Renal Function and Risk of Arterial Thrombotic Events in Patients Positive for Lupus Anticoagulant

Abstract Background: Patients with lupus anticoagulant (LA) are at risk for arterial and venous thromboembolic events. Recent work suggests that LA positive patients who experience thrombotic events in different vascular beds constitute distinct subgroups. To risk stratify patients, further work is needed to better characterize predictors for thromboembolic events in these subgroups. Aims: The aim of this study was to identify baseline characteristics and laboratory parameters associated with the development of arterial or venous thrombotic events. Methods: Patients with at least 2 previous positive LA tests were serially monitored for thrombotic events within the prospective Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Patients without clinical follow-up were excluded from this analysis. Statistical analysis was performed with RStudio (Version 1.1.442). Results: One-hundred-eighty-seven patients were followed (Table 1) for a median of 11.4 years and 1865 follow-up visits (median visit/patient=9). Fifty-seven prospective thrombotic events (TE), including 27 arterial thrombotic events (ATE) and 30 venous thrombotic events (VTE), were observed. This corresponded to 10-year prospective ATE, VTE and overall thrombosis incidences of 13.9% [95%CI: 8.3, 19.6], 18.8% [12.2, 25.4], and 32.0% [24.1, 39.8], respectively. (Figure 1). Thirty-seven of the 57 events occurred in patients with a prior history of thrombosis ("recurrent thrombosis"). In univariable competing risk analysis, age (subdistribution hazard ratio (SHR) = 1.02, 95% CI: 1.00-1.05, p=0.019), body mass index (BMI, 1.05, 1.00-1.11, p=0.042), history of ATE (3.14, 1.45-6.81, p=0.0038), active smoking (2.16, 1.00-4.62, p=0.049), diabetes (4.16, 1.47-11.8, p=0.0073), VKA use at baseline (0.42, 0.18-0.97, p=0.042), aCL IgM positivity (2.48, 1.05-5.83, p=0.038), aβ 2GPI IgM positivity (2.86, 1.18-6.93, p=0.020), mean platelet volume (1.17, 1.06- 1.30, p=0.0024), creatinine (3.76, 1.32- 10.7, p=0.013), and estimate glomerular filtration rate (eGFR, 0.98, 0.96-0.99, p=0.0011) were associated with prospective risk of ATE (Table 2). Conversely, the prospective risk of VTE was univariably associated only with prior history of VTE (3.26, 1.40-7.68, p=0.0061). After adjusting for traditional arterial thrombotic risk factors (age, sex, BMI, active smoking, diabetes,), history of ATE (SHR = 3.97, 95% CI: 1.71-9.025, p=0.0014), prior history of both ATE and VTE (3.87, 1.06-14.16, p=0.041), creatinine (3.93, 1.22-12.66, p=0.022), and eGFR (CKD-EPI, 0.96, 0.96-0.99, p=0.0037) remained independently associated with prospective risk of ATE (Table 2). In detail, the 10-year cumulative risk of ATE was 24.9% [95%CI: 8.8, 41.0], 15.0% [5.8, 24.2], and 6.7% [2.2, 13.8] in patients with a baseline eGFR less than 60 mL/min/1.73m 2, between 60 and 89 mL/min/1.73m 2, and greater than or equal to 90 mL/min/1.73m 2, respectively (Gray's test, p=0.019, Figure 2). Conclusion: Approximately 14% of patients persistently positive for LA experienced an ATE over 10 years. After adjusting for traditional arterial risk factors, decreased renal function was associated with an increased prospective risk of ATE. Notably, decreased renal function was not associated with development of VTE and the association with ATE was also independent of underlying SLE, LLD, or rheumatic disease (data not shown). Clinically, LA positive patients with decreased renal function may represent a subgroup that might benefit from more aggressive anti-thrombotic therapy or anti-thrombotic prophylaxis. Figure 1 Figure 1. Disclosures Pabinger: Bayer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Daiichi Sanchyo: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NovoNordisk: Consultancy, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding.

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Skin Cancers Among Chronic Lymphocytic Leukemia (CLL) Patients - the Effect of UV Radiation and CLL Clinical Characteristics

Blood ◽

10.1182/blood.v128.22.4772.4772 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4772-4772 ◽

Cited By ~ 4

Author(s):

Geffen Kleinstern ◽

Abdul Rishi ◽

Sara J Achenbach ◽

Kari Rabe Chaffee ◽

Neil E. Kay ◽

...

