Disease-Attributable Mortality in the Myelodysplastic Syndromes (MDS): A Study from the Spanish MDS Cooperative Group (GESMD)

Abstract Introduction: The MDS are a group of clonal hematopoietic disorders characterized by blood cytopenias and increased risk of transformation into acute myeloid leukemia (AML). The MDS predominate in old people (median age at diagnosis > 70 years) so that a fraction of the observed mortality would be driven by age-related factors shared with the general population rather than the MDS. Distinguishing between the MDS-related and unrelated mortality rates will help better assessment of the population health impact of the MDS and more accurate prognostication. This study was aimed at quantifying the MDS-attributable mortality and its relationship with the IPSSR risk categories. Methods: The database of the GESMD was queried for patients diagnosed with primary MDS after 1980 according to the WHO 2001 classification. Patients with CMML, younger than 16 years or who lacked the basic demographic or follow-up data were excluded. Relative survival and MDS-attributable mortality were calculated by the cohort method and statistically compared by Poisson multivariate regression as described by Dickman (Stat Med 2004; 23: 51). Three main parameters were calculated: the observed (all-cause) mortality, the MDS-attributable mortality (both as percentage of the initial cohort), and the fraction of the observed mortality attributed to the MDS. Results: In total, 7408 patients met the inclusion criteria and constitute the basis for this study. Among these patients, 5307 had enough data to be classified according to the IPSSR. Median age was 74 (IQR: 16-99) years and 58 % were males. The most frequent WHO categories were RAEB, type I or II (29% of cases), RCMD (28%), and RA with ring sideroblasts (16%). Most patients (72%) were classified within the very low and low risk categories of the IPSSR. At the study closing date (December 2014), 1022 patients had progressed to AML, 3198 had died (974 after AML) and 3210 were censored alive. The median actuarial survival for the whole series was 4.8 (95% CI: 4.6-5.1) years and 30% of patients are projected to survive longer than 10 years. The overall MDS-attributable mortality at 5 years from diagnosis was 39%, which accounted for three-quarters of the observed mortality (51%, figure). The corresponding figures at 10 years for the MDS-attributable and observed mortality were 55% and 71%, respectively. According to the IPSSR, the 5-year MDS-attributable mortality rates was 19% for the very low risk category, 39% (low risk), 70% (intermediate risk), 78% (high risk), and 92% (very high risk). On average, the incidence rate ratio for the MDS-attributable mortality increased 1.9 times (95% CI: 1.7-2.3, p<0.001) as the IPSSR worsened from one to the next risk category. The fraction of the observed mortality attributed to the MDS was 0.55 for the very low risk category, 0.79 (low risk), 0.93 (intermediate risk), 0.96 (high risk), and 0.99 (very high risk). After distinguishing between AML-related and unrelated mortality, the 5-year MDS-attributable mortality not related to AML was 10% for the very low risk category, 20% (low risk), 33% (intermediate risk), 42% (high risk), and 44% (very high risk). By comparing these figures with the above ones, we could estimate that about 50% of the MDS-attributable mortality was AML-unrelated and that such fraction kept nearly constant across the five IPSSR categories. Conclusions: About three-quarters of the mortality observed in patients with MDS is caused by the disease, the remaining one-quarter being due to MDS-independent factors shared with the general population. The MDS-attributable mortality increases with the IPSSR risk category, from half the observed mortality in the very low risk to nearly all the mortality observed in the high and very high risk groups. Half the MDS-attributable mortality is driven by factors unrelated to leukemic transformation, a proportion that keeps constant across the five IPSSR risk categories. Disclosures Valcarcel: AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ramos:AMGEN: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

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Patient-Reported Outcomes Associated with Different Treatments for Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v128.22.3602.3602 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3602-3602 ◽

Cited By ~ 1

Author(s):

Marlise R. Luskin ◽

Angel M. Cronin ◽

Martha Wadleigh ◽

David P. Steensma ◽

Richard M. Stone ◽

...

Keyword(s):

