Outcomes for Patients (Pts) with Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) with del5q Aged < 65 Years Treated with Lenalidomide (LEN) in MDS-003 and MDS-004: A Retrospective Combined Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1723-1723 ◽  
Author(s):  
Pierre Fenaux ◽  
Aristoteles Giagounidis ◽  
Alan F. List ◽  
Stephen D. Nimer ◽  
Eva Hellström-Lindberg ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Potential Risk ◽  
Research Funding ◽  
Advisory Committees ◽  
Secondary Failure ◽  
Potential Risk Factors ◽  
Rbc Transfusion ◽  
Reduced Risk

Abstract Abstract 1723 Background: Two multicenter studies (MDS-003/-004) found LEN leads to RBC transfusion independence (TI) in > 50% of pts with RBC transfusion dependent Low-/Int-1-risk MDS with del5q (List A et al. NEJM 2006;355: 1456–65; Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). RBC-TI ≥ 8 wks with LEN was associated with significantly reduced risk of AML progression and death (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). Alternative therapy is required for pts failing LEN therapy. Aims: To assess predictive factors of LEN response and long term outcomes (especially after primary or secondary LEN failure) of pts < 65 yrs included in MDS-003/-004; ie, those in whom intensive therapies including allogeneic stem cell transplantation (ASCT) may be considered. Methods: LEN was administered as follows (all 28-d cycles): 5 mg/d on d 1–28 and 10 mg/d on d 1–21 or 1–28. RBC-TI ≥ 26 wks and cytogenetic response (CyR; IWG 2000) are reported. Overall survival (OS) and AML progression were assessed using Kaplan-Meier method. Response rates and outcomes in pts < 65 yrs were retrospectively compared with pts ≥ 65 yrs. Primary failure was defined as lack of RBC-TI with LEN treatment and secondary failure as relapse after achievement of RBC-TI ≥ 26 wks. Cox proportional hazards models were used to evaluate the effect of potential risk factors (ie, age, sex, time since diagnosis, FAB classification, LEN dose, IPSS risk, WPSS risk, cytogenetics, bone marrow blast %, transfusion burden, no. of cytopenias, hemoglobin level, platelet and neutrophil counts, RBC-TI ≥ 26 wks [time-dependent variable] and CyR [categorical variable]) on OS and AML progression. Logistic model was used to evaluate the effect of potential risk factors on achievement of RBC-TI ≥ 26 wks. Results: The trials included 97 (33.9%) pts < 65 yrs. Of these, 73.2% were female; 20.6% were IPSS Low-, 52.6% Int-1-, and 4.1% Int-2-risk; 30.9% had del5q with ≥ 1 additional cytogenetic abnormality (8.2% had complex cytogenetics). At baseline (BL), median time since diagnosis was 2.4 yrs (range 0.2–20.7) and median RBC transfusion requirement was 6 units/8 wks (range 1–15). In pts ≥ 65 yrs (n = 189) most BL characteristics were similar except IPSS risk, which was lower (36.5% Low-, 37.0% Int-1-, 5.8% Int-2-risk; p =.012). RBC-TI ≥ 26 wks was achieved by 54 (55.7%) pts < 65 yrs (vs 49.7% pts ≥ 65 yrs; p =.563). The median duration of RBC-TI ≥ 26 wks in responders was not estimable in pts < 65 yrs or ≥ 65 yrs (log-rank p =.879). None of the potential risk factors assessed was a significant predictor of RBC-TI ≥ 26 wks in pts < 65 yrs, possibly due to small pt number. In pts < 65 yrs with available follow-up cytogenetics (n = 71), CyR was achieved by 32 (45.1%) pts (vs 64.5% pts ≥ 65 yrs; p =.014). At time of data cutoff, 51 (52.6%) pts < 65 yrs were alive (vs 36.0% pts ≥ 65 yrs; p =.008); 29 (29.9%) pts progressed to AML (vs 20.1% pts ≥ 65 yrs; p =.077). The 1-, 2-, and 3-yr AML-progression rates were 9.7%, 15.4%, and 24.0% in pts < 65 yrs; and 6.0%, 17.9%, and 22.3% in pts ≥ 65 yrs (log-rank p =.308). The 1-, 2-, and 3-yr OS rates were 91.7%, 78.1%, and 66.4% in pts < 65 yrs; and 83.1%, 65.2%, and 49.9% in pts ≥ 65 yrs (log-rank p <.001). In pts < 65 yrs, RBC-TI ≥ 26 wks was the only factor associated with longer median OS (4.9 yrs in responders vs 2.0 yrs in non-responders) and lower BL ANC was the only factor associated with a reduced risk of AML-progression. A total of 43 (44.3% of total population) pts < 65 yrs experienced primary LEN failure and 9 (16.7% of responders) secondary failure. In pts < 65 yrs with primary failure after 16 wks (median follow up from primary failure 2.6 yrs), 13 (30.2%) pts progressed to AML (1- and 2-yr cumulative AML rates 7.9% and 16.8%) and median OS was 2.67 yrs. In pts < 65 yrs with secondary failure (median follow up from secondary failure 1.7 yrs), 3 (33.3%) pts progressed to AML and median OS was not reached (1-yr cumulative OS rate was 64.8%). Conclusions: LEN-treated pts < 65 yrs had greater incidence of IPSS Int-1-risk, had similar rates of RBC-TI ≥ 26 wks, but achieved CyR less often and more progressed to AML vs pts ≥ 65 yrs. In pts < 65 yrs, achievement of RBC-TI ≥ 26 wks was the only factor associated with longer OS. After primary or secondary LEN failure, AML progression rates were ∼30% each, and median OS 2.67 yrs and 1-yr OS 64.8%, respectively. Low-/Int-1-risk pts < 65 yrs with del5q and primary or secondary LEN failure have a relatively poor outcome and should be considered potential candidates for ASCT. Disclosures: Fenaux: Celgene Corporation: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Johnson & Johnson: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment. Shammo:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. del Cañizo:Celgene Corporation: Spanish advisory committee.