Keyword(s):

Skin Cancer ◽

Uv Radiation ◽

Mayo Clinic ◽

Research Funding ◽

Sun Exposure ◽

Prior History ◽

Skin Cancers ◽

History Of ◽

Very High

Abstract Background: It is well established that the incidence of skin cancers in patients with CLL are significantly elevated compared to age- and sex- matched controls. However, little is known about the characteristics of CLL patients who develop skin cancer. Herein, we evaluate the associations of CLL clinical and prognostic characteristics, along with UV radiation exposure, with risk of first skin cancer following CLL diagnosis. Methods: Newly diagnosed CLL patients from Minnesota, Iowa, and Wisconsin were enrolled in the Mayo Clinic case-control study from 2002-2015 and systematically followed in the Iowa/Mayo Lymphoma SPORE. Clinical and prognostic CLL data were obtained from the Mayo Clinic CLL database, and skin cancer clinical data were abstracted from medical records using a standard protocol. The CLL international prognostic index (CLL-IPI) was computed using a weighted average of five independent CLL prognostic factors (IGHV mutational status, serum b2-microglobulin, Rai stage, age, and FISH 17p deletion/TP53 status). Self-reported history of midday sun exposure at various ages (birth to age 12; 13 to 21 years; 22 to 40 years, and 41+ years) was obtained from a risk factor questionnaire. For each age, we asked the extent of mid-day sun as: practically no exposure (under 3 hours per week), little exposure (4-7 hours per week), moderate exposure (8 to 14 hours per week) and extensive exposure (15+ hours per week). Midday sun exposure was modeled as an ordinal covariate. To evaluate associations with risk of skin cancer following CLL diagnosis, we calculated time from date of CLL diagnosis to date of first skin cancer, death, or last known follow-up. We used Cox regression analysis to estimate hazard ratios (HRs) and 95% CIs. CLL treatment was considered a time-dependent covariate. Results: Among 846 CLL patients enrolled, the median age at diagnosis was 63 years (range 28-91), 68% were male, 7% had Rai stage III-IV at diagnosis. Based on the CLL-IPI, 42% were categorized as low risk, 33% as intermediate risk, and 25% as high or very-high risk. 109 CLL cases (13%) had one or more reported skin cancers at or prior to CLL diagnosis. Melanoma was observed in 19 (2%) cases and non-melanoma was in 90 (11%) cases. At a median follow-up of 7 years from CLL diagnosis, 165 patients (20%) had one or more skin cancers after CLL diagnosis. Among these patients, 49 had skin cancer before CLL diagnosis. The most frequent skin cancer was squamous cell carcinoma (59%), followed by basal cell (31%), melanoma (5%), and Merkel cell (1%). 552 (65%) of the 846 patients returned a questionnaire. Significant associations of clinical and prognostic characteristics with risk of first skin cancer were observed for age (HR=1.35 per 10 year increase, 95% CI=1.17-1.56, P<0.001), male sex (HR=1.38, 95% CI 0.98-1.96, p=0.07), prior history of skin cancer (HR=4.19, 95% CI=2.98-5.88, P<0.001), and CLL-IPI (HR=1.26, 95% CI= 1.03-1.54, P=0.026, after adjusting for age, sex, and prior skin cancer). Of note, the risk of first skin cancer in those CLL patients categorized as very high via CLL-IPI had 2.28 fold risk (95% CI 1.02-5.11). Midday sun exposures for each of the ages considered showed no evidence of association with risk of first skin cancer (all P>0.05). 50 CLL patients were treated prior to first skin cancer following CLL diagnosis; we observed no evidence of association between treatment and risk of first skin cancer (HR=1.44, 95% CI= 0.93-1.92, P=0.12). Conclusion: CLL patients who are at an increased risk of skin cancer following CLL diagnosis are those who either have had a prior history of skin cancer or a more aggressive CLL disease at diagnosis, according to CLL IPI. Routine skin cancer screening is currently recommended for CLL patients. Our data suggest that more frequent screening would be particularly important among patients with aggressive CLL and who have a prior history of skin cancer. Unexpectedly, we found no evidence of association of skin cancer risk with UV radiation following CLL diagnosis or with CLL treatment. Further investigation is needed to determine whether other factors increase the risk of skin cancer following CLL diagnosis. Disclosures Shanafelt: Genentech: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding.

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Dasatinib or Nilotinib Discontinuation in Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) Patients (pts) with Durably Undetectable BCR-ABL Transcripts: Interim Analysis of the STOP 2G-TKI Study with a Minimum Follow-up of 12 Months – on Behalf of the French CML Group Filmc

Blood ◽

10.1182/blood.v124.21.811.811 ◽

2014 ◽

Vol 124 (21) ◽

pp. 811-811 ◽

Cited By ~ 16

Author(s):

Delphine Rea ◽

Franck E. Nicolini ◽

Michel Tulliez ◽

Philippe Rousselot ◽

Francois Guilhot ◽

...