High Risk ◽

Global Health ◽

Board Of Directors ◽

Low Risk ◽

Intermediate Risk ◽

Red Cell ◽

Advisory Committees ◽

Treatment Status ◽

Patient Reported ◽

Very High

Abstract Background: The myelodysplastic syndromes (MDS) are associated with shortened overall survival (OS) and inferior quality of life (QOL). Age, degree of comorbidity, MDS risk group, and treatment status are all likely predictors of both outcomes. We aimed to assess the association between treatment status and patient-reported QOL in a large cohort of community-treated MDS patients at the time of presentation to tertiary care, while controlling for the other three factors. Methods: Beginning in 2006, patients with MDS presenting for their first evaluation at Dana-Farber Cancer Institute (DFCI) were enrolled into a clinical database (consent rate 85%). Enrollment included administration of the EORTC QLQ-C30 (Aaronson, JNCI, 1993), a 30-item measure of QOL that includes subscales for global health (higher score better), fatigue (lower score better), and physical function (higher score better). Medical record review was performed to characterize baseline demographic, clinical, and laboratory data. Treatment status included therapies received in the community during the 30 days prior to QOL assessment, as these were most likely to directly impact QOL. Comorbidity was assigned via the Modified Charlson Comorbidity Index (mCCI; Charlson, Journal Clinical Epi, 1994). MDS prognostic group was assigned via the IPSS-R (Greenberg, Blood, 2012). Associations between treatment status and QOL scores were analyzed with separate multivariable linear regressions adjusted for age, sex, comorbidity, and IPSS-R. Results: In total, 287 patients with complete QLQ-C30 data were included, of which 22% were IPSS-R very high risk, 24% high risk, 22% intermediate risk, 26% low risk, and 6% very low risk. The majority of patients (66%) were male, median age was 68 years, and the mCCI was 0 in 40%, 1-2 in 35%, and 3+ in 24%. Relative to very low risk on the IPSS-R, the unadjusted hazard ratios for death were 1.5 for low risk, 2.2 for intermediate risk, 4.9 for high risk, and 7.2 for very high risk (Ptrend<0.001). In the 30 days prior to tertiary center evaluation, 52% of patients had received therapy: 40% red cell or platelet transfusions, 18% erythropoiesis-stimulating agents (ESAs), 11% either azacitidine or decitabine (HMA), 2.8% lenalidomide, and 2.8% deferasirox (treatments not mutually exclusive). Patients with higher risk disease on the IPSS-R were more likely to have received at least one treatment (41% for very low/low risk, 44% for intermediate risk, 57% for high risk, and 72% for very high risk; Ptrend<0.001). Associations between MDS therapies and QOL adjusted for age, sex, comorbidity, and IPSS-R are shown in the Table. Patients receiving any treatment in the 30 days prior to DFCI presentation experienced inferior global health and physical function, and increased fatigue in comparison to patients receiving no treatment. For patients with anemia, patients receiving an ESA without red cell transfusion experienced superior global health and physical functioning, and less fatigue compared to patients receiving transfusions (and no ESA). Patients receiving an HMA did not have significant differences in QOL compared to those who were not. Conclusions: These data suggest that patients receiving MDS treatments have inferior QOL when compared to patients who are not treated, indicating a need for agents that better address the negative impact of MDS on QOL. Our results encourage the prospective study of the impact of different treatments, established and in development, on QOL. Our data also support the practice of an ESA trial before initiation of transfusions for MDS-related anemia, as the latter was associated with worse QOL even after adjustment for IPSS-R which includes degree of cytopenias. Finally, these results complement a recent report of minimal improvement in OS with HMA treatment in clinical practice (Zeiden, Leukemia and Lymphoma, 2016), suggesting that such treatment may also not be associated with significantly better QOL. Disclosures Steensma: Amgen: Consultancy; Genoptix: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Millenium/Takeda: Consultancy; Ariad: Equity Ownership. Stone:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy; Merck: Consultancy; Xenetic Biosciences: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; ONO: Consultancy; Agios: Consultancy; Seattle Genetics: Consultancy; Celator: Consultancy; Jansen: Consultancy; Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy. DeAngelo:Novartis: Consultancy; Baxter: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Ariad: Consultancy.

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Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) and Validation of a Proposed Novel Risk Model (BALL Score) in Real-World Relapsed/Refractory (R/R) CLL Patients Receiving Idelalisib and Rituximab

Blood ◽

10.1182/blood-2019-126717 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5485-5485

Author(s):

Massimo Gentile ◽

Gianluigi Reda ◽

Francesca Romana Mauro ◽

Paolo Sportoletti ◽

Luca Laurenti ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Low Risk ◽

Intermediate Risk ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

The CLL-IPI score, which combines genetic, biochemical, and clinical parameters, represents a simple worldwide model able to refine risk stratification for CLL patients. This score, developed in the era of chemo-immunotherapy, has not been gauged extensively in R/R-CLL patients treated with novel targeted agents, such as BCR and BCL2 inhibitors. Soumerai et al (Lancet Hematol 2019) assembled a novel risk model for OS in the setting of R/R-CLL receiving targeted therapies in clinical trials. This model, consisting of four accessible markers (β2M, LDH, Hb, and time from initiation of last therapy; BALL score), is able to cluster 3 groups of CLL patients with significantly different OS. This multicenter, observational retrospective study aimed to validate the proposed Soumerai (BALL) and/or CLL-IPI scores for R/R-CLL real-world patients treated with idelalisib and rituximab (IDELA-R). The primary objectives were to determine whether: i) the CLL-IPI retains its prognostic power also in R/R patients treated with IDELA-R; ii) the BALL score is of prognostic value for IDELA-treated R/R-CLL patients, and iii) the BALL score is predictive of PFS. This study, sponsored by Gilead (ISR#IN-IT-312-5339), included CLL patients collected from 12 Italian centers, who received IDELA-R (idelalisib 150 mg b.i.d. and a total of 8 rituximab infusions intravenously) outside clinical trials as salvage therapy with available data for the calculation of the CLL-IPI and BALL scores at the time of treatment start. OS was estimated for all subgroups of both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test, and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by Harrell's C-index. Overall, 120 CLL patients were included in this analysis. The majority of patients were Binet stage B and C (94.2%). The median age was 75 years and 83 cases (69.2%) were male. The median number of previous therapies was 3 (range 1-9) Baseline patient features are listed in Table 1. After a median follow-up of 1.6 years (1 month to 5.8 years), 33 patients had died and 39 experienced an event (death or progression). CLL-IPI scoring (115/120 evaluable cases) indicated that 6 patients (5.2%) were classified as low-risk, 24 (20.9%) as intermediate-risk, 58 (50.4%) as high-risk, and 27 (23.5%) as very high-risk. Stratification of patients according to the CLL-IPI score did not allow prediction of significant differences in OS. Thus, low-risk patients had a 2-year OS probability of 75% (HR=1), with an intermediate-risk of 68% (HR=2.9, 95%CI 0.37-23.3, P=0.3), high-risk of 83% (HR=1.58, 95%CI 0.2-12.5, P=0.66), and very high-risk of 63% (HR=5.9, 95%CI 0.78-45.2, P=0.86). Next, we tested a modified CLL-IPI by assigning a more balanced score to the original CLL-IPI variables (Soumerai et al, Leukemia Lymphoma 2019), partially overlapping previous results. Specifically, modified CLL-IPI high-risk group showed a significantly different OS as compared with intermediate- and low-risk groups. However, differently from the original report no difference was observed between low- and intermediate-risk). According to the BALL score (120/120 evaluable cases), 33 patients (27.5%) were classified as low-risk, 68 (56.7%) as intermediate-risk, and 19 (15.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 92% (HR=1), intermediate-risk of 76% (HR=5.47, 95%CI 1.3-23.7, P=0.023), and high-risk of 54% (HR=15.1, 95%CI 3.4-67, P<0.0001) (Figure 1). Harrell's C-statistic was 0.68 (P<0.001) for predicting OS. To note, BALL score failed to significantly stratify patients in terms of PFS. As for Soumerai et al (Leukemia Lymphoma 2019), the original CLL-IPI score did not retain discriminative power in term of OS in R/R-CLL patients receiving IDELA-R. The modified CLL-IPI failed to stratify low- and intermediate-risk groups, likely due to the number of cases analysed in the current cohort and the heterogeneous IDELA-containing regimens included in the Soumerai study (Soumerai et al, Leukemia Lymphoma 2019). The CLL-IPI was designed for CLL patients treated with first-line chemo-immunotherapy. Herein, we confirm the prognostic power of the BALL score in this real-world series for OS, while losing the predictive impact of patient outcomes in terms of PFS. Disclosures Mauro: Gilead: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Varettoni:ABBVIE: Other: travel expenses; Roche: Consultancy; Janssen: Consultancy; Gilead: Other: travel expenses. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Use of Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation (AF) in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood-2020-142645 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 50-51