Eculizumab Protects Against TE and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3480-3480
Author(s):  
Gérard Socié ◽  
Hubert Schrezenmeier ◽  
Petra Muus ◽  
Jeffrey Szer ◽  
Alvaro Urbano-Ispizua ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Advisory Committees ◽  
Significant Protective Effect ◽  
Rbc Transfusion

Abstract Abstract 3480 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. PNH, in large part due to chronic hemolysis and platelet hyperactivation, is associated with thromboembolism (TE), one of the leading causes of disease mortality. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown in clinical trials to reduce hemolysis and the incidence of TE. The International PNH Registry provides the opportunity to understand from real world experience the impact of eculizumab on TE reduction in PNH patients. Aim: To assess the risk factors for TE and mortality in PNH patients enrolled in the Registry and to assess the effectiveness of eculizumab in reducing PNH-associated TEs. Methods: Patients are eligible for the Registry if they have a detectable PNH clone, regardless of disease severity, comorbidities, or treatments (past, current or planned). As of June 30, 2012, there were 1547 patients enrolled from 25 countries on 5 continents. Patients were excluded from analysis if they were missing key demographic variables or dates of eculizumab use, or did not yet have follow-up information. The cumulative incidence of TE was determined using competing risks methods to take into account bone marrow transplantation and death, while Kaplan-Meier methods were used for the cumulative incidence of mortality. Risk factors for TE and mortality were explored using a Cox proportional hazards model with stepwise selection (the significance level was relaxed to P=0.20 due to the small number of events for analysis). Variables examined in the models included: ethnicity; prior TEs, bone marrow disorders, impaired renal function, impaired hepatic function (IHF), abdominal pain, dysphagia, dyspnea, easy bruising/bleeding, fatigue, headache, hemoglobinuria, Karnofsky performance score, granulocyte clone size and lactate dehydrogenase (LDH) at enrollment, red blood cell (RBC) transfusions 6 months prior to enrollment as a marker for hemolysis, and treatments after enrollment (eculizumab and warfarin/heparin). Results: The mean age of the 1047 patients eligible for analysis was 45 years; 537 patients (51.3%) were female and 868 were Caucasian (82.9%). Anti-coagulants (heparin/warfarin) were used by 28% of patients and eculizumab was used by 51% during follow-up (18% used both). During a mean (SD) follow-up of 22.5 (18.4) months, 16 patients had a TE and 51 were deceased. Patients taking eculizumab during follow-up had a cumulative incidence of TE at 1 year of 0.41% and 1.35% at 2 years, while patients not taking eculizumab had TE incidence of 1.70% and 2.61% at 1 and 2 years, respectively. In the multivariate Cox model, the greatest associations with TE were RBC transfusions in the 6 months before enrollment (hazard ratio [HR]=9.61), history of IHF (HR=4.78), dyspnea (HR=2.42) and headache (HR=2.33) at enrollment. While controlling for these variables, eculizumab had a significant protective effect (HR=0.23, 95% CI = 0.08–0.66). The cumulative incidence of mortality in eculizumab-treated patients was 2.31% and 4.21% at 1 and 2 years, while in untreated patients it was 4.40% and 7.01%, respectively. In the multivariate model of mortality, the greatest associations were age 60+ years (HR=4.72), Karnofsky score <80 (HR=2.34), fatigue at enrollment (HR=1.94), and recent RBC transfusion (HR=1.75). While controlling for these variable, eculizumab had a significant protective effect (HR=0.41, 95% CI = 0.23–0.73). Conclusions: This analysis of a large international cohort of ‘real world’ patients with PNH showed that eculizumab is associated with a significantly reduced risk of TE and mortality, consistent with prior research. Recent RBC transfusion, a surrogate marker for hemolysis, was associated with increased risk of TE and mortality. Several symptoms and hepatic dysfunction also showed increased risks for these outcomes. As might be expected, older age and low performance status were associated with mortality. These data should be interpreted within the context of a contemporary cohort of PNH patients who may or may not be treated (with either eculizumab and/or anticoagulation). These analyses are limited due to small number of TE and mortality outcomes. Disclosures: Muus: Alexion Pharmaceuticals : Sat on advisory board of Alexion Pharmaceuticals. Other. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Kanakura:Shire: Consultancy. Rosse:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion Pharmaceuticals, Inc: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Engraftment Syndrome in the Setting of Autologous Stem Cell Transplantation for Multiple Myeloma-a Single Institution Review of over 600 Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4576-4576
Author(s):  
Sudarsan Kollimuttathuliam ◽  
Phyllis McKiernan ◽  
David S. Siegel ◽  
Scott D. Rowley ◽  
Noa Biran ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Clinical Manifestations ◽  
Advisory Committees ◽  
Autologous Transplant ◽  
Engraftment Syndrome ◽  
Equity Ownership ◽  
Reduced Risk

