refine any of the newer models. The MDAPSS refined the FPSS LR and IR and the IPSS-R high and very-high groups. The FPSS refined IPSS-R very high risk group but not the not the MDAPSS. The R-IPSS did not refine the MDAPSS or the FPSS. Response rates were not statically significantly different within the prognostic groups in any of the scoring systems. Conclusions The IPSS-R, MDAPSS, and the FPSS all functioned well to separate aza-treated pts with IPSS HR-MDS into prognostic groups with different survivals, but the IPSS-R and MDAPSS appear superior to the FPSS. None of the prognostic systems predicted response to aza therapy. HR-MDS patients with poor projected survival with aza therapy might be considered for experimental approaches. Disclosures: Off Label Use: entinostat for MDS. Lancet:Celgene: Research Funding. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

scholarly journals Comprehensive Clinical-Molecular Transplant Risk Model for Myelofibrosis Undergoing Allogeneic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 689-689 ◽  
Author(s):  
Nico Gagelmann ◽  
Markus Ditschkowski ◽  
Rashit Bogdanov ◽  
Marie Robin ◽  
Bruno Cassinat ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Research Funding ◽  
Triple Negative ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Karnofsky Performance Score ◽  
Very High ◽  
Reduced Intensity

Abstract Background The dynamic International Prognostic Scoring System (DIPSS) is commonly applied to predict survival among patients with primary myelofibrosis (PMF) but has been shown to perform less precisely in secondary myelofibrosis (SMF) and after transplantation. Furthermore, the prognostic relevance of mutation profile resulted in the mutation-enhanced IPSS (MIPSS) in PMF, as well as in a model specific to SMF (MYSEC-PM) after essential thrombocythemia (ET) or polycythemia vera (PV). The aim of the current study was to develop a comprehensive prognostic system including clinical and molecular information, specifically in myelofibrosis undergoing transplantation. Methods Previously published methods were used to sequence myelofibrosis-associated genes (i.a. CALR1/2, JAK2, MPL,ASXL1, SRSF2, EZH2, IDH1/2, DNMT3A, TET2, TP53). Outcome was calculated from date of transplant (95% confidence interval). Variables associated with overall survival (OS) constructed a Cox regression with a stepwise selection procedure. Hazard ratios (HR) were used as weights for model development. Validation was done using repeated random subsampling. Performance of the model was verified via Harrel's concordance index C and was also tested in predefined cohorts: disease (PMF, SMF), conditioning, and ruxolitinib pretreatment. Results Population. The total cohort consisted of 361 patients from four different centers in Germany and France (260 PMF, 101 SMF). Median age at transplant was 57 years (range, 22-75), 58% were male and 42% had a Karnofsky performance score (KPS) <90. The median follow-up was 62 months and was similar between PMF and SMF (p=0.50). Overall 5-year OS was 60% (54-67) being similar in PMF (63%) and SMF after ET (59%) and slightly lower after PV (45%). Most frequent mutations were: JAK2 V617F (57%), CALR (20%; types 1/2/other 66%/23%/11%), MPL (5%), ASXL1 (31%), TET2 (19%), SRSF2 (9%), DNMT3A (6%), TP53 (6%). Two or more mutations were present in 60%. Most transplants were received from matched unrelated (46%), mismatched unrelated donors (MMUD, 27%), identical siblings (27%), and mismatched siblings (1%). Reduced intensity was given more frequently (64%) than myeloablative conditioning (36%). Frequencies at transplant were 9% (low), 29% (intermediate-1), 48% (intermediate-2), 14% (high) according to DIPSS and 3% (low), 40% (intermediate), and 57% (high) for MIPSS. Factors on outcome. In univariate analysis, mutations in CALR and MPL showed better OS (79% and 76%) vs. JAK2 (53%) and triple negative (50%; p=0.001). Outcome was similar according to CALR type (p=0.99). ASXL1 and DNMT3A mutations also entered the multivariate model. The following eight clinical, molecular and transplant-related variables were identified (corresponding HR): leukocytes >25x109/l (1.71), platelets <150x109/l (1.53), KPS <90 (1.63), age >57 years (1.69), recipient/donor CMV serostatus (+/- vs. other, 1.68), ASXL1 (1.74), JAK2/triple negative (2.10), and MMUD (2.11). Myelofibrosis Transplant Scoring System (MTSS). A weighted score of 1 was assigned to leukocytosis, thrombocytopenia, KPS <90, age >57, recipient/donor CMV serostatus (+/-), and ASXL1 mutation, whereas 2 points were assigned to JAK2/triple negative and MMUD. Four risk groups constructed the MTSS: low (score 0-2), intermediate (score 3-4), high (score 5-6), and very high (score 7-9). The 5-year OS according to risk groups was 88%, 71%, 50%, and 20% (Figure 1). The hazard for death (with low-risk as reference) was 2.36 for intermediate-risk, 4.65 for high-risk, and 9.72 for very high-risk. The score was predictive of OS overall as well as for PMF and SMF (p<0.001, respectively). The MTSS showed overall C statistics of 0.718 (0.707-0.730) after cross-validation yielding a median of 0.727 in PMF and 0.708 in SMF indicating improved performance and replicability vs. DIPSS (0.572), MIPSS (0.577), and MYSEC-PM (0.601). The system was also predictive of OS in different conditioning settings (reduced intensity and myeloablative) and in patients with ruxolitinib pretreatment (p<0.001, respectively). Conclusions The new MTSS includes modern disease- and transplant-associated risk variables pertinent to both PMF and SMF. This proposed system consistently predicts outcome facilitating posttransplant decision-making and can be applied to different conditioning settings and to patients receiving ruxolitinib pretreatment. Figure 1. Figure 1. Disclosures Beelen: Medac: Consultancy, Other: Travel Support. Kroeger:Novartis: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Sanofi: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document