Keyword(s):

Treatment Duration ◽

Research Funding ◽

Prior History ◽

Molecular Response ◽

Free Survival ◽

Advanced Phase ◽

History Of ◽

Tki Treatment ◽

Tki Discontinuation

Abstract Background: Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL have revolutionized the prognosis of pts suffering from CML but these drugs are considered as non-definitively curative and current recommendation is to treat pts during their entire lifespan. However, prospective trials such as STIM, TWISTER and EUROSKI suggest that imatinib may be successfully stopped in pts with deep and sustained molecular responses. Here, we report on the feasibility of second generation TKIs discontinuation in the setting of the French STOP 2G-TKI study. Methods: Adult CP-CML pts on dasatinib or nilotinib first line or after imatinib without prior allogeneic transplantation or progression to advanced phase CML were proposed TKI discontinuation when presenting: (1) b2a2 or b3a2 BCR-ABL transcripts subtype, 2) TKI treatment duration for at least 36 months, (3) CMR4.5 achieved and maintained for at least 24 months. The primary objective was treatment-free survival without loss of major molecular response (MMR). After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 12 months, every 3 months during the 2ndyear and every 3 to 6 months thereafter. Molecular relapse was defined by MMR loss on a single occasion and triggered TKI reintroduction. Data as of August 1, 2014 are reported in pts with at least 12 months of follow-up (n=52) and median follow-up was 32 months (12-56). Results: Median age was 60 years (34-81) and 61.5% of pts were female. Sokal risk group was low in 58%, intermediate in 23%, high in 13% and unknown in 6%. 2G-TKIs were given after imatinib intolerance in 67% of pts, suboptimal response or resistance to imatinib in 23% and upfront in 10%. Median duration of CML, TKI treatment, 2G-TKI treatment and CMR4.5 was 83 months (36-218), 78 months (36-136), 39 months (19-72) and 28 months (24-64), respectively. Twenty four pts lost MMR after a median time of 4 months (1-38) at last follow-up. Importantly, no loss of CHR or progression to advanced phase CML was observed. The 12- and 24-month probabilities of treatment-free survival without MMR loss were 61.4% (95% CI, 48.1-74.6) and 57% (95% CI, 43.3-70.6), respectively. The majority of relapses occurred within 6 months and in a landmark analysis, pts who were still in MMR without therapy at 6 months had 12- and 24-month probabilities of treatment-free survival without MMR loss of 91.2% (95% CI, 81.6-100) and 84.7% (95% CI, 72.2-97.1), respectively. All pts but 1 who lost MMR restarted 2G-TKI treatment and regained MMR after a median time of 3 months (1-8). Pts in MMR without any therapy (n=28) displayed varying patterns of spontaneous molecular response including stable CMR4.5 in 7 and fluctuations between CMR4.5 and MR4.5, CMR4.5 and MR4, CMR4.5 and MMR in 9, 4 and 4 pts, respectively. Gender, age, prior interferon exposure, 2G-TKI type, treatment duration and duration of CMR4.5 were not found to have any impact on outcome. By contrast, prior history of suboptimal response or resistance to imatinib was associated with a significantly lower chance of successful treatment discontinuation, with a 12-month probability of treatment-free survival without MMR loss of 41.7% (95% CI; 13.8%-69.6%), compared to 67.3% (95% CI, 52.6%-81.8%) in other patients (p=0.04). Conclusions: 2G-TKI could be safely and successfully discontinued in CP-CML pts with long-lasting undetectable BCR-ABL transcripts, especially in those without prior history of suboptimal response or resistance. Most of molecular relapses had an early onset and all were sensitive to 2G-TKI resumption. The recurrence of low levels of detectable residual disease below MMR after 2G-TKI withdrawal did not automatically herald CML relapse and did not preclude the possibility to remain treatment-free. Disclosures Nicolini: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Rousselot:Novartis: Research Funding. Gardembas:BMS: Honoraria. Legros:Novartis, BMS: Honoraria. Etienne:Novartis, BMS,Pfizer, ARIAD Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Connect MM®—the Multiple Myeloma (MM) Disease Registry: Incidence of Second Primary Malignancies (SPM)

Blood ◽

10.1182/blood.v124.21.4749.4749 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4749-4749

Author(s):