Engraftment syndrome (ES) is a well-defined entity characterized by non-infectious fever and other clinical manifestations including skin rash, pulmonary infiltrates, diarrhea, weight gain and neurological symptoms which happens in the setting of autologous HSCT during early neutrophil recovery phase. (Spitzer ,2001).These clinical manifestations usually occur immediately before or at the time of neutrophil engraftment possibly due to the release of inflammatory cytokines. ES may require therapy with corticosteroids and other immunosuppressive drugs. Our study cohort included 645 patients with multiple myeloma treated with autologous stem cell transplantation between January 2010 and June 2019. The majority of patients had a single autologous transplant (80%), 18 % received a second autologous transplant and 3 patients had a third autologous transplant. Fifty seven percent of patients were male, 61 % had IgG myeloma and 50 percent had standard risk cytogenetics. Sixty three percent of patients were under the age of 65 years. ES was defined as a combination of at least 2 symptoms not attributed to other causes, including non-infectious fever, diarrhea, skin rash, pulmonary infiltrates or hepatic dysfunction, occurring from 3 days prior to 10 days post engraftment. (Cornell ,2015).One hundred and ninety seven patients in this cohort met the criteria for engraftment syndrome of whom 173 were treated with corticosteroids and 9 required the addition of tacrolimus or cyclosporine. Univariate and multivariate statistical analyses were performed looking at risk factors for the development of ES and the overall effect of ES on patient outcome. Results of our univariate analysis showed that age >65, female sex, use of plerixafor were significant risk factors for developing engraftment syndrome while use of cyclophosphamide-based mobilization had significantly reduced risk. Multivariate analysis using Gray Fine model revealed that patients over 65 years were twice as likely to develop ES than patients who were younger than 65 years (HR=1.881, CI: 1.405 to 2.518). Females had a 36% higher risk of ES than male patients (HR=1.355, CI: 1.011 to 1.815). Patients who were infused with more than 7x106 CD34+ cells/kg had a 40% reduced risk of developing ES (HR=0.559, CI: 0.385 to 0.812). Receiving the new formulation of melphalan: EVOMELAⓇ, as preparative regimen, was associated with a 60% increased risk of developing ES compared to patients treated with the standard formulation (HR=1.597, CI: 1.116 to 2.285). The use of plerixafor was found to be a risk factor for ES even when adjusted for age(HR=1.463,CI:1.024 to 2.089). Follow- up of patients that did not develop ES (n=445) had a median of 59 months (IQR: 29.0 -80.0months), range: 0 - 136 months. Follow-up time of patients that developed ES (n=197) was 41.0 months (IQR: 16.0 - 66.0 months), range: 0.0 - 131 months.An overall survival analysis of patients who developed engraftment syndrome showed a trend for improved survival in patients who did not develop engraftment syndrome, however this did not meet statistical significance and PFS curves were similar with no statistically significant difference between the two groups. Our study of this large cohort of patients suggests that selection of mobilization regimen and conditioning chemotherapy could decrease the incidence of ES, thereby decreasing morbidity and prolonged hospital stay. There can also be a consideration for pre-emptive treatment of patients in the very high risk category based on age, gender and available cell dose. Disclosures Siegel: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Goy:Takeda: Other: Grants outside of the submitted work; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Hakensackumc: Research Funding; University of Nebraska: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prognostic Factors of Long-Term Outcomes In Low- or Int-1-Risk MDS with del5q Treated with Lenalidomide (LEN): Results From a Randomized Phase 3 Trial (MDS-004)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4027-4027
Author(s):  
Pierre Fenaux ◽  
Aristotles Giagounidis ◽  
Odile Beyne-Rauzy ◽  
Ghulam Mufti ◽  
Moshe Mittelman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 3 ◽  
Advisory Committees ◽  
Free Survival ◽  
Lower Baseline ◽  
Younger Age ◽  
Equity Ownership ◽  
Rbc Transfusion

