High Prevalence of CHF and Diabetes in AML Long-Term Survivors - a Patient Forever?

Abstract Introduction: As outcomes of patients with acute myeloid leukemia (AML) have improved over the past decades, the fraction of patients surviving long-term is increasing. Information on long-term somatic and psycho-social health consequences of AML and its treatment is sparse. Previous studies suggested a higher prevalence of cardiovascular diseases in AML survivors, especially those treated with allogeneic stem cell transplantation (alloHSCT). The aim of our study was to perform a multi-dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on somatic, especially cardiovascular, morbidity in AML-LTS. Overall and health-related quality of life are reported separately (Telzerow et al.). Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessment by the patients' physicians, and medical and laboratory reports. An age- and sex-matched control cohort was derived from German population-based health surveys (Robert Koch Institute, DEGS1 survey; n=6013; persons diagnosed with leukemia [n=11] were excluded). Results: 427 AML-LTS, aged 28 to 93 years, participated in this study. Data on somatic health status is available for 355 survivors, 5 to 19 years after their AML diagnosis. Thirty-eight percent of survivors were treated with chemotherapy with or without an autologous transplant (autoHSCT), whereas 62% had undergone alloHSCT. Focusing on cardiovascular diseases and risk factors, we found that that 49% of AML-LTS had hypertension, 33% had hypercholesterolemia, 15% had type 1/2 diabetes, 10% had congestive heart failure (CHF), and 9% had coronary artery disease (Figure A). The mean body-mass index (BMI) of AML-LTS was 26.7, similar to the DEGS1 cohort (mean BMI, 26.8). Next, we compared the prevalence of cardiovascular diseases and risk factors between AML-LTS and the general German population (represented by the DEGS1 sample), using multivariate models adjusting for age and sex (Table B). Compared to persons not diagnosed with leukemia, AML survivors had similar risks of hypertension, coronary heart disease and myocardial infarction. Prevalence of diagnosed hypercholesterolemia was higher in AML-LTS compared to non-AML controls. In addition, AML-LTS had a 2-fold higher risk of having type 1/2 diabetes, and a 3.5-fold increased risk of CHF compared to the general population. To identify factors associated with the increased risks of diabetes and CHF among AML-LTS, we constructed multivariate models incorporating patient- and treatment related covariables (age, sex, BMI, smoking, prior AML relapse, treatment [chemotherapy + autoHSCT vs. alloHSCT], and type of leukemia [de novo versus secondary / therapy-related]). We found an increased risk of CHF for AML-LTS who had had a relapse (OR, 3.16; 95% CI: 1.46 - 6.83; P=0.004) and, in trend, for patients with sAML or tAML (OR 2.19; 95%CI: 0.92 - 5.22, P=0.076). In addition, we found an increased risk of type 1/2 diabetes for AML-LTS who are smokers (OR: 3.43; 95% CI: 1.43 - 8.21; p: 0.006). Disease- or treatment-related factors did not significantly associate with any of the other comorbidities we studied. Conclusion: To the best of our knowledge, this is the largest analysis of somatic health outcomes in AML-LTS. Strengths of our study include the relatively large cohort representing a wide age range, the long follow-up period of 5 to nearly 20 years, and the heterogeneity regarding therapy regimens (chemotherapy + autoHSCT vs. alloHSCT). We found that, compared to the general population, AML-LTS have increased risks for CHF and diabetes, but not for hypertension or coronary artery disease. We identified AML relapse as a risk factor for the development of CHF, suggesting that cumulative chemotherapy exposure might be causally involved. On the other hand, we found no treatment- and disease-related risk factors that might explain the higher prevalence of diabetes in AML-LTS. Notably, AML-LTS who had undergone alloHSCT did not have increased risks of CHF, cardiovascular disease, hypertension or diabetes, compared to survivors treated with chemotherapy only. Our results may guide future recommendations for follow-up and inform personalized treatment decisions. Figure 1 Figure 1. Disclosures Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: Janssen: Research Funding; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; AbbVie: Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Pfizer: Consultancy; Astellas: Honoraria.

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Eliglustat, an Investigational Oral Therapy for Gaucher Disease Type 1: Phase 2 Results After 4 Years of Treatment

Blood ◽

10.1182/blood.v120.21.1038.1038 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1038-1038

Author(s):

M. Judith Peterschmitt ◽

Elena Lukina ◽

Nora Watman ◽

Marta Dragosky ◽

Gregory M Pastores ◽

...

Keyword(s):

Stock Options ◽

Research Funding ◽

Trough Level ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Therapeutic Goals ◽