Robert M. Rifkin ◽

Rafat Abonour ◽

Jatin J. Shah ◽

Jayesh Mehta ◽

Mohit Narang ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Solid Tumor ◽

Research Funding ◽

Significant Risk ◽

Significant Risk Factor ◽

Prior History ◽

Advisory Committees ◽

History Of

Abstract Background: Increased rates of SPM have been observed as newer cancer treatments have improved survival over the past 2 decades (Fraumeni et al. NCI, 2006). Higher incidence of specific types of hematologic SPM following MM, especially acute myeloid leukemia and myelodysplastic syndromes, have been reported relative to the general population (Dores et al. NCI, 2006; Mailankody et al. Blood, 2011; Ravazi et al. Blood, 2011; Landgren and Mailankody. Leukemia, 2014). A complex interplay between myeloma-, host-, environmental-, and treatment-related factors likely contributes to the increased incidence of SPM in MM. Connect MM is the first and largest prospective, observational, US-based, multicenter registry designed to characterize patients (pts), treatment patterns, and outcomes in newly diagnosed MM (NDMM) pts. Methods: Between September 2009 and November 2012,a total of 1493 NDMM pts were enrolled from 234 US sites within 2 mos of the first diagnosis of MM. Patient data were collected at baseline and each subsequent quarter using a standardized form. Invasive SPM included hematologic and solid tumor second cancers and non-invasive SPM were defined as non-melanoma skin cancers (NMSC). SPM incidence and incidence rate (IR; number of pts with SPM per 100 patient-yrs [PY]) were calculated for all pts and by exposure to specific treatments, including lenalidomide (LEN). PYs were calculated as the observation period from the start of treatment until the detection of the first reported SPM (per category), death, or end of follow-up (pt lost or data cutoff). Results: As of Dec 10, 2013, SPM data were available for 1493 NDMM pts. The median age was 67 yrs (range, 24-94 yrs), 82% of patients were white and 57% were male. Median follow-up was 29.0 mos (0-49 mos). The median OS of treated pts was 44.4 mos. Fifty pts did not receive treatment and had no SPM reported. A total of 74 of the 1443 treated pts (5.1%) reported SPM. Invasive SPM were observed in 51 pts (3.5%): 37 pts (2.6%) with solid tumors and 14 pts (1.0%) with hematologic SPM. Lung/bronchus and myelodysplastic syndromes were the most frequently reported solid tumor and hematologic SPM respectively. NMSC were reported for 26 pts (1.8%). 3 pts had both an invasive SPM and NMSC. The IRs for invasive, hematologic, and solid tumor SPM by LEN exposure are listed in Table 1. By multivariate analysis, the only significant risk factor for the occurrence of SPM was prior history of invasive malignancy. Demographics (including age, ethnicity, race, and gender), International Staging System stage, family history of myeloma or other cancers, history of smoldering MM or monoclonal gammopathy of unknown significance, or prior radiation therapy were not associated with the occurrence of SPM. Conclusions: This analysis shows that there was no increased risk of invasive SPM in this disease-specific registry of pts with NDMM. The risk of SPM for LEN exposed pts was not greater than that for pts not exposed to LEN. In addition, multivariate analysis indicated the only significant risk factor for SPM was prior history of invasive malignancy. As additional agents are approved for the treatment of MM and the length of pt survival increases, longer prospective observation with expanded enrollment on the registry will better characterize the occurrence of SPM in this pt population. Correlations with risk factors including age, pre-existing MDS, risk status, as well as type and duration of therapy will continue to be investigated. Table 1. Incidence rates (per 100 PYa) by treatment exposure IR per 100 PY (95% CI) SPM LEN-Exposed (n = 977) Non–LEN Exposed (n = 466) Invasive 0.85 (0.61-1.19) 1.16 (0.72-1.86) Hematologic 0.17 (0.08-0.36) 0.47 (0.22-0.99) Solid tumor 0.67 (0.46-0.98) 0.68 (0.36-1.26) NMSC 0.50 (0.32-0.77) 0.41 (0.18-0.91) a PY of exposure is the sum of exposure of all pts. Disclosures Rifkin: Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Shah:Celgene Corp: Consultancy, Research Funding. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Lu:Celgene Corp: Employment. Kenvin:Celgene Corp: Employment. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Durie:Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees.

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Iniencephaly

Journal of Islamabad Medical & Dental College ◽

10.35787/jimdc.v10i4.646 ◽

2021 ◽

Vol 10 (4) ◽

pp. 239-241

Author(s):

Feriha Fatima Khidri ◽

Hina Riaz ◽

Faiza Kamran Ali

Keyword(s):

Risk Factors ◽

Lower Abdominal Pain ◽

Consanguineous Marriage ◽

Prior History ◽

Second Trimester ◽

Baby Girl ◽

Cardiac Deceleration ◽

Pathological Evaluation ◽

History Of

Iniencephaly is an uncommon form of neural tube defects which is characterized by retroflexion of the head and absence of neck as a consequence of defective closure of the vertebral body and arch. Multiple identified risk factors for its causation include environmental, genetic and drugs. We report a case of 38-year-old woman with prior history of still birth and abortions who presented at 35 weeks of gestation with lower abdominal pain and high blood pressure. Mother had consanguineous marriage. Her hypothyroidism was untreated in the first and second trimester. She delivered an iniencephalic baby girl via emergency c-section with multiple malformations at 38 weeks gestation secondary to fetal cardiac deceleration. Baby survived for less than 18 hours. In this case, proper antenatal care and follow up visits were needed along with postnatal genetic and pathological evaluation including assessment of risk factors. Appropriate management is important to prevent complications and recurrence in subsequent pregnancies.