Author(s):

Georgios Christopoulos ◽

Zachi I. Attia ◽

Peter A. Noseworthy ◽

Timothy G. Call ◽

Wei Ding ◽

...

Keyword(s):

Artificial Intelligence ◽

High Risk ◽

Sinus Rhythm ◽

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Advisory Committees ◽

Increased Risk ◽

Very High

Background: Clinical factors including previous history of AF, heart failure, hypertension, valvular heart disease, increased age and male gender increase the risk of AF in CLL patients (Shanafelt, Leukemia and Lymphoma 2017). Treatment with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib has also been associated with an increased risk of AF in CLL. We evaluated the role of artificial intelligence electrocardiography (AI-ECG) in predicting ibrutinib-induced AF (and, for reference, AF unrelated to ibrutinib) in patients with CLL. Methods: We identified two cohorts of CLL patients using the Mayo Clinic CLL Database. Cohort 1 included patients evaluated within 12 months of CLL diagnosis who did not ever receive ibrutinib. Cohort 2 included patients who were treated with ibrutinib. The electrocardiographic signature of AF in sinus rhythm was detected by an AI-ECG algorithm previously developed using a convolutional neural network (Attia, Lancet 2019). The baseline AI-ECG AF score (positive defined as >0.10 on a scale of 0-1 which offers best balance between sensitivity and specificity per Attia et al.) was computed based on ECGs obtained within 10 years prior to CLL diagnosis (Cohort 1) or 10 years prior to initiation of ibrutinib therapy (Cohort 2). Patients with AF at baseline, missing data, or with ECGs previously used to train the AI algorithm were excluded. Reverse Kaplan Meier diagrams were plotted for both cohorts grouped by AI-ECG positivity. Cox proportional hazards were fitted to assess the predictive ability of AI-ECG in both cohorts. Results: After screening 2,739 patients and applying exclusion criteria (126 patients had baseline AF) a total of 1,149 patients with median 4 (interquartile range [IQR] 2-9) baseline ECGs were included in the analysis (Figure 1A). Cohort 1 included 951 patients with a median follow up of 3.0 (IQR 0.6-7.0) years and positive baseline AI-ECG in 546 (57%) patients. Cohort 2 included 198 patients with a median follow up of 1.6 (IQR 0.7-3.2) years and positive baseline AI-ECG in 91 (46%) patients. In Cohort 1, the median age was 67 years (IQR 58-72), 681 (72%) of patients were men, 68% had low/intermediate risk CLL-International Prognostic Index (IPI), and 32% had high/very high-risk CLL-IPI. In Cohort 2, the median age was 69 years (IQR 62-75), 139 (70%) of patients were men, 13% had low/intermediate risk CLL-IPI, and 87% had high/very high-risk CLL-IPI. AF occurred during follow up in 164 patients (17%) in Cohort 1 and 46 patients (23%) in Cohort 2. In both Cohorts 1 and 2, a positive baseline AI-ECG significantly increased the incidence of AF during follow up (log rank <0.001) (Figure 1B and C). Hazard ratios (for positive vs. negative AI-ECG) were 33.9 (95% confidence interval [CI] 15.0-76.6) for Cohort 1 and 14.8 (95% CI 5.3-41.3) for Cohort 2. Conclusion: The addition of AI to a standard 12-lead ECG obtained during normal sinus rhythm - an inexpensive and ubiquitous test - predicts the occurrence of future AF in patients with CLL. This holds true irrespective of BTKi -based therapy and has important implications for the management of CLL patients. Disclosures Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Kenderian:BMS: Research Funding; Gilead: Research Funding; Novartis: Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Juno: Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; Kite: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Torque: Consultancy. Wang:Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Kay:Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria; GlaxoSmithKline: Research Funding. Parikh:MorphoSys: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria, Research Funding.