Gaucher Disease Type 1

Abstract Abstract 1038 Introduction: In Gaucher disease type 1 (GD1), genetically caused deficiency of the enzyme acid β-glucosidase results in undegraded glucosylceramide to accumulate in tissue macrophages (Gaucher cells), resulting in multisystemic manifestations that include thrombocytopenia, anemia, hepatosplenomegaly, and bone disease. A variable clinical course and progression among patients have led to the development of therapeutic goals for the different disease manifestations (Pastores et al., Semin Hematol. 2004;41[suppl 5]:4–14). Eliglustat, a potent and specific inhibitor of glucosylceramide synthase, is under late-stage development as an oral substrate reduction therapy for GD1. Objective: To report long-term efficacy and safety results. Methods: This ongoing, open-label, uncontrolled, multicenter Phase 2 clinical trial enrolled 26 adult patients with GD1 who were not on treatment for the previous 12 months and who had splenomegaly with thrombocytopenia and/or anemia. Patients received 50 mg or 100 mg eliglustat twice daily depending on the plasma trough level. Efficacy outcomes were assessed periodically and included changes from baseline in hemoglobin, platelets, spleen and liver volumes, skeletal manifestations, disease-related biomarker levels, and achievement of therapeutic goals. Results: Nineteen patients completed 4 years of eliglustat treatment; no patient discontinued in the last 2 years. After 4 years of treatment, mean hemoglobin level and platelet count increased by 2.3±1.5 g/dL (from 11.3±1.5 g/dL to 13.6±1.2 g/dL) and 95% (from 68,700±21,200/mm3 to 125,400±51,100/mm3), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (from 17.3±9.5 to 6.1±3.4 MN) and 28% (from 1.7±0.4 MN to 1.2±0.3 MN), respectively. All patients met at least 3 of 4 long-term therapeutic goals (spleen, 100% of patients; liver, 94%; hemoglobin, 100%; platelets, 50%). Baseline platelet count was not found to be a predictive factor of response to treatment. However, a strong linear, statistically significant correlation was found between the mean plasma trough level of eliglustat and the platelet response in patients after 4 years of treatment with eliglustat (r=0.731, P=0.0004). Median chitotriosidase and CCL-18 each decreased by 82%; plasma GL-1 and GM3 normalized. Mean lumbar spine bone mineral density increased by 0.7 Z-score (from −1.2±0.9 to −0.5±1.1) and by 0.8 T-score (from −1.6±1.1 to −0.88±1.3). The greatest increases in lumbar spine T-scores occurred in patients with osteoporosis at baseline. Femur dark marrow, which is believed to reflect Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Eliglustat was well-tolerated. Most adverse events (AEs) were mild and unrelated to treatment. Ten drug-related AEs, all mild, occurred in 8 patients. No new serious AEs were reported in any patient between 3 and 4 years of treatment. Discussion: Eliglustat continues to show promising efficacy and safety, with clinically meaningful improvements across several disease parameters. Results from two controlled Phase 3 studies in untreated and enzyme replacement therapy maintenance patients will be available in 2013. Disclosures: Peterschmitt: Genzyme: Employment. Lukina:Genzyme: Honoraria, Research Funding. Watman:Genzyme: Membership on an entity's Board of Directors or advisory committees. Pastores:Amicus: Research Funding; Actelion: Research Funding; Biomarin: Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Arreguin:Genzyme: Research Funding. Rosenbaum:Pfizer: Study Investigator Other. Zimran:Protalix Biotherapeutics: Consultancy; Protalix Biotherapeutics: stock options, stock options Other; Protalix Biotherapeutics: Scientific Advisory Board, Scientific Advisory Board Other; Genzyme: Research Funding; Shire HGT: Honoraria; Actelion: Honoraria; Pfizer: Honoraria. Aguzzi:Genzyme: Employment. Ross:Genzyme: Employment. Puga:Genzyme: Employment.

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Cardiac and Renal Complications of Carfilzomib Therapy in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4491.4491 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4491-4491 ◽

Cited By ~ 2

Author(s):

Meletios A. Dimopoulos ◽

Maria Roussou ◽

Maria Gavriatopoulou ◽

Erasmia Psimenou ◽

Dimitrios Ziogas ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Cardiac Toxicity ◽

Cardiac Events ◽

Advisory Committees ◽

Artery Disease ◽

Higher Doses

Abstract Carfilzomib (CFZ) combinations have shown activity in phase 2 and 3 studies in multiple myeloma (MM) patients but also a small but consistent signal of cardiac and renal toxicity. The aim of our study was to analyze potential cardiac and renal toxicity of CFZ combinations in consecutive MM patients. The analysis included 60 patients treated with different combination of CFZ in a single center (University of Athens, Greece): 48 (80%) had relapsed or refractory (RRMM) and 12 (20%) had newly diagnosed MM (NDMM). All had baseline evaluation of cardiovascular risk factors and echocardiography with a LVEF ≥40%. Regimens included Kd in 31 (52%), KRd in 17 (28%) and KMP in 12 (20%) patients. CFZ dose was 20/27 in 27 (45%) patients, 20/36 in 12 (20%) and 20/56 in 21 (35%). Median age was 72 (range 39-76) years and 65% were males. Median number of prior therapies was 2 (range 0-7). Median baseline eGFR was 88 ml/min (range 16 to> 120 ml/min), 33% had eGFR <60 ml/min and 7% had eGFR <30 ml/min. Median duration of CFZ therapy was 10 (range 1-43) cycles. During therapy with CFZ, 7 (12%) patients had a reduction in LVEF ≥20% within a median of 6 months (range 1-13 months) from initiation of CFZ. In 6/7 patients, dyspnea of grade (gr) ≥2 was also present and was associated with a significant increase of NTproBNP (median 2412, range 2219-10162 pg/ml) without increase in troponins. With discontinuation because of disease progression or other unrelated reasons as a competing event, the incidence of LVEF reduction ≥20% was 5% at 3 months, 8% at 6 months, 10% at 12 months and 12% at 15 months. The respective CFZ discontinuation rate unrelated to cardiac toxicity was 17%, 35%, 41% and 49%, respectively (Figure). Among cardiovascular risk factors (age, smoking, hypertension, hypelipidemia, diabetes, renal dysfunction) only peripheral artery disease was associated more often with cardiac events (3/7, 43% vs 4/53,8%, p=0.02). The use of ACE-I, ARBs or CCBs was not associated with cardiac events, however, the use of b-blockers was more common in patients who had LVEF reduction (3/10, 30% vs 4/50, 8%, p=0.048); patients on b-blockers also experienced LVEF reduction earlier [2% vs 20% at 3 months, 6% vs 20% at 6 months and 6% vs 30% at 12 months (p=0.02)], while non-toxicity discontinuation at 12 months was 44% vs 57% (p=0.66). There was no association with prior anthracycline exposure or prior HDT and the dose of CFZ was not associated with cardiac event frequency or timing. Baseline parameters of cardiac function assessed by echocardiography did not show correlation with cardiac events. Further evaluation in all patients who had EF reduction established the diagnosis of coronary artery disease (CAD) in 3/7. In all patients LVEF improved after holding CFZ (<28 days) and 6/7 patients continued therapy with CFZ with dose reduction; only in one patient reinstitution of CFZ was associated with repeated reduction of LVEF. We also evaluated the effects of CFZ in renal function, excluding renal dysfunction associated with disease progression. Per CTCAE v4.03, 22 (37%) patients had a creatinine increase ≥gr 1 (18% gr1, 17% gr2 and 2% gr3). According to the same criteria for acute kidney injury (AKI), 17 (28%) patients experienced AKI ≥gr 1 (gr1 in 25% and gr3 in 3%) while 21 (35%) had a reduction of their eGFR by ≥25%, which was transient in 13/21 (62%). These events occurred mostly early, within the 1st cycle in 9/21 (43%). Two patients, both in CR, developed TTP, one after 22 and the other after 8 cycles of CFZ. Higher doses of CFZ were associated with higher frequency of eGFR reduction ≥25% (22% vs 33% vs 52% for 20/27, 20/36 and 20/56 doses respectively, p=0.093). Age >65 years was not associated with higher risk of AKI (25% vs 35% for those <65 years, p=0.3). Among patients with baseline eGFR <60 ml/min (n=20), 11 (55%) patients improved their eGFR to >60 ml/min. In conclusion, cardiac toxicity after CFZ occurred in 12% of patients, but was essentially unpredictable and reversible in all patients; standard cardiovascular risk factors were not predictive of cardiac toxicity. However, in about half of the patients was associated with underlying CAD, indicating that further investigation is needed regarding the effects of CFZ to vascular function and endothelium. Decrease in eGFR and low grade AKI is common but transient, and can be associated with higher doses of CFZ. Importantly, 55% of patients with moderate CKD improved their renal function after treatment with CFZ. Figure Figure. Disclosures Dimopoulos: Celgene: 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; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Kastritis:Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