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Risk Factors of Thrombosis in Adults with Primary Immune Thrombocytopenia. a French Nationwide Cohort Study

Blood ◽

10.1182/blood-2018-99-112506 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3745-3745

Author(s):

Guillaume Moulis ◽

Bérangère Baricault ◽

Charlotta Ekstrand ◽

Margaux Lafaurie ◽

Christian Fynbo Christiansen ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Additional Risk Factor ◽

Discharge Diagnosis ◽

Additional Risk ◽

Icd 10 ◽

History Of

Abstract Background: Immune thrombocytopenia (ITP) is associated with an increased risk of venous and arterial thrombosis (VT and AT, respectively) as compared with the general population. However, the impact of thrombosis risk factors and of ITP treatments, particularly of thrombopoietin-receptor agonists (TPORAs), is not well known in the routine clinical practice. Aim: The objective of this cohort study was to assess the risk factors of VT and AT in adults with primary ITP, including ITP treatments. Methods: The population was the cohort of all incident primary ITP adults in France during 2009-2015 built within the national health insurance database (French Adult Immune Thrombocytopenia - FAITH - cohort; NCT03429660). Incident ITP patients were identified using a validated algorithm combining drug exposures and diagnosis codes according to the international classification of diseases, version 10 (ICD-10). Risks of first hospitalization with a validated primary discharge diagnosis code of VT and AT (coded with the ICD-10) were assessed separately. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Variables included in multivariable models were: age, sex, history of AT and of VT, diabetes, cardiovascular disease, chronic kidney disease, chronic liver disease, cancer; exposures to antihypertensive, lipid-lowering, antiplatelet, anticoagulant drugs and ITP treatments including splenectomy were modeled as time-dependent variables. Results: The cohort included 7225 adult patient with incident primary ITP: 3807 (52.7%) were ≥60 year-old, 3199 (44.3%) were males, 692 (9.6%) had a history of cardiovascular disease, 937 (13.0%) had diabetes. During the follow-up, 5737 (79.4%) were exposed to corticosteroids, 3364 (46.6%) to intravenous immunoglobulin (IVIg), 995 (13.8%) to TPORAs, and 755 (10.4%) were splenectomized. During the follow-up (23 852 patient-years in total; mean follow-up: 39.5 months), 174 patients had a hospitalization with a primary discharge diagnosis of VT and 333 of AT, leading to incidences of 7.4 (95% CI: 6.4-8.6) and 14.4 (95% CI:12.9-16.0)/1000 patient-years, respectively. In multivariable Cox models, the most important risk factors for VT were higher age (≥60 years vs. <40 years: HR: 2.22, 95% CI: 1.39-3.53), a history of VT (HR: 4.38, 95% CI: 1.07-18.02), splenectomy (HR: 3.22, 95% CI: 2.06-3.03), exposure to IVIg (HR: 2.30, 95% CI: 1.41-3.75), corticosteroids (HR: 3.29, 95% CI: 2.39-4.53) and TPORAs (HR: 3.16, 95% CI: 2.04-4.88). All classical baseline cardiovascular risk factors listed above as covariables were associated with the risk of AT. The HRs for AT were 0.97 (95% CI: 0.59-1.61) for splenectomy, 1.05 (95% CI: 0.80-1.40) for corticosteroids, 2.35 (95%CI: 1.58-3.50) for IVIg, 1.25 (95%CI: 0.46-3.37) for danazol and 1.31 (95%CI: 0.84-2.06) for TPORAs. It is of note that among the 25 patients who had a VT while treated by TPORA, 18 (72.0%) were>50 year-old, 14 (56.0%) were women, 6 (24.0%) were splenectomized, 9 (36.0%) were concomitantly exposed to corticosteroids and 3 (12.0%) to IVIg; only 3 women aged<50 years had no additional risk factor. Among the 21 patients who had an AT while treated by TPORA, 18 (85.7%) were>50 year-old, 15 (71.4%) were men, 8 (38.1%) were splenectomized, 5 (23.8%) were concomitantly exposed to corticosteroids and one to IVIg; only one 48-year-old man had no additional risk factor for AT. Conclusions: Baseline risk factors for VT and AT were highly associated with VT and AT occurrence in adults with primary ITP. Splenectomy, corticosteroids, IVIg and TPORAs were risk factors for VT. Most patients who had a thrombosis while treated by TPORA had additional risk factors. These findings help choosing a tailored treatment strategy for a given patient depending on his/her risk profile for VT and AT. Disclosures Christiansen: Amgen: Research Funding. Bahmanyar:Amgen: Research Funding.

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Analysis of Pre-Transplant Therapy with Brentuximab Vedotin for Relapsed/Refractory Hodgkin Lymphoma on Outcomes of Reduced Intensity Conditioned Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v126.23.4406.4406 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4406-4406 ◽

Cited By ~ 2

Author(s):

Baldeep Wirk ◽

Barry E. Storer ◽

David G Maloney ◽

Ajay K Gopal ◽

Ryan D Cassaday ◽

...