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How Are Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS) Treated? Impact on Clinical Evolution and Overall Survival: A Report from the Erasme Study

Blood ◽

10.1182/blood.v126.23.5239.5239 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5239-5239

Author(s):

Julia Montoro ◽

Helena Pomares ◽

Itziar Oiartzabal ◽

Teresa Bernal ◽

Edgardo Barranco ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Median Time ◽

Lower Risk ◽

Low Risk ◽

Advisory Committees ◽

Very High ◽

Rbc Transfusion

Abstract Introduction: As MDS includes a wide range of heterogeneous neoplastic disorders, the therapeutic approaches for treatment of MDS vary greatly. The aim of this study was to evaluate the use of different therapies, and assess time from diagnosis to therapy initiation and pt outcomes, in an unselected Spanish population with MDS from the ERASME study. Methods : The ERASME study (CEL-SMD-2012-01) is an observational, prospective, multicenter study of pts with either MDS or chronic myelomonocytic leukemia (CMML); disease was defined using the 2008 World Health Organization (WHO) classification system. Initial pt management strategy was classified into 3 groups: active therapy (AT), such as chemotherapy and treatment with azacitidine (AZA); allogeneic hematopoietic cell transplantation (HCT), which included pts receiving other therapies before transplantation; and observation and support (OB&SP), which included red blood cell (RBC) and platelet transfusions, and growth factors. Here, we present overall survival (OS) data from a prespecified interim analysis of pts with International Prognostic Scoring System (IPSS)-defined Low- and Intermediate-1-risk (lower-risk [LR]) MDS using the Kaplan-Meiermethod. Results : A total of 207 IPSS-defined LR MDS pts (117 with Low-risk and 81 with Intermediate-1-risk MDS) were recruited from Jan 2013 to Feb 2014; median follow-up was 16.1 months (interquartile range [IQR] 11.5-19.1). Pt characteristics are described in the Table. We identified 14 pts with high-risk features (HRF) for MDS based on the presence of ≥ 1 of the following: neutropenia (n = 6; absolute neutrophil count < 0.5 × 109/L); thrombocytopenia (n = 4; platelet count < 50 × 109/L); grade 2-3 bone marrow fibrosis (n = 1); or adverse cytogenetic risk (n = 3). At baseline, 28 (14%) pts had RBC transfusion-dependence (RBC-TD), 166 (80%) were RBC transfusion-independent (RBC-TI), and 13 (6%) had missing data. Probability of RBC-TD increased over time with 41 of 166 pts having RBC-TD after 12 months. Median OS of RBC-TD versus RBC-TI pts was not reached (NR) (95% confidence interval [CI] 19.65 months-NR) versus NR (95% CI 22.93 months-NR), respectively (hazard ratio [HR] 3.2, 95% CI 1.13-9.22; P = 0.0275). At diagnosis, 117 (57%) pts (including 4 with HRF) were considered for OB, and 76 (37%) pts for SP (69 pts [5 HRF] for erythropoiesis-stimulating agents, and 7 pts [3 HRF] for RBC and platelet transfusions). Only 10 (5%) pts were considered for AT, which included AZA (n = 5; 1 HRF), lenalidomide (n = 4; 1 HRF), and alemtuzumab (n = 1). HCT was considered in 4 pts (2%; 3 with prior AZA treatment and 1 with prior chemotherapy). After 12 months, 13 (11%) of 117 OB pts switched to AT; median time to AT was 30 weeks (IQR 24.0-44.0). Of 76 pts receiving SP, 23 (30%) switched to AT; median time to AT was 23.9 weeks (IQR 16.3-39.1). Of 184 pts with Revised-IPSS (IPSS-R) scores, at 12 months' follow-up 35 had died (15 of 140 Very Low/Low-risk pts, 15 of 32 Intermediate-risk pts, and 5 of 12 High/Very High-risk pts). At 12 months, 36 of 207 (17%) LR MDS pts had died, including 6 of the 14 HRF pts. Median OS was shorter among HRF pts versus non-HRF pts (19.45 months [95% CI 5.52-NR] vs NR [95% CI NR-NR], respectively) (HR 3.5, 95% CI 1.47-8.53; P = 0.0048). Median OS for IPSS-R Very Low/Low-risk and Intermediate/High/Very High-risk pts was NR (95% CI NR-NR) and 19.45 months (95% CI 11.99-NR), respectively (HR 5.4, 95% CI 2.8-10.7; P < 0.001). Conclusions : The typical treatment of LR MDS pts in Spain consists mainly of supportive care. We observed that risk of RBC-TD increased after diagnosis. These data suggest more attention should be provided at diagnosis or during follow-up of LR MDS pts with poor prognosis, and that they should be considered for more intensive treatment. Abstract presented on behalf of the ERASME Study Investigators Group. Disclosures Off Label Use: Azacitidine was used in IPSS Intermediate-1-risk patients with MDS, and lenalidomide was used in MDS patients with del(5q) plus > 1 cytogenetic abnormality. Castellanos:SCLHH: Other: Membership; SEHH: Other: Membership. Navarro:Celgene Corporation: Employment. López:Celgene SL Unipersonal: Employment, Equity Ownership, Honoraria. Valcárcel:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Prognostic Value of TTM with TTM Distribution and Ball Score in Relapsed/Refractory Ibrutinib Treated B-CLL - in the Real-World Setting

Blood ◽

10.1182/blood-2020-143030 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Ozren Jaksic ◽

Marija Ivic ◽

Rajko Kusec ◽

Zdravko Mitrovic ◽

Mario Pirsic ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Response Assessment ◽