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Sarcopenia and myokines profile as risk factors in cardiovascular diseases?

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0013.5442 ◽

2019 ◽

Vol 73 ◽

pp. 550-562

Author(s):

Mariusz Ciołkiewicz ◽

Anna Kuryliszyn-Moskal ◽

Anna Hryniewicz ◽

Karol Kamiński

Keyword(s):

Physical Activity ◽

Risk Factors ◽

Cardiovascular Diseases ◽

Cerebral Stroke ◽

Medical Procedures ◽

Carotid Artery Atherosclerosis ◽

Inflammatory State ◽

Artery Disease ◽

Multiple Morbidities

Skeletal muscles and substances released during physical activity (myokines) have a beneficial influence on the functioning of the organism. Myokines (released also by myocardium) together with hepatokines and adipokines play an important role not only in energetic metabolism, but they also influence, among others, the function of the circulatory and nervous systems, modulation of inflammatory state and atherogenesis. Under pathological conditions connected with the presence of chronic diseases, chronic inflammatory state, low physical activity, long-term immobility the following consequences are observed: reduction of muscle mass and strength (sarcopenia) and changed profile of released myokines. The incidence of sarcopenia is connected with an unfavorable course of the aging process, often leading to disability and multiple morbidities. Sarcopenia can also lead to frailty syndrome, which not only worsens the prognosis of various diseases, but it can also increase the risk of medical procedures. Sarcopenia and adverse przymyokine profile are modifiable risk factors of cardiovascular diseases and affecting them may improve functional status and prognosis. An important intervention to improve muscles function and myokine profile, apart from nutritional treatment and pharmacotherapy, is regular physical activity as a component of cardiac rehabilitation. In our paper we focused on a review of the newest research regarding the association of sarcopenia and the profile of released myokines with incidence and course of cardiovascular diseases such as chronic heart failure, coronary artery disease, carotid artery atherosclerosis or ischemic cerebral stroke.

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IDH Mutations Are Associated with an Increased Risk of Coronary Artery Disease and Cardiotoxicity in Patients with Established AML

Blood ◽

10.1182/blood-2020-143026 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Badder Kattih ◽

Amir Shirvani ◽

Piroska Klement ◽

Abel Martin Garrido ◽

Razif Gabdoulline ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Board Of Directors ◽