Keyword(s):

Salvage Therapy ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Brentuximab Vedotin ◽

Prior History ◽

Prior Therapy ◽

History Of ◽

The Impact ◽

Refractory Hodgkin Lymphoma

Abstract Background: The impact of prior salvage therapy with brentuximab vedotin (BV) for relapsed/ refractory Hodgkin lymphoma (HL) on long-term outcomes after reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) is unknown. Early studies (Chen et al Biol Blood Marrow Transplant 2014; 20: 1864-1868) suggested an improved 2-year progression free survival (PFS) with BV salvage given before allo-HCT compared to patients without prior BV treatment. In the current study, we analyzed the impact of prior therapy on the incidence of chronic graft-versus-host disease (cGVHD) and other major outcomes in patients, who received an RIC allo-HCT for relapsed HL. Methods: This is a retrospective study of relapsed/refractory HL patients who had RIC allo-HCT between 2005-2014 at the Fred Hutchison Cancer Research Center. Patients were grouped according to prior history of salvage therapy with or without BV pre allo-HCT. Baseline patient characteristics are shown in the Table. Results: Of the 62 consecutive allo-HCT recipients in this study, 25 had prior therapy with BV (BV group) and 37 received other chemotherapy alone (No BV group) for relapsed HL before allo-HCT. More patients in the BV group were in complete remission at allo-HCT (Table). The 100 day acute GVHD and 5 year cGVHD incidence for the BV vs. no BV group were 58% (95% confidence intervals [CI]: 39%-78%) vs. 65% (95% CI: 50%-80%), p=0.6 and 46% (95% CI: 26%-67%) vs. 51% (95% CI: 35%-68%), p=0.66, respectively. The 5 year non-relapse mortality and relapse/ progression for the BV vs. no BV group were 8% (95% CI: 1%-19%) vs. 25% (95% CI: 11%-38%), p=0.13 and 46% (95% CI: 24%-67%) vs. 38% (95% CI: 22%-53%), p0.98. The 5 year PFS and overall survival for BV vs. no BV group were 46% (95% CI: 25%-68%) vs. 38% (95% CI: 22%-53%), p=0.44 and 78% (95% CI: 60%-95%) vs. 56% (95% CI: 40%-72%), p=0.14. The major cause of death in both groups was relapsed HL. Conclusion: With longer follow-up, similar incidences of cGVHD, PFS and OS were observed in patients who received salvage therapy for relapsed/refractory HL prior to allo-HCT with or without BV. Any potential differences in cGVHD and other major outcomes need to be tested in a larger population. Table 1. Characteristics Prior treatment with Brentuximab vedotin Yes N=25 No N=37 Median age, years (range) 27 (14-47) 32 (17-64) Disease stage at diagnosis, n (%) I II III IV 2 (8)11 (44)7 (28)5 (20) 0 (0)15 (41)12 (32)10 (27) Prior history of local radiation pre allo-HCT 20 (80) 29 (78) No. of prior lines of therapies pre allo-HCT 4 (2 - 10) 3 (2 - 7 ) Prior autologous HCT, n (%) 0 1 2 (tandem auto) 1 (4) 21 (84) 3 (12) 0 (0) 35 (96) 2 (4) Disease status at allo-HCT, n (%) Complete remission Partial remission Progressive disease 9 (36) 13 (52) 3 (12) 7 (19)20 (54)10 (27) Median interval from diagnosis to allo-HCT, months (range) 33 (10.7-222) 30.7 (5-292) Graft type, n (%) Bone Marrow Peripheral blood stem cells 9 (36) 16 (64) 15 (41) 22 (59) Donor type, n (%) Haploidentical Matched related Matched unrelated Mismatch unrelated 16 (64) 5 (20) 4 (16) 0 (0) 17 (46) 14 (38) 5 (14) 1 (2) Conditioning for allo-HCT, n (%) FLU/CY/TBI (2 Gy) FLU/TBI (2 Gy) FLU/TBI (3 Gy) TBI (2 Gy) 16 (64) 6 (24) 1 (4) 2 (8) 17 (46) 15 (40) 0 (0) 5 (14) GVHD prophylaxis, n (%) CNI/MMF/post transplant CY CNI+MMF+/- other 16 (64) 9 (36) 17 (46)20 (54) Median follow-up, months (range) 34 (4 - 99) 84 (34 - 121) Abbrev: FLU fludarabine, CY cyclophosphamide, TBI total body irradiation,CNI calcineurin inhibitor, MMF mycophenolate mofetil Disclosures Maloney: Seattle Genetics: Honoraria; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding. Gopal:Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Cassaday:Seattle Genetics: Research Funding; Pfizer: Research Funding. Sandmaier:Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

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Thrombotic Events in Lupus Anticoagulant Positive Patients Prospectively Correlate with Clinical Risk Factors - the Vienna Lupus Anticoagulant and Thrombosis Study (LATS)

Blood ◽

10.1182/blood.v126.23.652.652 ◽

2015 ◽

Vol 126 (23) ◽

pp. 652-652

Author(s):

Florian Posch ◽

Johanna Gebhart ◽

Jacob H. Rand ◽

Bas de Laat ◽

Silvia Koder ◽

...