Low Risk ◽

Prognostic Models ◽

Intermediate Risk ◽

Discriminative Power ◽

Advisory Committees ◽

Early Relapse ◽

Novel Drugs

There is a high number of clinical and biological parameters with impact on prognosis in B-CLL and number of successful prognostic models were developed (clinical stages, CLL IPI, MDACC score, etc.). However, rapidly changing therapeutic landscape with more successful targeted terapines with different modes of action, render most of these models developed in era of chemo and chemoimmunotherapy less useful. Recently simple prognostic score (BALL score) based on 4 parameters (LDH>UNL, B2microglobulin>5mcg/l, Hemoglobin<120 g/l in males and 110g/l in females, and time from start of last therapy- 0-1 parameters - low risk, 2-3 - intermediate risk and 4 high risk) was developed and validated in number of cohorts (Soumerai et al, Lancet Hematol). High cost of novel drugs in less affluent countries led to a higher criterion for reimbursement. Until recently in Croatia ibrutinib was reimbursed only for early relapse (less than 24 months from last therapy) or refractory disease with additional criteria for high risk disease including Rai stages III and IV or high tumor burden demonstrated by TTM score >15. TTM score (www.b-cll.org) is old, simple and continuous parameter useful for prognosis and response assessment (Jaksic B et al BJH 1980) and because it cover tumor mass in all major lymphoid compartments and allow tumor distribution assessment (Jaksic O et al, Haematologica 2001) it can be very useful for response assessment to novel agents were redistribution of lymphocytes can be significant (Jaksic O BJH 2014). In other to evaluate usefulness of novel BALL score and old TTM score in real life setting where the novel drug is available only to patients with higher risk defined by respective scores, we have evaluated series of 42 RR CLL patients treated with ibrutinib at our institution since March 2015. There were 15 females and 27 males, median age 70 years (range 53 to 82), 9 patients had 17p deletion, median TTM was 14 (range 1.2-28), 20 patients had Rai stage III/IV. Median follow up was 24 months, and maximal 64 months. Since all patients were in early relapse or refractory, we have actually used simplified BALL score based on only 3 parameters. There was no significant relationship between BALL and TTM in our patient population. In our patient cohort low risk BALL score had only 3 patients, 28 patients had intermediate risk and 11 high risk and it showed only marginal discriminative power (p=0.054) While TTM>15 did not show discriminative power (p=0.14). When we added TTM>18 as an additional parameter (point) to BALL score, this modified score (0-3 low/intermediate - 23 patients and 3-4 high risk - 19 patients) showed significant discriminative power (p=0.002) (Figure 1). Observed results indicate that: 1) performance of prognostic models may be significantly dependent on discriminative power of its components and if these components are criteria for initiation of therapy with novel agent(i.e. only high risk group defined by these parameters) it significantly lower its prognostic power, and vice versa 2) such criteria for therapy selection/initiation until these criteria are met may actually mean that we treat patients with novel agents when these are less effective. We have shown that addition of TTM significantly improves BALL score. Refinement of prognostic scores with parameters that may have predictive power for novel drugs, as well as adaptation criteria for reimbursement in future studies (including pharmacoeconomics) may further improve quality of care of B-CLL patients. Disclosures Jaksic: Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Pejsa:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pliva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alvogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oktal Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Prediction of Molecular Response of Chronic Phase CML Patients by the EUTOS Score: Results of the Randomized CML-Study IV,

Blood ◽

10.1182/blood.v118.21.3762.3762 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3762-3762

Author(s):

Susanne Saussele ◽

Michael Lauseker ◽

Verena Hoffmann ◽

Ulrike Proetel ◽

Benjamin Hanfstein ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Risk ◽

Molecular Response ◽

Intermediate Risk ◽

Advisory Committees ◽

High Risk Patients ◽

Risk Patients ◽

Eutos Score

Abstract Abstract 3762 Introduction: The EUTOS Score was developed and validated as a prognostic tool for the achievement of complete cytogenetic response (CCR) at 18 months for chronic phase (CP) CML patients under imatinib therapy. The score identifies high-risk patients not reaching CCR at 18 months with a positive predictive value of 34% and a specificity of 92% using only two variables, peripheral blood basophils and spleen size at diagnosis (Hasford et al. Blood 2011). We sought to evaluate the clinical impact of the EUTOS score to predict molecular response. Therefore, we analyzed the EUTOS score with patients from the German CML-Study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with interferon alpha vs. imatinib in combination with araC vs. imatinib after interferon failure). Results: From July 2002 to December 2010, 1,502 patients with BCR-ABL positive CML in CP were randomized. 129 patients with imatinib after interferon alpha and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1,337 patients were evaluable for overall and progression-free survival (OS and PFS), 1,252 for molecular responses. 749 of these patients were part of the score development sample. Therefore cytogenetic analyses are not described here. By EURO score, 36% of patients (n=475) were low risk, 51% (n=681) intermediate risk, and 12% (n=167) high risk. The EUTOS score was low risk in 88% (n=1163) and high risk in 12% (n=160). The high-risk patients differed between the two scores: EUTOS high-risk patients were classified according to EURO score in 12% as low (n=19), in 45% as intermediate (n=68) and in 43% as high risk (n=73). Patients with high, intermediate, and low risk EURO score achieved MMR in 22, 16, and 13 months and CMR4 (BCR-ABL <=0.01%) in 59, 41, and 34 months. P-values for low vs. intermediate risk groups were borderline only (0.03 for MMR and 0.04 for CMR4), whereas p-values for high vs. low/intermediate risk groups were for both molecular response levels <0.001. At 12 months the proportion of patients in MMR was 38%, 46%, 54% for high, intermediate, and low risk patients, respectively. Similar results were observed with the Sokal score. Patients with high risk EUTOS score achieved deep molecular responses (MMR and CMR4) significantly later than patients with low risk EUTOS score (MMR: median 21.0 vs. 14.8 months, p<0.001, Fig. 1a; CMR4: median 60.6 vs. 37.2 months, p<0.001, Fig. 1b). The proportions of patients achieving MMR at 12 months were significantly lower in the EUTOS high-risk group than in the EUTOS low-risk group (30.8% vs. 50.6%, p<0.001). OS after 5 years was 85% for high and 91% for low risk patients (p=n.s.), PFS was 85% and 90%, respectively. Conclusions: The EUTOS score clearly separates CML patients also according to MMR and CMR4 (MR4). The new EUTOS score should be used in future trials with tyrosine kinase inhibitors in CML. Disclosures: Neubauer: Novartis: Honoraria, Research Funding; Roche: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