Research Funding ◽

Idh Mutation ◽

Advisory Committees ◽

Mutation Status ◽

Increased Risk ◽

Idh Mutations ◽

Artery Disease

Introduction: Clonal hematopoiesis initiated by acquired somatic mutations in hematopoietic cells has been identified as an independent driver of increased all-cause mortality, risk of coronary artery disease and heart failure. Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) lead to conversion of αKG to R-2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of TET2 and a known oncometabolite. Oncometabolite R-2HG (produced by IDH mutant cells) has been implicated in pathological cardiac remodeling and dysfunction in preclinical studies. Whether IDH mutant leukemic cells in patients with established AML are also associated with the development of cardiovascular diseases or exacerbate cardiotoxicity during anthracycline containing chemotherapy is still unknown. Methods: In this observational study, a propensity score-based analysis was performed in 363 adult AML patients being stratified by mutation status in the IDH gene. To analyze whether the IDH mutation status in AML patients was associated with increased cardiotoxicity, we analyzed echocardiographic left ventricular ejection fraction (LVEF) in the control group (AML patients without IDH mutation) and the exposed group (AML patients with IDH mutation) at baseline and at different time points during AML therapy. Results: IDH 1 and IDH2 mutations occurred in 26 (7.2%) and 39 adult AML patients (10.7%), respectively. The median age of the total population was 60 years. The estimated 2-year relapse-free survival and overall survival rates in the overall study cohort were 49.4% (5-year RFS 38.9%) and 59.2% (5-year OS 43.1%) during a median follow-up of 7.6 years. IDH1 mutant AML patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p=0.002). A propensity score analysis by inverse probability-weighting was performed based on the 295 patients who received intensive cytarabine and anthracycline-containing chemotherapy. This analysis revealed an increased risk for a declining cardiac function during AML treatment in IDH1/2 mutated compared to IDH1/2 wild type patients [LVEF pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (P<0.001) vs 58.5% to 55.4% (P=0.27), respectively], suggesting that the IDH mutations in AML patients were associated with a declining cardiac function during AML therapy, which was independent of measured baseline characteristics. To validate whether the oncometabolite R-2HG drives vulnerability of cardiac cells in patients with IDH mutant AML, human iPS-derived cardiomyocytes were exposed to R-2HG (or control) during anthracycline treatment. Indeed, an exaggerated sarcomere disarray when R-2HG was added to anthracycline treatment was identified by immunostaining in human induced pluripotent stem cell (hIPS) derived cardiomyocytes. By RNA sequencing of R-2HG exposed hiPS-derived cardiomyocytes during anthracycline treatment, we demonstrate the transcriptomic basis for putative biological processes mediating the increased cardiotoxicity. Conclusion: The presence of an IDH mutation in adult AML was associated with a higher prevalence of coronary artery disease and an exacerbated cardiotoxicity during anthracycline treatment, which was at least in part mediated by the oncometabolite R-2HG. Disclosures Thol: Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganser:Novartis: Consultancy; Celgene: Consultancy. Heuser:BerGenBio ASA: Research Funding; Roche: Research Funding; Astellas: Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; PriME Oncology: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Bayer: Consultancy, Research Funding; Karyopharm: Research Funding.

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Risk Factors for Thrombotic Events in Patients with PNH: A Nested Case-Control Study in the International PNH Registry

Blood ◽

10.1182/blood-2020-136767 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-8

Author(s):

Britta Hoechsmann ◽

Regis Peffault De Latour ◽

Anita Hill ◽

Alexander Röth ◽

Timothy Devos ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Index Date ◽

Case Control Study ◽

Advisory Committees ◽

Clone Size ◽

Increased Risk ◽

History Of ◽

Control Study

INTRODUCTION Although thrombotic events (TEs) are the leading cause of paroxysmal nocturnal hemoglobinuria (PNH)-related mortality, the risk factors predictive of TEs are not well established. Several small or previous studies reported that the proportion of PNH cells, elevated lactate dehydrogenase (LDH), age, thrombosis at diagnosis, and treatment may impact TE risk.1-5 The International PNH Registry (NCT01374360) is an observational cohort study containing the largest database of safety, quality-of-life, and outcome data from patients with PNH. Here, we analyzed patient data from the Registry to identify risk factors for TEs. METHODS Data from Registry patients who were untreated at enrollment, had an incident TE after enrollment, non-zero follow-up time, and with documented birthdate, sex, enrollment date, treatment status, and country, were included in this analysis. The first TEs experienced by eligible patients after enrollment were identified as TE cases; the date of the index TE event was defined as the Index Date. Up to five controls were selected from the risk set for each TE case matched on age (±5 years at Index Date), gender, country, and history of bone marrow disease (BMD). Cases that could not be matched with at least one control were excluded from the study. For covariates included in the analysis, conflicting or absent values were marked as "missing." Univariate conditional logistic regression was used to estimate odds ratios (ORs) with 95% Wald confidence intervals (CIs) of TE associated with candidate risk factors: glycophosphatidylinositol (GPI)-deficient granulocytes, GPI-deficient erythrocytes, LDH ratio, recent high-disease activity (HDA; defined as within six months prior to the Index Date, LDH ratio ≥1.5xULN, and hemoglobin <10 g/dL or at least one of the following symptoms: abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, and/or male erectile dysfunction), LDH ratio and number of HDA symptoms, history of TE, history of major adverse vascular event (MAVE), and recent prophylactic anticoagulant (PA) use. RESULTS Due to the strict eligibility criteria, 57 TE cases and 189 non-TE controls met the conditions and were matched for the case-control study. The mean age at Index Date was 46.8 years for TE cases and 47.1 years for non-TE control (Table A). Cases were more likely to have a clone size of ≥ 50% GPI-deficient granulocytes, an LDH ratio ≥ 1.5xULN, recent HDA, and a history of TE or MAVE, compared with controls. From univariate analyses, the following factors were found to be associated with statistically significantly increased risk of TE: recent HDA (OR, 2.65; 95% CI, 1.10-6.61), LDH ≥1.5xULN and 2-3 HDA symptoms (OR, 8.61; 95% CI, 1.46-96.96), LDH ≥1.5xULN and ≥4 HDA symptoms (OR, 14.50; 95% CI, 1.70-209.25), and a history of TE (OR, 3.60; 95% CI, 1.41-9.24) or MAVE (OR, 2.17; 95% CI, 0.96-4.80), and recent PA use (OR, 4.35; 95% CI, 1.57-13.13) (Figure A). The strengths of this analysis include a robust study design for evaluation of a rare outcome and multiple risk factors, increased generalizability with an international patient population, and the ability to evaluate both medical history and recent clinical characteristics relevant to PNH and TE; however, not all patients had available data for each parameter assessed and the number of TE cases identified were relatively small. Despite these limitations, factors that were statistically significantly associated with increased TE risk were identified from the analysis. CONCLUSIONS Based on this observational PNH Registry analysis, we identified several clinical features of PNH that were associated with an elevated risk of TE, including ≥50% GPI-deficient granulocyte clone size, LDH ratios ≥1.5xULN, recent HDA, LDH ≥1.5xULN plus HDA symptoms, a history of TE or MAVE, and recent PA use compared with non-TE controls; for recent PA use, these patients were most likely at increased risk of TE, which may explain why they received treatment. Our data add to the findings of previously published studies1,4 by expanding the results to a broader patient population. These results highlight the importance and urgency of identifying and monitoring risk factors for TE in patients with PNH to inform treatment decisions. Disclosures Hoechsmann: Roche: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Research Funding. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hill:Alexion Pharmaceuticals, Inc.: Current Employment. Röth:Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Devos:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin:Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:Alexion Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zu:Alexion Pharmaceuticals, Inc.: Ended employment in the past 24 months; Merck & Co.: Current Employment. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Incidence, Risk Factors, Treatment and Long Term Outcome of Refractory and First Relapse AML Patients in the OSHO Studies