Abstract Abstract 4027 Background: Transfusion dependence is a significant negative predictor of overall survival (OS) and risk of AML-progression in MDS (Malcovati L, et al. JCO 2007;25:3503-10). LEN 5 mg and 10 mg induced significant RBC-transfusion independence (TI) versus placebo (PBO) in a randomized, phase 3, multicenter, double-blind (DB) study (MDS-004) in RBC transfusion-dependent patients (pts) with Low- or Int-1-risk MDS with del5q (Fenaux P, et al. Blood 2009;114:Abstract 944). The aim of this analysis is to identify prognostic factors for AML-free survival and OS during LEN treatment in the MDS-004 study after prolonged follow-up (pts enrolled between July 8, 2005 and July 26, 2007; last pt visit June 14, 2010; final data cutoff July 9, 2010). Methods: LEN-naïve pts with RBC transfusion-dependent Low- or Int-1-risk del5q MDS were randomized to receive LEN 5 mg on days 1–28 or LEN 10 mg on days 1–21, both of every 28-day cycle, or PBO. First response was assessed at 16 wks. Responders continued DB treatment for up to 52 wks, until erythroid relapse or disease progression. Pts who completed 52 wks of therapy could enter an open label (OL) extension phase at their current LEN dose. PBO and LEN 5 mg recipients who did not respond by wk 16 or who had erythroid relapse could receive LEN 5 or 10 mg, respectively, in the OL phase. This analysis included data through completion of the OL phase for pts randomized to LEN 5 and 10 mg combined in the DB phase; pts randomized to PBO were excluded as all except 11 pts crossed-over to LEN 5 mg. LEN 5 and 10 mg dose groups were comparable, allowing data for the two groups to be combined. A Cox proportional hazard model was used to evaluate effect of potential baseline risk factors, with RBC-TI ≥ 26 wks and cytogenetic response (CyR) as time-dependent covariates on AML-free survival and OS. The full model with all covariates and the final model, based on backward model selection method, are presented. Results: All 138 pts randomized to LEN who received ≥ 1 dose were included: median age 68 y (range 36–86); 74% of pts were female; 66% had an isolated del5q abnormality and 28% had ≥ 1 additional abnormality; and 43% of pts had WHO-based Prognostic Scoring System (WPSS) low/int risk, 32% high/very high, and 25% missing data. At baseline, median time since diagnosis was 2.7 y (range 0.2–29.2) and median RBC transfusion requirement was 6 units/8 wks (range 1–25). Duration of LEN was 12.9 mo (range 0.3–36.7); 54 of 62 responders entered the OL phase. Median follow-up for the cohort was 36 mo (range 0.4–59.4). Overall, 31 (22%) pts progressed to AML (median time to AML progression 4.01 y; 95% confidence interval [CI] 3.17–4.03) and 66 (48%) died (median OS 3.68 y; 95% CI 2.93–not estimable). The cumulative 3-year AML-progression rate was 34.8% and the 3-year OS rate was 56.0%. Multivariate results are presented in the Table. Achieving RBC-TI ≥ 26 wks was associated with a 45% and 51% reduction in the risk of AML progression (P=0.022) and death (P=0.008), respectively. Lower baseline ferritin level and younger age were associated with a reduced risk of AML-progression and death. Conclusion: Achievement of RBC-TI with LEN was associated with a significantly reduced risk of AML progression and death. Other predictors for longer AML-free survival and OS were lower baseline ferritin levels and younger age. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; J&J: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Beyne-Rauzy:Amgen: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Backstrom:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Hellström-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 463-463 ◽  
Author(s):  
David P. Steensma ◽  
Uwe Platzbecker ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership ◽  
Grade 3 ◽  
Rbc Transfusion

Abstract BACKGROUND: Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria. METHODS: IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations. RESULTS: Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL. As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]). Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities. SUMMARY / CONCLUSIONS: In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. Disclosures Steensma: Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

scholarly journals Impact of Bortezomib- or Lenalidomide-Based Induction Treatment on High Risk Cytogenetic Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Enrolled in the Gimema-MM-03-05 and EMN01 Trials

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 744-744 ◽  
Author(s):  
Alessandra Larocca ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Francesca Patriarca ◽  
Lorenzo De Paoli ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Significant Difference ◽  
Reduced Risk

Abstract Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p&lt;0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani: celgene: 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. Musto: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

scholarly journals RBC Alloimmunization Burden Is High in Regularly RBC-Transfused Myelodysplastic Syndrome (MDS) Patients: A Report from South Australian-MDS Registry

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3562-3562
Author(s):  
Deepak Singhal ◽  
Sophia Hague ◽  
David Roxby ◽  
L Amilia Wee ◽  
Oi-Lin Lee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Scoring System ◽  
Research Funding ◽  
Cox Regression ◽  
Competing Risk ◽  
Competing Risk Analysis ◽  
Advisory Committees ◽  
Rbc Transfusion