Keyword(s):

Risk Factors ◽

Lupus Anticoagulant ◽

Risk Group ◽

Multivariable Analysis ◽

Low Risk ◽

Active Smoking ◽

Thrombotic Risk ◽

Glycoprotein I ◽

Prolonged Aptt

Abstract INTRODUCTION: Patients with the lupus anticoagulant (LA) are at an increased risk of thrombotic events (TE), which in turn increase the risk of death (Gebhart J et al. Blood. 2015. 125:3477). Understanding the determinants of thrombotic risk in LA patients may pave the way towards targeted thromboprophylaxis. To date, several retrospective studies have investigated the association between anamnestic thrombosis and certain factors, such as antibodies against cardiolipin and beta2-glycoprotein I. However, robust prospective evidence is still limited. We aimed to investigate clinical and laboratory risk factors for development of TE in patients with a persistently positive LA. PATIENTS & METHODS: In this prospective, observational cohort study with a baseline biobank we followed 150 patients (median age: 41.3 years, interquartile range (IQR): 32.3-60.2, female gender: n=122 (81.3%)), who tested repeatedly positive for the LA until the development of TE, death, or censoring. The primary endpoint was the time-to-TE during the observation period, defined as a composite of arterial or venous, independently-adjudicated thrombotic complications. Ninety-eight (65.3%) of the 150 patients had a history of at least one TE event (arterial TE: n=21, venous TE: n=84, both: n=7), and 70 (46.7%) were on oral anticoagulation at baseline. Sixty-five (43.3%) patients also had IgM and/or IgG isotype antibodies against cardiolipin and beta2-glycoprotein I ("Triple positivity"). For investigation of the LA, lupus-sensitive aPTT reagents were used (aPTT-LA, Diagnostica Stago, Asnieres, France). Prospective associations were analyzed using competing risk analysis treating death-from-any-cause as the competing event. Evaluated risk factors included (1) the lupus-sensitive activated partial thromboplastin time (aPTT-LA), (2) antibodies against cardiolipin, beta2-glycoprotein I, domain 1 of beta2-glycoprotein I, prothrombin, and "triple positivity", (3) general cardiovascular risk factors (diabetes, hypertension, smoking, and hypertriglyceridemia, body mass index), and (4) AnnexinA5 resistance (A5R). RESULTS: During a median follow-up period of 8.7 years (range: 12 days - 12.4 years), 30 TE events occurred (arterial TE: n=14, venous TE: n=16), and 20 patients died. The cumulative incidence of TE at 1, 5, and 10 years of follow-up were 4.0% (95% Confidence Interval (CI): 1.7-8.1), 12.8% (95% CI: 7.9-18.9), and 24.4% (95% CI: 16.8-32.8), respectively. In univariable analysis, a prolonged aPTT-LA (Subhazard ratio (SHR) for aPTT≥118 seconds (i.e. 75th percentile of the aPTT-LA distribution)=2.59, 95%CI: 1.27-5.31, p=0.009), diabetes (SHR=4.36, 95%CI: 1.44-13.19, p=0.009), active smoking (SHR=2.35, 95%CI: 1.16-4.77, p=0.018), and elevated triglycerides (SHR per 50mg/dL increase=1.14, 95%CI: 1.09-1.18, p<0.001) were associated with a higher risk of TE events. In multivariable analysis, the only independent predictors of a higher thrombotic risk were a prolonged aPTT-LA (adjusted SHR=2.33, 95%CI: 1.06-5.13, p=0.035), diabetes (adjusted SHR=3.79, 95%CI: 1.12-12.89, p=0.033), and active smoking (adjusted SHR=2.62, 95%CI: 1.24-5.52, p=0.012). These results prevailed after adjusting for anticoagulation at baseline. Using these three parameters allowed identification of clinical subgroups with a very high and a low risk of TE events (cumulative risk of TE after 5 years 43.3% in the high risk group and 5.6% in the low risk group, respectively, Figure 1). The other risk factors did neither in univariable nor in multivariable analysis emerge as predictors of thrombotic risk in this large cohort. CONCLUSION: Diabetes and smoking, which are established risk factors for vascular events in the general population, turned out to be relevant also in patients with the LA. Moreover, a very long lupus sensitive aPTT was as well predictive for occurrence of TE in these patients. This effect was independent of anticoagulation. Interestingly, disease defining antibodies, such as those against cardiolipin or beta2-glycoprotein I (including those against domain I) were not associated with future occurrence of TE in this LA positive patient population. These data suggest that above standard anticoagulation, interventions to control and improve metabolic status and smoking habits might influence the rates of future TE in patients with known persistent LA. Disclosures No relevant conflicts of interest to declare.