Blood ◽

10.1182/blood-2019-125262 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1358-1358

Author(s):

Dietger Niederwieser ◽

Rainer Krahl ◽

Christoph Kahl ◽

Hans-Heinrich Wolf ◽

Sebastian Scholl ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Remission Induction ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

Advisory Boards

Introduction: Outcome of patients (pts) with refractory AML or following relapse is considered dismal and usually reported as refractory/relapsed. Here we analyzed long term outcome of refractory and relapsing pts separately over a 10 year (y) period from two prospective, non-age-limited, adult AML studies. Results have been published or presented previously as part of the German AML Intergroup studies1,2. However, incidence, characteristics, treatment and outcome of refractory and relapsed pts have not been evaluated. Patients and Methods: A total of 1621 pts from the OSHO 2002 ≤60 y (n=740) and 2004 >60 y (n=881) with newly diagnosed AML (except acute promyelocytic leukemia) and eligible for chemotherapy were analyzed. The gender was male in 51.7% of pts. AML type was de novo in 66.6%, followed by secondary AML in 25.8% and therapy related in 7.6%. Cytogenetic risk status was normal in 47.9%, intermediate in 16.3%, unfavorable in 15.3%, monosomal in 12.6% and favorable in 7.9%. Molecular analysis revealed wildtype (wt) FLT3 in 80.9% and FLT3 ITD mutated (mut) in 19.1% of pts. NPM was mutated in 30.2% of 1124 pts. In the AML 2002 and 2004 studies (NCT 01414231; NCT 01497002; NCT00266136), pts were randomly (9:1) assigned to remission induction by cytarabine (1 g/m2 bid d 1, 3, 5, 7) and Idarubicin (AML 2002) 12 mg/m2/d d 1-31 or mitoxantrone (AML 2004) 10 mg/m2/d iv d 1 - 32 or to a common arm consisting of a 3+7 scheme 3. Pts in complete remission (CR) received consolidation and stem cell transplantation (HSCT) according to cytogenetic risk and donor availability1,2. Pts with partial remission (PR) or non-response (NR) to two induction cycles were considered refractory. Pts achieving CR and relapsing thereafter were considered relapses and treated with MitoFlag or Flag-Ida4. Results: The majority of pts [median age 62 (range 17-87) y] entered CR or CRi after one or two induction cycles (n=1144; 70.6%). OS was 31.9 (29.5-34.4) % @5y and 26.0 (23.4-28.9) % @10y. Results were age dependent and superior in younger pts with an OS of 46.8 (43.1-50.7) % @5y compared to 19.3 (16.7-22.4) % @ 5y in elderly. Age, cytogenetics and NPM1 were determinants for CR and WBC (p<0,001), gender (p<0,05) and AML type (p<0,01) for OS. FLT3-ITD mut was an important determinant for relapse free survival in pts ≤60y. A total of 238 (14.7%) of 1621 pts, 23.5% in the younger and 76.5% in the elderly study, were refractory (PR 60.1%, NR 39.9%). Pts had a median age of 66 (range 23-83)y. OS of refractory pts was 11.4 (7.9-16.6)% @5y, and dependent upon PR [(13.1 (8.1-21.1) % @10y] and NR [5.2 (2.1-12.6) % @5y; p=0.0003]. Intensive chemotherapy ± HSCT and hypomethylating agents (HMA) were able to induce CR in 24.8% of pts. CR and non-CR pts had an OS of 42.7 (31.4-58.2) % @5y and an OS of 3.7 (1.7-8.0) % @2y, respectively. Risk factors for OS in refractory pts were age and type of therapy (p<0.0001). Almost all long term survivors were treated with HSCT. Of the 1144 CR/CRi pts, 582 relapsed 1-121 months (mts) after CR. Relapse occurred in 34.0% ≤6 mts, in 38,8% between 7-18 mts and in 12,2% >18 mts. Age, cytogenetic risk, type of AML, interval CR to relapse and HSCT were the dominant factors for relapse. CR2 was achieved after intensive chemotherapy ± HSCT, ± DLI and HMA in 227 pts (39.0%), 54.5% in the AML 2002 and 28.4% in the AML 2004. OS of relapsed pts was 13.8 (11.1 - 17.3) % @5y and 10.9 (7.4 - 16.2) % @10y and was higher in the younger with 23.4 (18.2-29.9) % @5y as compared to elderly pts 6.9 (4.4 - 11.0) % @5y. Pts with CR2 had a LFS of 24.9 (19.5-31.7) % @5y and was highest in patients <60y when intensive chemotherapy followed by HSCT was involved. Independent risk factors for OS in relapsed pts were age, cytogenetic risk, interval CR1 to relapse and type of therapy. Relapsed pts with HSCT in CR1 showed a trend for reduced survival. Conclusions Outcome of pts with refractory and relapsed AML is unsatisfactory but consistent >10% @5y. A differential response is observed in refractory and relapsed pts and is dependent upon PR, NR and the achievement of CR. Increase of CR rate in younger but especially in elderly pts with second generation TKI, reduction of TRM using FLT3-inhibitor monotherapy and the option to treat pts ineligible to chemotherapy promise better outcome in refractory and relapsed AML. 1Büchner et al. JCO 2012; 2Niederwieser et al Blood 2016; 3Mayer et al. NEJM 1994; 4Thiel et al. Ann Oncology 2015 Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Scholl:Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards; Pfizer: Other: Advisory boards; Novartis: Other: Project funding. Zojer:Amgen: 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. Sayer:Novartis: Other: none. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.