Abstract Introduction: Anemia is one of the commonest presenting features of MDS and approximately 30-40% of patients require regular RBC-transfusion. RBC-transfusion dependency (RBC-TD) is a poor-prognostic factor independent of revised International Prognostic Scoring System (IPSS-R) (Hiwase et al ASH 2014). Although RBC transfusion increases the risk of alloimmunization, there is limited literature characterizing this risk in MDS patients as compared to other hematological disorders (such as thalassemia). Methods: This retrospective study assessed the alloimmunization rate in 784 MDS and AML (20-30% blasts) patients registered in the South Australian-MDS registry (SA-MDS registry) between 1991 and 2015. RBC-TD was defined as ≥1 unit of RBC transfused every eight weeks for four months according to WHO based Prognostic Scoring System. The cumulative incidence of RBC-alloimmunization was calculated using competing risk analysis (death being the competing risk). Factors associated with increased rate of RBC antibody formation were investigated by Cox regression analysis. Results: The median age of the 784 patients at diagnosis was 75 years with 66% males. The estimated median follow up time was 7.3 years. 70% of patients (549/784) were diagnosed with primary MDS, while the remaining patients were diagnosed with AML (20-30% blasts; n=57), CMML (n=91) or therapy-related myeloid neoplasm (T-MN; n=87). At last follow-up 30% patients were alive, 67% were deceased and 3% were lost to follow-up. During the study period, 658 (84%) patients required ≥1 unit of RBC transfusion and median RBC units transfused were 29 (range 0-708). The WPSS definition of RBC-TD was met in 47% (366/784 patients), while 36% (282/784) patients required intermittent RBC-transfusions (RBC-TI). During follow up, 83 (13%) patients formed 155 RBC-alloantibodies and 50% of these cases (42/83) developed >1 RBC-alloantibody. Autoantibodies were also detected in 31 cases, mainly in association with RBC-alloantibodies (n=27; complex alloimmunization) while 4 cases had only autoantibodies. Interestingly, in 19/27 of cases autoantibodies were detected only after alloimmunization. The pathophysiologic mechanism of this remains unclear. The most common alloantibody specificities were Rh (57%) and Kell (21%) (Table 1). The median interval between 1st RBC transfusion and antibody detection was 10 (0.2-225) months. In 9 cases (6 females) alloantibodies were detected prior to the 1st unit of RBC-transfused. The incidence of RBC alloimmunization reached a plateau at 16% by 100 units of RBC (Fig. 1A), however 80% of antibodies were detectable by 30-40 RBC units transfused. It indicates that most "responders" will form antibodies during the first 30-40 units of RBC transfused. Since most chronically transfused MDS patients do not form RBC alloantibodies it is important from a clinical and resource-utilization standpoint to identify who is at greatest risk of RBC alloimmunization. Multivariate analysis using Cox-regression model was performed. The only factor which was associated with significantly higher risk of RBC alloimmunization was RBC-TD (HR 2.52; p=0.0005). Age, sex, IPSS-R category and number of RBC units transfused did not independently predict alloimmunization rate. Using competing risk analysis, the cumulative incidence of RBC-alloimmunization was significantly higher in RBC-TD group compared to RBC-TI group (p=0.0004; Fig. 1B). Conclusion: RBC-alloimmunization is a substantial risk in MDS patients, especially in RBC-transfusion dependent cases. Extended phenotype matching (D,C,c,E,e and Kell) could have prevented alloantibody formation in 79% of alloimmunized MDS patients. Table 1. Specificity of 155 RBC-alloantibodies Table 1. Specificity of 155 RBC-alloantibodies Disclosures Yeung: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals The Burden of Atrial Fibrillation in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3119-3119
Author(s):  
Chinonso Ukeje ◽  
Bahaa Al-Azzam ◽  
Santosh L. Saraf ◽  
Dawood Darbar ◽  
David Tofovic
Keyword(s):  
Risk Factors ◽  
Life Expectancy ◽  
Board Of Directors ◽  
Research Funding ◽  
Observation Time ◽  
Hemoglobin Level ◽  
Categorical Variables ◽  
Cell Disease ◽  
Advisory Committees

Abstract Introduction Life expectancy amongst individuals with sickle cell disease (SCD) has plateaued, with cardiopulmonary complications now becoming a leading cause of death (Fitzhugh et al. Am. J. Hematology 2010). Indeed, SCD is associated with increased rates of pulmonary hypertension (pHTN) and diastolic dysfunction (Sachdev et al. Blood 2005). In the general population, atrial fibrillation (AF) is associated with an increased mortality in the setting of either pHTN or diastolic dysfunction. Although cardiac structural and biochemical changes likely create an electrophysiological substrate for AF in SCD, the prevalence and risk factors for AF in SCD remain unclear. We determined the prevalence, incidence, and clinical characteristics of AF in a large cohort of patients with SCD. Methods We conducted a retrospective, longitudinal cohort study of all adult patients with SCD seen at our large, urban single center from January 2008 to December 2017. SCD patients were identified using a previously described semi-automated system with a subset with direct chart review (Srisuwananukorn et al. Blood Advances 2020). We performed manual review of ~17,000 available electrocardiograms of all enrolled subjects to look for AF. For univariate analyses, the associations of linear and categorical variables with AF were assessed using the Kruskal-Wallis test and Pearson's χ 2 test, respectively. We used Bonferroni correction for categorical variables with greater than two groups. Logistic regression analysis with stepwise addition of variables (p&gt;0.15) was used to evaluate for the effects of previously described AF risk factors, degree of anemia, hydroxyurea use, and genotype on AF development. Results Our cohort consisted of 763 adult SCD patients with a median age of 27.95 years, 59.50% female, 72.4% with Hb SS or Sβ 0-thalassemia genotype, and 61.2% were prescribed hydroxyurea. Mean observation time for the cohort was 8.3 ± 6.3 yrs. We identified AF in 30 out of 763 adult SCD individuals with a mean age onset of 51 ± 10 years (median age 52 years). The period prevalence of AF was 3.93% and the incidence density was 3.02 per 1000 patient years observed. Individuals with AF tended to be older at initial (40 vs. 25 years, p&lt;0.0001) and follow-up (53 vs. 35 years, p&lt;0.0001) visits and were observed for a longer period (13.3 vs. 9.5 years, p=0.0014). There was no difference in gender (p=0.7), ethnicity (p=0.5), or SCD genotype (p=0.03) between groups (see Table 1). Those with AF were more likely to carry diagnoses of chronic obstructive pulmonary disease (p=0.0004), hypertension (p&lt;0.0001), chronic kidney disease (p&lt;0.0001), type 2 diabetes (p&lt;0.0001), and any cancer (p=0.04). However, hydroxyurea use was not associated with AF development (p=0.3). SCD patients with AF were more likely to receive diuretics, atrioventricular nodal blocking agents, antihypertensives, antiplatelets, and statin therapies (see Table 1). AF was associated with worse anemia and reduced renal function. Regression analysis identified significant odds ratios (ORs) for age at initial visit (OR 1.06, p=0.03), serum creatinine per 1 mg/dL increase (OR 2.34, p=0.02), hemoglobin level per 1 g/dL increase (OR 0.52, p=0.0009), fetal hemoglobin level per 1% increment (OR 0.81, p=0.008), and total observation time per year follow up (OR 1.26, p=0.0006). Conclusion We showed that the prevalence and incidence of AF is high in patients with SCD with the median age of onset occurring 1-2 decades earlier than in the general populace (Feinberg et al. JAMA Internal Medicine 1995). AF in patients with SCD is associated with advanced age, worse renal function, a higher degree of anemia, and greater usage of cardio- and nephro-active medications. The high incidence of AF in patients with SCD may contribute to the plateauing of life expectancy and identifying the causative risk factors and the underlying mechanisms may not only improve life expectancy but also the quality of life. Further study is warranted. Figure 1 Figure 1. Disclosures Saraf: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.