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Independent Validation of the 2008 World Health Organization (WHO) Reclassification of Myelodysplastic Syndromes (MDS) Associated with Ring Sideroblasts

Blood ◽

10.1182/blood.v112.11.2686.2686 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2686-2686 ◽

Cited By ~ 2

Author(s):

David P. Steensma ◽

Curtis A Hanson ◽

Ayalew Tefferi

Keyword(s):

High Risk ◽

Median Survival ◽

Scoring System ◽

Who Classification ◽

Risk Group ◽

Low Risk ◽

Risk Category ◽

Intermediate Risk ◽

Multilineage Dysplasia ◽

Ring Sideroblasts

Abstract Background: The 2001 WHO classification of myeloid neoplasms distinguished 2 forms of MDS associated with >=15% ring sideroblasts and <5% marrow blasts: refractory cytopenia with multilineage dysplasia and with ring sideroblasts (RCMD-RS) vs. refractory anemia with ring siderblasts (RARS, erythroid-restricted dysplasia). However, the real prognostic value of separating RCMD-RS from RCMD with <15% ring sideroblasts and from RARS is uncertain, and the WHO has proposed merging RCMD-RS and RCMD in the 2008 classification revision. Furthermore, the WHO-based Prognostic Scoring System (WPSS), proposed by Malcovati and colleagues in 2005 as a dynamic system that overcomes some of the limitations of the 1997 International Prognostic Scoring System (IPSS), has undergone limited independent external validation to date and its applicability to sideroblastic MDS in particular is unclear. We assessed the validity of the 2008 WHO reclassification and the WPSS for MDS cases associated with >=15% ring sideroblasts and a normal blast proportion. Methods: We reviewed WPSS and IPSS component parameters at diagnosis and the clinical outcomes of 465 patients (68% males, median age 72) evaluated at our institution over a 13-year period: 140 with RARS, 114 with RCMD-RS, and 211 with RCMD. Patients were assigned a WPSS score and risk category (very low-risk group=0 points; low=1; intermediate=2, high=3 or 4) by summing 3 subscores: 2001 WHO classification (0 for RARS, 1 point for RCMD or RCMD-RS), IPSS cytogenetic risk group (0=good, 1=indeterminate, 2=poor), and red cell transfusion dependence (0=no, 1=yes). Survival was assessed by Kaplan-Meier estimates, and prognostic factors examined by proportional hazards analysis. Results: The median time until death or last followup was 26 months, and 70% of patients were known to have died. The median survival by WHO MDS subtype was 75 months for RARS, 25 months for RCMD-RS, and 26 months for RCMD (Log-Rank p<0.0001 for RARS vs. either RCMD-RS or RCMD; p=0.60 for RCMD vs. RCMD-RS ). Both the WPSS and IPSS predicted overall survival in patients with ring sideroblasts. Median survival for the patients grouped by WPSS risk category was 89 months for very low risk (n=95), 41 for low risk (n=198), 31 for intermediate risk (n=82), and 11 for high risk (n=91) (p<0.0001, except for low risk vs. intermediate risk, p=0.31). (Very high risk WPSS scores cannot be achieved without excess marrow blasts, and such patients were excluded from this analysis.) Median survival by IPSS was 73 months for low-risk, 33 months for intermediate-1, and 8 months for intermediate 2 (p<0.0001). The IPSS’ predictive power was unchanged if patients with secondary MDS were included or excluded (the IPSS was based on a review of 816 patients with apparently de novo MDS). Conclusions: These data support the WHO’s proposal to merge RCMD and RCMD-RS, and suggest that the adverse prognostic significance of multilineage dysplasia renders the presence of ring sideroblasts unimportant. The WPSS is a valid prognostic tool in patients with MDS associated with ring sideroblasts, but in this subgroup both the WPSS and IPSS stratify patients into 3 risk groups, and the WPSS does not offer additional value over the IPSS. Figure Figure

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The Combination of ISS 3, High LDH and t(4;14) and/or Del(17p) Identify a Simple Prognostic Index for Overall Survival in Patients Treated with Novel Agents-Based Induction Therapy and Front-Line Autologous Stem Cell Transplantation, and Allow the Definition of a Subgroup of Patients At High-Risk of Early Death From Progressive Disease

Blood ◽

10.1182/blood.v120.21.598.598 ◽

2012 ◽

Vol 120 (21) ◽

pp. 598-598 ◽

Cited By ~ 1

Author(s):

Philippe Moreau ◽

Lucie Planche ◽

Michel Attal ◽

Cyrille Hulin ◽

Thierry Facon ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Progressive Disease ◽