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Eliglustat, An Investigational Oral Therapy for Gaucher Disease Type 1: Phase 2 Results After 3 Years

Blood ◽

10.1182/blood.v118.21.1104.1104 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1104-1104

Author(s):

M. Judith Peterschmitt ◽

Elena Lukina ◽

Nora Watman ◽

Marta Dragosky ◽

Marcelo Iastrebner ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Disease Type ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Therapeutic Goals ◽

Gaucher Disease Type 1

Abstract Abstract 1104 Introduction: Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme acid β-glucosidase. This enzymatic deficiency leads to accumulation of undegraded glucosylceramide primarily in tissue macrophages (Gaucher cells) and results in multisystemic manifestations, including thrombocytopenia, anemia, hepatosplenomegaly, and bone disease. The variable clinical course and progression among patients have led to the development of therapeutic goals for the different disease manifestations (Pastores, Semin Hematol. 2004;41(suppl 5):4–14). Eliglustat, a novel, small molecule, specific inhibitor of glucosylceramide synthase, is currently under clinical development as an oral substrate reduction therapy for GD1. Objective: To report long-term efficacy and safety results of eliglustat. Methods: This ongoing, open-label, uncontrolled, multicenter, Phase 2 clinical trial enrolled 26 adults with GD1 not on treatment for the previous 12 months, who had splenomegaly with thrombocytopenia and/or anemia. Efficacy outcomes included changes from baseline in hemoglobin, platelets, spleen and liver volumes, and bone mineral density (mean±SD); biomarker levels (median); and achievement of therapeutic goals for anemia, thrombocytopenia, splenomegaly, and hepatomegaly. Results: Nineteen patients completed 3 years of treatment; 7 patients discontinued the trial. After 3 years, hemoglobin increased by 2.6±1.39 g/dL (from 11.3±1.63 to 13.8±1.37); platelets increased by 91±65.9% (from 70,000±21,700 to 126,800±40,500/mm3); and spleen and liver volumes (multiples of normal, MN) decreased by 61±12.2% (from 16.8±9.5 to 6.2±3.6 MN) and 29±15.8% (from 1.7±0.5 to 1.2±0.3 MN), respectively. Most patients met long-term therapeutic goals for hemoglobin (100%), spleen volume (100%), liver volume (89%), and platelets (63%). All patients met ≥3 therapeutic goals at 3 years. GD1 biomarkers were elevated in most patients pre-treatment. Statistically significant decreases (P<0.0001) following eliglustat treatment were seen in median plasma GL-1 (80%, from 12.15 to 2.70 μg/mL) and GM3 (64%, from 19.25 to 6.60 μg/mL), which normalized; and median chitotriosidase (80%, from 7304 to 1426 nmol/hr/mL) and CCL-18 (73%, from 3560 to 789.3 ng/mL), which both remained above normal. Mean lumbar spine BMD increased by 0.6 Z-score (from −1.3±1.0 to −0.7±1.1). Eliglustat was well tolerated. Most adverse events (AEs) were mild and unrelated to treatment. The most common AEs were viral infections (6 pts); urinary and upper respiratory tract infections (4 pts each); and headache, increased blood pressure, abdominal pain and diarrhea (3 pts each). Eight drug-related AEs, all mild, occurred in 6 patients. Conclusions: Eliglustat has shown promising efficacy and safety, with clinically meaningful hematologic, visceral, and bone improvements. Most patients met long-term therapeutic goals. Eliglustat was well-tolerated through 3 years and continues to have a safety profile that supports clinical investigations in Phase 3 studies. Disclosures: Peterschmitt: Genzyme: Employment. Lukina:Genzyme: Honoraria. Watman:Genzyme: Membership on an entity's Board of Directors or advisory committees. Pastores:Protalix: Research Funding; Shire HGT: Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; Actelion: Research Funding; Amicus: Research Funding. Arreguin:Genzyme: Research Funding. Aguzzi:Genzyme: Employment. Ross:Genzyme: Employment. Puga:Genzyme: Employment.

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Predictors of Response Duration and Survival with Second-Line Bosutinib Therapy in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Prior Imatinib

Blood ◽

10.1182/blood.v126.23.4041.4041 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4041-4041

Author(s):

Jorge E. Cortes ◽

Tim H. Brümmendorf ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

Philippe Schafhausen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Second Line ◽