scholarly journals Validation of the International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET) in Patients with Pre-Fibrotic Primary Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1657-1657
Author(s):  
Paola Guglielmelli ◽  
Alessandra Carobbio ◽  
Elisa Rumi ◽  
Valerio De Stefano ◽  
Lara Mannelli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Incidence Rate ◽  
Research Funding ◽  
Risk Model ◽  
Univariate Analysis ◽  
Thrombotic Event ◽  
Advisory Committees ◽  
Thrombotic Risk

Introduction. Prefibrotic myelofibrosis (pre-PMF) is a unique entity in the 2016 WHO classification of myeloproliferative neoplasms with distinct clinical phenotype and outcome [Guglielmelli P, Blood 2017]. Compared to essential thrombocythemia (ET), pre-PMF is characterized by more pronounced disease manifestations, adverse mutation profile and worse outcome. Previous studies [Rumi E, Oncotarget 2017] showed that patients (pts) with pre-PMF present a risk of vascular events similar to ET. However, no studies performed a comprehensive assessment of risk factors for thrombosis in pre-PMF. The current study aimed to identify risk factors for thrombosis and bleeding in a large series of pre-PMF pts and explore the effectiveness of contemporary prognostic models developed specifically for ET. Patients and Methods. The study included 382 pre-PMF pts, diagnosed by 2016 WHO criteria, referred by 4 Italian Centers. Previously published methods were used to genotype JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2; a high molecular risk (HMR) category was defined according to Vannucchi A, [Leukemia 2013]. Thrombosis‐free survival (TFS) was determined from diagnosis to the first thrombotic event. Pts were grouped according to the conventional risk stratification system [Barbui T, JCO 2011], IPSET‐thrombosis [Barbui T, Blood 2012] and revised IPSET‐thrombosis [Barbui T, BCJ 2015]. Cox-regression model was used for univariate analysis. Harrell's concordance (C) statistic was calculated to measure the incremental accuracy of multivariable models sequentially adjusted for new predictors of thrombotic risk. A P <0.05 was considered statistically significant. Results. At diagnosis, 65 pts (17%) experienced major thrombotic events which included 35 (9%) arterial and 31 (8%) venous thromboses. With a median follow-up of 6.9 y (range 0.08-32.6), 56 (15%) pts developed an arterial or venous thrombotic event, with a total incidence rate of 1.99% pts/year (pt-y); 30 (8%) were arterial and 28 (7%) venous events with incidence rate of 1.00% pt-y and 0.95% pt-y, respectively. Splanchnic vein thrombosis (SVT) represented the most frequent venous events before/at diagnosis (26%). During the follow-up, 16% and 8% of pts experienced myelofibrotic or leukemic progression, and 105 (27%) died, with incidence rate of 2.05% pt-y, 0.95% pt-y and 3.41% pt-y, respectively. In univariate analysis, factors significant for arterial thrombosis after diagnosis were age >65y (HR 2.88; P=0.005), WBC>10x109/L (HR 2.43; P=0.026), presence of >1 generic CV risk factor (HR 2.16; P=0.047), JAK2V617F (HR 3.35; P=0.027) and HMR status (HR 13.1; P=0.027). Conversely, only history of previous thrombosis (HR 3.06; P=0.005) and previous venous event (HR 5.53; P<0.0001) retained significance for predicting venous thrombosis. Pts were effectively stratified according to IPSET and conventional risk model. The risk of thrombosis in IPSET low-, intermediate-, and high-risk categories was 0.67%, 2.05% and 2.95% pt-y, and 1.47% pt-y and 2.71% pt-y in 2-tiered thrombotic risk model. (Figure 1); in revised-IPSET, 0.54%, 2.23%, 2.44% and 2.69 %pt-y in the very low, low, intermediate- and high-risk category. When WBC>10x109/L or HMR variables were incorporated into IPSET model, the C-statistic increased significantly for the prediction of arterial events: from baseline value of 0.68 to 0.74 adding WBC and 0.91 HMR status. The proportion of pts who experienced major bleeding was 3% prior/at diagnosis,and 7% during follow-up, with total incidence rate of 0.94% pt-y. In univariate analysis, predictors for major bleeding during follow-up were age >75y (HR 3.34; P=0.011), WBC>13x109/L (HR 2.33; P=0.035), presence of >1 generic CV risk factor (HR 2.41; P=0.035), particularly hypertension (HR 2.63; P=0.016) and grade-1 fibrosis (HR 2.28; P=0.05). High platelet count and treatment, including antiplatelet and anticoagulant drugs, did not reach statistical significance. Conclusions. Overall, this study identified independent risk factors for major thrombosis and bleeding in pre-PMF. Of interest, we report that HMR status predicted for arterial thrombosis during the follow-up. Pre-PMF pts showed remarkably high rate of venous thrombosis, mostly represented by SVT. The 3-tiered IPSET prognostic model for thrombosis reliably predicted occurrence of thrombotic events in pre-PMF and should be considered as standard reference. Figure 1 Disclosures Rumi: novartis: Honoraria, Research Funding. Thiele:Shire: Research Funding; Incyte: Consultancy, Honoraria, Other: Remuneration, Research Funding; Sanofi: Consultancy, Honoraria, Other: Remuneration; Novartis: Consultancy, Honoraria, Other: Remuneration, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Research Funding. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals The Canadian Tyrosine Kinase Inhibitor Discontinuation Trial with Imatinib Discontinuation As a First Attempt and with Dasatinib Discontinuation As a Second Attempt of Treatment-Free Remission: Results of 4 Years of Follow-up