Prognostic Index ◽

Early Death ◽

Novel Agents ◽

Advisory Committees ◽

High Risk Disease ◽

Definition Of ◽

Very High

Abstract Abstract 598 Background: Several biological parameters have been described, which define patients with multiple myeloma with a high-risk of progression. Nevertheless, apart from the International Staging System (ISS), no clear, simple and reliable prognostic index has yet been identified, especially for the classification of patients with very high-risk disease. We aimed to characterize the group of patients who have a high risk of early death from progression in the context of frontline therapy using novel agents-based induction therapy and autologous stem cell transplantation. Methods: We investigated prognostic parameters of patients enrolled in the IFM2005-01 trial, which compared bortezomib-dexamethasone versus VAD induction followed by ASCT (Harousseau et al, J Clin Oncol 2010;28:4621–4629). Results: In a multivariate logistic regression analysis, the risk of death from progressive disease (and not toxicity) (42 cases out of 482 patients) within the first 2 years from the start of therapy was related to 3 independent adverse baseline characteristics: high LDH > normal value (p = 0.0014), ISS 3 (p = 0.0097) and cytogenetic abnormalities defined by the presence of either t(4;14) or 17p deletion (p = 0.0002). These 3 variables enabled the definition of a simple scoring system consisting of 4 categories (scores 0–3) that predicts for overall survival (OS). Score 0 was defined by the absence of adverse factors (neither high LDH, nor ISS 3, nor t(4;14) and/or del(17p)); in this group of patients, representing 57% of the overall population, the 4-year OS rate was 84%. A score of 1 was defined by the presence of only 1 adverse factor (either high LDH or ISS 3 or t(4;14) and/or del(17p)). The 4-year OS rate in this group of patients (32% of the overall population) was 73%. A score of 2 defined by the presence of high LDH plus ISS 3 in the absence of t(4;14) and/or del(17p), was found in 6% of the overall population. The 4-year OS rate in this group was 68%. Score 3 was defined by the presence of t(4;14) and/or del(17p) in addition to either ISS 3 or high LDH. In this group of patients, representing 5% of the overall population, the median OS was only 19 months (Figure). Conclusion: We have defined a new and simple scoring system that allows the identification of a small group of patients with very high-risk disease and a shortened survival despite the use of intensive novel agents-based therapy. These preliminary findings require confirmation using data from a large number of patients enrolled in the most recent prospective clinical trials investigating triplet induction regimens prior to ASCT. The subgroup of patients with a score of 3, which is associated with a detrimental outcome, might benefit from innovative therapeutic approaches. Disclosures: Moreau: janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Attal:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Hulin:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Facon:millenium: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees. Kolb:celgene: Honoraria; janssen: Honoraria. Roussel:janssen: Honoraria; celgene: Honoraria. Leleu:celgene: Honoraria; janssen: Honoraria. Avet-Loiseau:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees.

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Do Unexpected and Cryptic FISH Lesions Of Chromosomally Normal MDS Patients Have Any Prognostic Relevance?

Blood ◽

10.1182/blood.v122.21.1549.1549 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1549-1549

Author(s):

Paolo Bernasconi ◽

Irene Dambruoso ◽

Marina Boni ◽

Paola Maria Cavigliano ◽

Ilaria Giardini ◽

...

Keyword(s):

High Risk ◽

Disease Progression ◽

Low Risk ◽

Disease Stage ◽

Intermediate Risk ◽

Disease Evolution ◽

Prognostic Relevance ◽

Increased Risk ◽

Very High ◽

Disease Specific

Abstract Conventional cytogenetic (CC) still remains a mandatory step in the routine diagnostic work-up of every MDS patient (pt), is one of the major determinant of disease outcome and guides potential treatment decisions. However, CC is not informative in about 50% of chromosomally normal (CN) pts and provides limited information in those with very rare defects even if the revised IPSS cytogenetic categories have tried to overcome this drawback. More sensitive techniques (aCGH, SNP-a and NGS), still used in the research setting only, suggest that CN pts may instead contain novel unexpected chromosomal lesions which prognosis is still undefined. Thus, the principal goal of our study was to establish whether FISH with disease specific probes (i.e. for chromosomal regions most commonly affected in MDS) along with non-disease specific probes (i.e. for regions which alteration in MDS has been demonstrated by aCGH only) may effectively unmask clonal cryptic defects. Other aims were to establish the nature of these defects, to identify the potentially targeted genes and to estimate their possible prognostic relevance. The one-hundred twenty-seven consecutive CN MDS pts of the present study came to our observation in the period January 2003-December 2012. They were forty-nine females and seventy-eight males, median age 66 years (range 24-88). Twenty-one pts were diagnosed as RARS, 29 as RA, one as CRMDS, one as U-MDS, 25 as RCMD, 26 as RAEB-1 and 24 as RAEB-2. On CC 122 pts presented a normal karyotype and five no mitotic figures. Considering the revised IPSS score, 62 pts were considered very low-risk, 32 low-risk, 23 intermediate risk, 8 high-risk and 2 very high-risk. Median follow-up was 22 months (range 1-90). At the time of the study nine pts have died. FISH probes were chosen based on the frequency of their involvement in MDS and their Mb position determined using UCSC genome browser on Human Mar. 2003 assembly. They were obtained from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA), labelled and applied as previously described. These probes were: RP11-912D8 (19q13.2); RP11-196P12 (17q11.2); RP11-269C4 (14q12); RP11-351O1 (10q21.3); RP11-144G6 (10q11.2); RP11-122A11 (7q34); RP11-951K18 (5q13.1); RP11-101K5 (4p14); RP11-544H14 (2q33). i-FISH cut-off values were fixed at 10%. Thirty-one pts (24.4%) presented at least a single defect, always represented by deletions or gains of chromosomal material. Among them 8 pts (25.8%) presented at least two defects. Bands most commonly targeted by deletions/amplifications were 19q13.2 (61.3%), 14q12 (32.2%), 17q11.2 (16.1%), 5q13.1 (12.9%), 7q34 (12.9%), 4p14 (9.6%). Deletions of bands 10q11.2, 10q21.3 and 2p33 were more rare. As the RMD-1 gene, involved in DNA double strand breaks and homologous recombination, maps at band 19q13.2, the most commonly deleted chromosomal area, additional molecular tests are being developed to analyse this gene. An abnormal FISH pattern was observed in 2/21 (9.5%) RARS, in 7/29 (24.1%) RA, in 5/25 (20.0%) RCMD, in 8/26 (30.6%) RAEB-1 and in 9/24 (37.5%) RAEB-2. Considering IPSS, an abnormal FISH pattern was revealed in 7/62 (11.3%) very low-risk, in 8/32 (25%) low-risk, in 10/23 (43.4%) intermediate risk, in 5/8 (62.5%) high-risk and in 1/2 very high-risk patients. Disease evolution occurred in a total of 34 pts (3 RARS, 7 RA, 5 CRMD, 11 RAEB-1 and 8 RAEB-2), 16 (one RARS, 3 RA, 2 CRMD, 6 RAEB-1 and 4 RAEB-2) with an abnormal FISH pattern. All the 8 patients with at least two chromosomal deletions experienced disease progression. In conclusion, i) FISH reveals novel unexpected karyotype defects, most commonly deletions pinpointing genes involved in DNA repair, in about 24.4% of CN MDS; ii) band 19q13.2 deletion is the most common defect, frequently associated with disease evolution; ii) an abnormal FISH pattern is correlated with an advanced disease stage and an intermediate/high revised IPSS score; iii) >two lesions are associated with an increased risk of disease progression. Disclosures: No relevant conflicts of interest to declare.