Advisory Committees ◽

Imatinib Resistance ◽

Increased Risk

Abstract Bosutinib (BOS), a Src/Abl tyrosine kinase inhibitor (TKI), is approved for adults with Philadelphia chromosome-positive (Ph+) CML that is resistant/intolerant to prior therapy. In this retrospective analysis, baseline and on-treatment characteristics of chronic phase (CP) CML pts receiving second-line BOS following imatinib resistance (IM-R) or intolerance (IM-I) in an ongoing open-label, phase 1/2 study and a long-term extension study were examined to identify potential predictors of duration of major cytogenetic response (MCyR), overall survival (OS), and progression-free survival (PFS), using a backward-elimination multivariate Cox regression model. A total of 284 (IM-R, n=195; IM-I, n=89) pts who received BOS starting at 500 mg/d were included in this analysis. Median (range) age was 53 (18‒91) y; time from CML diagnosis was 3.7 (0.1‒15.1) y; treatment duration was 25.6 (0.2‒106.7) mo; follow-up duration was 53.7 (0.5‒106.8) mo. For the last enrolled patient, time from first BOS dose was ≥6 y. After ≥6 y of follow-up, median MCyR duration and OS were not yet reached. Kaplan-Meier estimated probability of maintaining MCyR at 6 y was 71%, OS rate was 83%, and cumulative incidence of on-treatment disease progression or death was 21%. Several factors were identified as predictive of MCyR duration, OS or PFS, including baseline Ph+ ratio ≥95% vs ≤35% and MCyR by week 12, which were significant predictors of all 3. Other significant predictors of decreased OS included: age ≥65, BOS-sensitive mutations vs no mutations and higher peripheral blood (PB) blasts at baseline (all P ≤0.031; Table). Other significant predictors of decreased PFS included: higher PB blasts and no dose reduction to 400 mg/d due to AEs (all P ≤0.025; Table). Prior IM response or resistance did not predict long-term outcomes, nor did any treatment-emergent adverse events examined except for abnormal liver function test (LFT), which was predictive of increased OS. In conclusion, pts with CP CML resistant/intolerant to IM treated with BOS were identified as having an increased risk of poorer outcomes if they had the following characteristics: baseline Ph+ ratio ≥95% vs ≤35%, higher PB blasts at baseline or no MCyR by week 12. Having a better understanding of factors that may be predictive of long-term patient outcomes with TKI therapies may aid healthcare providers in the future selection of optimal treatment regimens for pts with Ph+ CML. Disclosures Cortes: ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Brümmendorf:Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent: Patents & Royalties: Patent on the use of imatinib and hypusination inhibitors. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Nadanaciva:Pfizer Inc: Employment. Bardy-Bouxin:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Other: Stock Ownership. Leip:Pfizer Inc: Employment. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gambacorti-Passerini:Pfizer: Consultancy, Research Funding; BMS: Consultancy.

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Treatment and Lifestyle Risk Factors for Cardiovascular Disease Post Lymphoma Diagnosis: A Prospective Study in the Modern Treatment Era

Blood ◽

10.1182/blood-2019-127203 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 422-422

Author(s):

Nicholas J Boddicker ◽

Matthew J. Maurer ◽

Melissa C Larson ◽

Cristine Allmer ◽

Susan L. Slager ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Cumulative Incidence ◽

Medical Records ◽

Research Funding ◽

Cardiac Risk ◽

Advisory Committees ◽

Increased Risk ◽

Modern Treatment ◽

New Onset

Background With lymphoma survival rates increasing and a growing population of long-term survivors, the development of cardiovascular disease (CVD) in this patient population is of increasing importance. Anthracyclines are critical in the management of many lymphoma subtypes. However, there is a risk of developing anthracycline-induced CVD. Here, we estimate the cumulative incidence of CVD in adult lymphoma survivors and investigate risk factors associated with post diagnosis CVD. Methods Participants were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). From 2002-2015, the MER offered enrollment to all patients with newly diagnosed lymphoma who are US residents and age >18 years. Participants completed a risk factor questionnaire, and clinical and treatment data were abstracted from medical records. Patients were contacted every 6 months for the first 3 years after diagnosis and annually thereafter to assess disease status, re-treatment and new onset morbidity including CVD. CVD events, including congestive heart failure (CHF), coronary artery disease (CAD), valvular heart disease (VHD), and arrhythmia were identified and validated against medical records. CHF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. CAD, arrhythmia, and VHD were validated using clinical definitions. We calculated the cumulative incidence of CVD, with death modeled as a competing risk. The association of risk factors and treatments with risk of CVD was estimated using hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression with a competing risk of death. Risk factors included age, sex, diabetes, smoking, body mass index (BMI), and treatment with anthracyclines or radiation therapy. Results The study consisted of 3,063 lymphoma patients after excluding those with chronic lymphocytic leukemia and CVD prior to lymphoma diagnosis. The median age at diagnosis was 59 years (range 18-95), and 56% were males. At a median follow-up was 6.9 years (range 0.8-17.1), 640 patients (21%) had died without CVD and 485 patients self-reported CVD post lymphoma diagnosis, of which 280 (57.7%) were validated. Cardiovascular events included 86 CHF, 78 CAD, 40 VHD, and 164 arrhythmias. The cumulative incidence of CVD (Figure 1) at 5 and 10 years was 6.0% (95% 5.2%-7.0%) and 10.7% (95% CI 9.5%-12.1%), respectively. In multivariable analysis, increasing age (HR=3.93 per 5 years, p<0.001), male sex (HR=1.33, p=0.03), former smoker (HR=1.04, p=0.77), current smoker (HR=1.96, p<0.001), BMI>30 kg/m2 (HR=1.50, p=0.01), and anthracycline treatment (HR=1.49. p<0.001) were all significantly associated with risk of overall CVD, while there was no association with diabetes (HR=0.92, p=0.70) or radiation therapy (HR=1.05, p=0.78) in the multivariable model. Anthracycline use was significantly associated with increased risk of CHF (HR=2.64, p<0.001) and arrhythmia (HR=1.51, p<0.01), but not VHD (HR=0.83, p=0.56) or CAD (HR=1.23, p=0.31) after adjustment for the cardiac risk factors. The number of anthracycline cycles ranged from 0 to 12. 63.2% of individuals that received anthracyclines received 6 cycles. The 5-year cumulative incidence of CVD for 0, 1-5, 6, and >6 anthracycline cycles was 5%, 6.9%, 7.4%, and 7.7%, respectively. Adjusting for cardiac risk factors, the number of anthracycline cycles was significantly associated with increased risk of CVD (1-5 cycles HR=1.34, p=0.11; 6 cycles HR=1.51, p<0.01; >6 cycles HR=2.04, p=0.03). Furthermore, the number of anthracycline cycles was associated with CHF (1-5 cycles HR=2.82, p<0.001; 6 cycles HR=2.46, p<0.001; >6 cycles HR=5.33, p<0.001) and arrhythmia (1-5 cycles HR=1.31, p=0.27; 6 cycles HR=1.60, p<0.01; >6 cycles HR=1.65, p=0.27). Conclusions In the modern treatment era, the risk of new onset CVD in patients with lymphoma without a history of CVD is approximately 1% per year after diagnosis. Arrhythmia and CHF were the most commonly occurring CVD events in this cohort. Both traditional CVD risk factors and treatment with anthracyclines was associated with an increased risk of developing CVD, and anthracyclines were a risk factor for arrhythmia and CHF in particular. Prevention of CVD in lymphoma patients will need to address both treatment and traditional lifestyle factors. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Celgene: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Characteristics and Outcomes of Therapy Related Myeloid Neoplasms in Patients with Multiple Myeloma Following Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123065 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4560-4560 ◽