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1644-1644
Author(s):  
Dennis Dong Hwan Kim ◽  
Isabelle Bence-Bruckler ◽  
Lambert Busque ◽  
Donna L. Forrest ◽  
Lynn Savoie ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Total Duration ◽  
Transcript Level ◽  
Molecular Response ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Reduced Risk

Introduction: The Canadian trial entitled "Treatment Free Remission Accomplished By Dasatinib" (BMS CA180543, NCT#02268370) is ongoing since Jan 2015, and has completed accrual of 131 patients. The study was designed to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation following imatinib (IM) treatment. The preliminary results (ASH 2018) indicate: 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4; 3) The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months [7.9-39.5%]). Herein, we report the 4-year follow-up results with updated TFR2 after second TFR attempt following DA discontinuation. Methods and materials: This prospective clinical trial has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level above MR4.0 on 2 consecutive occasions, or an increase in BCR-ABL transcript level above MR3.0 on a single occasion. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving MR4 following a 2nd TFR attempt. Results: As of Jun 25, 2019, 58 (44.3%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 59.1% [50.1-67.0%] and 56.8% [47.8-64.8%] at 6 and 12 months, respectively. TFR using loss of MMR as an event was 69.8% at 6/12 months. Of the 58 patients who lost response, 53 patients (91.4%) lost response within 6 months after IM discontinuation: 7 (10.1%) lost response within 2 months, 20 (34.5%) within 3 months, 14 (24.1%) within 4 months, 9 (15.5%) within 5 months, and 3 (5.2%) within 5-6 months. Beyond 6 months, 5 patients (15.5%) lost response within 7, 8, 10, 20, 21 months, respectively. Only two patients experienced late relapse occuring 15 months after IM discontinuation. 54 patients started DA, of whom 49 patients (90.7%) achieved MR4.5 on DA. Median time to MMR, MR4 and MR4.5 was 0.94, 1.95, and 2.48, respectively. The incidence of MMR, MR4 and MR4.5 at 3 months was 99.0% (86.3-99.0%), 91.5% (78.4-96.7%), and 76.6% (60.9-86.0%), respectively. 32/49 patients receiving DA attained MR4.5, and discontinued DA for a 2nd TFR attempt (TFR2). 25/32 (78.1%) of these patients lost molecular response at a median of 3.67 months after DA discontinuation. The estimated TFR2 after DA discontinuation was 18.5% at 6 months [6.8-34.7%], TFR2 using loss of MMR as a definition of molecular relapse was 20.4% [7.6-37.4%], while TFR2 using two consecutive losses of MR4 was 25.4% [9.4%-45.2%]. Two patients continued to attain deep molecular response at MR4.2 and undetectable level (equivalent to MR5.5) beyond 18 months after DA discontinuation. At last follow-up of Jun 25, 2019, 30 patients are still being monitored on trial on IM discontinuation (n=20), DA rechallenge (n=4) or DA discontinuation phases (n=6). With a median follow-up duration of 36 months, risk factor analyses were performed using Cox's proportional hazard regression model suggesting a strong correlation of mRFS with total duration of IM treatment prior to IM discontinuation (p<0.001, HR 0.864), MR4 duration (p<0.001, HR 0.867), but not with time to achieve MR4 (p=0.216). When patients attained MR4 or deeper for longer than 10.59 years, their mRFS was 91.8% [71.1-97.9%] at 12 months. The group who attained MR4 duration of 6.93 years or longer had 40.3% reduced risk of mRFS (HR 0.597 [0.449-0.794], p<0.001] compared to those with MR4 duration less than 6.93 years. The group who attained 10.59 years of MR4 duration or longer had a 65.5% reduced risk of mRFS (HR 0.345 [0.171-0.699], p=0.003] compared to those with MR4 duration less than 10.59 years. Conclusion: The 4-year follow-up results suggests that DA rechallenge after failing a first IM discontinuation attempt for TFR was safe, feasible and well tolerated. It was effective in most cases rapidly regained at least MR4. Based on the two cases who successfully discontinued DA more than 18 months after DA consolidation following achievement of deep molecular response, second generation TKI therapy after imatinib discontinuation failure is a feasible option. Further follow-up is strongly warranted in order to reach a clear conclusion on this issue. Disclosures Busque: ExCellThera: Patents & Royalties; Paladin: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals The Interaction between IPSS Score and JAK2 Mutation Identifies Patients at Different Vascular Risk in Primary Myelofibrosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 236-236
Author(s):  
Tiziano Barbui ◽  
Arianna Ghirardi ◽  
Alessandra Carobbio ◽  
Arianna Masciulli ◽  
Greta Carioli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Primary Myelofibrosis ◽  
Vascular Risk ◽  
Advisory Committees ◽  
Jak2 Mutation ◽  
Thrombosis Rate