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Persistent Improvement In Clinical Outcomes With Bortezomib-Thalidomide-Dexamethasone Vs Thalidomide-Dexamethasone Incorporated Into Double Autologous Transplantation For Multiple Myeloma: An Updated Analysis Of Phase 3 Gimema-MMY-3006 Study

Blood ◽

10.1182/blood.v122.21.2090.2090 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2090-2090 ◽

Cited By ~ 4

Author(s):

Michele Cavo ◽

Monica Galli ◽

Annalisa Pezzi ◽

Francesco Di Raimondo ◽

Claudia Crippa ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Low Risk ◽

Standards Of Care ◽

Consolidation Therapy ◽

Phase 3 ◽

Advisory Committees ◽

Cox Regression Analysis

Abstract Over the last years, incorporation of novel agents into autologous stem cell transplantation (ASCT) has improved markedly the outcomes of younger patients with newly diagnosed multiple myeloma (MM). Superior results with experimental treatments vs previous standards of care have been frequently reported after preliminary analyses and need to be confirmed with longer follow up. The randomized phase 3 GIMEMA-MMY-3006 study was designed to compare bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double ASCT. Data from the initial analysis, with a median follow up of 36 months, demonstrated that patients randomized to the VTD arm enjoyed superior complete/near complete response (CR/nCR) rates after both induction and consolidation therapy, and had a significantly longer PFS compared to those prospectively assigned to the TD arm. We performed an updated analysis of the study after a median follow up of 59 months and results are herein reported. A persistent TTP and PFS benefit with incorporation of VTD into ASCT was confirmed. On an intention-to-treat analysis of 236 patients randomized to the VTD arm, median TTP was 62 months and median PFS was 57 months. The median values for 238 patients randomly assigned to the TD arm were 45 months for TTP (HR=0.64, p=0.001) and 42 months for PFS (HR=0.66, p=0.001) (Fig. 1). With the longer follow up of this analysis, an initial divergence between OS curves could be appreciated after 4 years, although the difference was not yet statistically significant at 6 years (75% for VTD vs 69% for TD). Superiority of VTD over TD for TTP and PFS was retained across prespecified subgroups of patients with high risk and low risk disease. In particular, PFS benefit with VTD was seen for patients age >60 years (HR=0.62, p=0.013) and younger than 60 years (HR=0.70, p=0.026), with ISS stage 1 (HR=0.59, p=0.009) and ISS stage 2-3 (HR=0.69, p=0.018), and for those with t(4;14) and/or del(17p) (HR=0.43, p<0.001) and with t(4;14) alone [t(4;14) positivity but lack of del(17p)] (HR=0.41, p=0.001). In comparison with patients with t(4;14) positivity who were randomized to TD, those assigned to the VTD arm had significantly longer PFS (median: 24 vs 53 months, HR=0.41, p=0.0007) (Fig. 2) and a trend towards longer OS (4-year estimates: 66% vs 81%, p=0.052). By the opposite, similar PFS curves were seen for patients in the VTD group regardless of the presence or absence of t(4;14) (Fig. 3). On multivariate Cox regression analysis, randomization to the VTD arm was an independent factor predicting for prolonged PFS (HR=0.64, P=0.001). Additional disease- and treatment-related variables independently affecting PFS included attainment of CR/nCR after both induction (HR=0.64, p=0.010) and consolidation therapy (HR=0.57, p<0.001), β2-m >3.5 mg/L (HR=1.7, p<0.001) and presence of t(4;14) and/or del(17p) (HR=2.0, p<0.001). On multivariate analysis, β2-m, cytogenetic abnormalities and attainment of CR/nCR after consolidation therapy were independently associated with OS. With an updated median follow-up of 49 months from the landmark of starting consolidation therapy, median PFS was 50 months for patients receiving VTD consolidation and 38 months for those treated with TD (HR= 0.69, P=0.015) (Fig. 4). Superior PFS with VTD vs TD consolidation therapy was observed for patients who failed CR/nCR after the second ASCT (HR=0.48, P=0.003) and was retained in both low risk and high risk subgroups. Finally, duration of OS from relapse or progression was similar between the two treatment groups (median, 42 for VTD vs 35 months for TD, p=0.47), even when bortezomib was incorporated into salvage therapy. In conclusion, this updated analysis of the GIMEMA-MMY-3006 study demonstrated: 1) a persistent PFS benefit with VTD vs TD in the overall population, as well as in subgroups of patients with high risk and low risk MM; 2) the ability of VTD, but not of TD, incorporated into double ASCT to overcome the adverse prognosis related to t(4;14); 3) the significant contribution of VTD consolidation to improved outcomes seen for patients randomized to the VTD arm; 4) the lack of more resistant relapse after exposure to VTD as induction and consolidation therapy compared to TD. A longer follow up is required to assess the OS benefit, if any, with VTD plus double ASCT. Disclosures: Cavo: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Tacchetti:Janssen and Celgene: Honoraria. Zamagni:Celgene: Honoraria; Janssen-Cilag: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Brioli:Celgene: Honoraria.

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