Cited By ~ 1

Author(s):

Kalyan Nadiminti ◽

M Hasib Sidiqi ◽

Kapil Meleveedu ◽

Hassan B. Alkhateeb ◽

Aref Al-Kali ◽

...

Keyword(s):

Risk Factors ◽

Research Funding ◽

Survival Advantage ◽

High Dose ◽

Term Survival ◽

Myeloid Neoplasms ◽

Pathologic Features ◽

Increased Risk

Introduction: Patients who develop therapy-related myeloid neoplasms (t-MN) have dismal outcomes. Previous studies reported the incidence and risk factors associated with t-MN development. Lenalidomide, in the setting of oral, but not intravenous, melphalan is associated with a higher risk of t-MN (Palumbo et. al, Lancet Oncology, 2014). We carried out this study to evaluate the clinical and pathologic features of t-MN, therapies employed, and factors that predict long-term survival after diagnosis. Patients and methods: We identified patients who received the first ASCT 1998-2016 at our institution. t-MN was defined per the WHO 2016 classification. Median overall survival (OS) was calculated from the time of t-MN diagnosis to last follow-up or death. Statistical analyses were performed using SAS (JMP v14.1) or GraphPad Prism (v7). Results: Out of 2115 patients that underwent at least one ASCT, 53 (2.5%) developed t-MN. Thirty-five of 53 (66%) patients who developed t-MN had received lenalidomide. Among 2062 patients that did not develop t-MN, 916 (44.4%) patients received lenalidomide. Lenalidomide exposure was associated with development of t-MN (χ2 with Yate's correction 8.9, p=0.003). Ten patients were excluded from further analyses due to lack of follow up. Clinical characteristics are shown in Table 1a (N=43). Median age at t-MN diagnosis was 70 years (range 44-79). Median time from ASCT to t-MN was 5 years (range 1-15). After a median follow-up of 70 months (95% CI, 38-134), the median OS was 12 months (95% CI, 9-17, Figure). Primary causes of death were t-MN (71%), MM (12%), both (6%), and other including infection, GVHD, and unknown (12%). Seven (16%) had t-AML and 36(84%) had t-MDS. Three (42%) of 7 patients with t-AML had pure erythroid phenotype. At the time of last follow-up, 9 (21%) were alive. Seven (17%) underwent two ASCT, 16 (36%) received more than 2 years cumulative dose of lenalidomide. Median number of cycles of alkylator therapy including high-dose melphalan (HDM) used for ASCT was 2 (range 1-6). On univariate analysis, factors predicting OS from t-MN diagnosis were ≥ 2 alkylator vs. < 2 cycles (11 vs. 27 months, p=0.02), ≥10% vs. <10% blast at the time of t-MN diagnosis (5.5 vs. 17 months, p=0.01), and the presence of complex karyotype (CK) vs. not (11 vs. 17 months, p=0.03). There was no difference in survival among t-MDS patients who transformed to t-AML vs. those who did not, those who received 1 vs. 2 ASCT, and those with lenalidomide duration ≥ 2 vs. <2 years. On multivariate analysis, the number of alkylator therapies and CK, but not % blasts predicted OS from t-MN diagnosis (Figure). Eight (19%) patients proceeded to receive an autologous (n=4) or allogeneic (n=4) transplant for t-MN (Table 1b). There was no survival advantage for patients who underwent SCT for t-MN, compared to those who did not (17 vs. 10 months, p=0.3). Similarly, there was no survival advantage for patients who received allo SCT compared to auto SCT (21 vs. 16 months, p=0.7). Survival for t-MDS and t-AML was also not different (15 vs. 6 months, p=0.2). There is only one long-term survivor in the transplant group (s/p allogeneic SCT). Four of seven (57%) patients died of progressive t-MN, 1 died of progressive MM, progressive MM and t-MN, and TRM each. Conclusions: Lenalidomide, in the setting of HDM, is associated with an increased risk of t-MN. Increased exposure to alkylators, a higher tumor burden, and the presence of CK predict poor survival in t-MN. As HDM/ASCT followed by lenalidomide maintenance remains the standard of care for eligible patients, minimizing exposure to other alkylator regimens may be prudent. While considered the standard, only a minority undergo transplant; and post-transplant outcomes remain poor. Studies to identify prognostic genetic and epigenetic risk factors are ongoing. Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

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