Abstract BACKGROUND The rate of major arterial and venous thrombosis in primary myelofibrosis (PMF) and post-ET (PET) and post-PV (PPV) secondary myelofibrosis has been evaluated in a limited number of studies. In the present paper we describe the clinical epidemiology of thrombosis in a large series of patients with overt PMF and PPV/PET MF looking at the rate and risk factors. Moreover, we report findings on thrombosis rate in two cohorts of patients treated with Hydroxyurea (HU) or Ruxolitinib (Ruxo). METHODS Patients were registered in the European Registry for Myeloproliferative Neoplasms (ERNEST). This project, promoted by the European LeukemiaNet, is coordinated by FROM - Foundation for Research, Papa Giovanni XXIII Hospital, Bergamo (Italy) and supported by Novartis through a research collaboration . Patients were diagnosed in 6 Centers from Italy, Spain and Sweden, between Jan, 2001 and Dec, 2012, with the required follow-up information. Patients (n= 1010) with PMF (n=584, 59%), PET-MF (n=207, 20%) and PPV-MF (n=219, 21%) were evaluated for incident thrombosis as primary endpoint. Considering death as a competitive event, uni-and multivariate analyses were performed by applying Fine & Gray competing-risk regression models. RESULTS After a median follow-up of 3.8 years (IQR: 1.8-7.1) from diagnosis, 108 thromboses (10.7%) occurred, for an overall incidence rate of 2.0% pts-yr (95% CI: 1.7-2.5). Arterial thromboses were found in 50 patients (46.3%) including cerebral (n=21, 19.4%), myocardial infarction (n=13, 12.0%) and peripheral events (n=9, 8.3%). Venous thromboses were 58 (53.7%), of which 25 (23.0%) were DVT ± PE and 11 (10.2%) were splanchnic. Thrombosis rate was 1.91, 1.60 and 2.79% pts-yr in PMF, PET-MF and PPV-MF, respectively. In univariate analysis, factors significantly associated with an increased thrombotic risk in PMF were age (p=0.013) and the presence of the JAK2 mutation (p=0.003); in addition, a significant higher proportion of PMF patients at low and intermediate-1 vs intermediate-2 or high risk IPSS score, had thrombosis during the follow-up (p=0.008). In multivariate analysis, only JAK2 mutation retained statistical significance (SHR=3.12, 95% CI: 1.40-6.94, p=0.005). Conversely, neither in univariate nor in multivariable analysis, significant risk factors were not found.To investigate the possible interaction of IPSS score and JAK2 mutation we created a model whose results are presented in Fig. 1A: the cumulative incidence function (CIF) of thrombosis was significantly lower in patients with JAK2 wild-type and intermediate-2 or high IPSS score (CIF: 4% projected at 10 years; SHR=1 [reference category]), while patients at the highest risk for thrombosis harbored JAK2 mutation and were categorized at low or intermediate-1 by IPSS score (CIF: 20% projected at 10 years, SHR=7.13, p=0.008). Of note, thrombosis had a significant impact on mortality. After adjusting for sex, age, year of diagnosis, type of MF and IPPS, HR was 1.51, (95% CI. 1.15-1.98, p=0.003).The influence of drug exposure to incident thrombosis was investigated in two cohorts of 559 consecutive patients exposed to HU (n=470) or to Ruxo (n=89), median treatment 2.6 and 3.0 years, respectively. HU- compared to Ruxo-treated patients were older (median age 67 vs. 63 years, p=0.001), more frequently triple negatives (12% vs. 2%, p=0.036), less splenomegalic (spleen length &gt;10 cm: 30% vs. 88%, p &lt;.001) and less symptomatic (49% vs. 79%, p=0.031). Of note, median time from MF diagnosis to therapy start in Ruxo group was 4 years, whereas patients started HU at MF diagnosis. In 56 of 89 Ruxo-treated patients (62.9%), the drug was given after a prior HU therapy. The thrombosis rate from the time of initiation of therapy was 2.40% pts-yr (95% CI 1.78-3.24) under HU and 1.28% pts-yr (95% CI 0.48-3.41) under Ruxo (CIF curves in Fig. 1B). In multivariate analysis corrected for MF type, DIPPS at first drug administration, JAK2 mutation and time from MF diagnosis, exposure to Ruxo showed a non-significant trend towards a protection of approximately 70% compared to HU (SHR=0.33, 95% CI: 0.08-1.32, p=0.117). CONCLUSION IPSS score, in addition to the survival risk assessment, may be useful, if associated with the JAK2 mutation, to recognize patients at vascular risk and to suggest appropriate anti-thrombotic prophylaxis. The trend towards a benefit of Ruxo, compared to HU, warrants a study in larger case series. Figure 1 Figure 1. Disclosures Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Vannucchi: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures.

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