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Incidence, Risk Factors and Outcome of Late Onset Noninfectious Pulmonary Complications after Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective Cohort Study

Blood ◽

10.1182/blood.v128.22.4562.4562 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4562-4562

Author(s):

Anne Bergeron ◽

Sylvie Chevret ◽

Regis Peffault De La Tour ◽

Karine Chagnon ◽

Cedric De Bazelaire ◽

...

Keyword(s):

Risk Factors ◽

Cohort Study ◽

Research Funding ◽

Late Onset ◽

Cox Model ◽

Pulmonary Complications ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

History Of

Abstract Introduction: Late onset noninfectious pulmonary complications (LONIPCs) occurring beyond the third month following allogeneic hematopoietic stem cell transplantation (HSCT) are various and are associated with a poor outcome. Bronchiolitis obliterans (BO) is the most frequent LONIPC. Available epidemiological data are conflicting and exclusively come from retrospective studies. Methods: We conducted a prospective observational cohort study where all consecutive patients who were scheduled to receive an allogeneic HSCT between January, 31, 2006 and December, 31, 2008 at the university-teaching Saint Louis Hospital (Paris, France) were prospectively screened for inclusion in the study. Those allogeneic HSCT recipients surviving at day 100 were included in the cohort. They were followed-up for at least three years after HSCT. Clinical outcomes were the 3-year incidence and mortality of LONIPC, and the identification of early risk factors for LONIPC and specifically BO. This study is registered with ClinicalTrials.gov, number NCT 01219972. Results: 198 patients were included after a median of 101 [IQR: 99-106] days following HSCT, from a total of 243 screened patients. The actual median follow up of the 198 included patients was 72.3 months [IQR: 15.2-88.5]. 68 patients died within the first 36 months resulting in a 3-year overall survival after inclusion of 65.4% (95%CI: 59.1-72.4%). Fifty five episodes of LONIPC were diagnosed in 43 patients. These 55 LONIPC were diagnosed as BO (n=22), interstitial lung disease (n=12), and others. Ten patients had more than one LONIPC during the follow-up. At 36 months after inclusion, the estimated cumulative incidence of LONIPC was 19.8% (95%CI: 14.2-25.3%). The 36 months cumulative incidence of BOS was 10.7%, (95%CI: 6.3-15.1%). 18 patients with a LONIPC died during the follow up with an estimated median survival of 78.5 months (95%CI: 20.0-not reached) after the diagnosis of LONIPC. The occurrence of LONIPC was associated with an increased hazard of death (HR=2.18, 95%CI= 1.14; 4.15; p= 0.0181). Based on a multivariable Cox model, a chest irradiation prior to HSCT, a history of pneumonia within the 100 days post HSCT and a low FEF 25-75 at day 100 were associated with the development of LONIPC. The use of PBSC was predictive for BOS based on a multivariable Cox model both after multiple imputation and on the complete cases whereas both a history of post transplantation pneumonia and bronchial abnormalities on CT scan at day 100 were also identified as predictive factors after multiple imputation and a 10% FEV1 decline from baseline to day 100 was a predictive factor for BOS on the complete cases. Conclusion: our data give clues to identify high-risk patients for developing LONIPC/BO. These patients should be targeted for close monitoring, and so offer earlier treatment of LONIPC or prophylactic treatment to improve the outcome. Funding: The study was supported by an institutional grant from the French Ministry of Health (CRC 04118). Disclosures Peffault De La Tour: PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding.

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High-Oxygen-Affinity Hemoglobinopathy-Associated Erythrocytosis: Clinical Outcomes and Impact of Therapy in 41 Cases

Blood ◽

10.1182/blood-2021-153956 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1492-1492

Author(s):

Naseema Gangat ◽

Jennifer L Oliveira ◽

James D Hoyer ◽

Mrinal M. Patnaik ◽

Animesh Pardanani ◽

...

Keyword(s):

Risk Factors ◽

Family History ◽

Research Funding ◽

Oxygen Affinity ◽

Aspirin Therapy ◽

High Oxygen ◽

History Of ◽

High Oxygen Affinity ◽

Systemic Anticoagulation

Abstract Background Approximately 100 high oxygen affinity (HOA) hemoglobin (Hgb) variants have been reported to date; review of the Mayo Clinic laboratory database (1974-2018) identified 80 distinct variants including 12 novel variants (60 β, 20 α). One-third of HOA Hgb variants result in secondary erythrocytosis, provoking concern regarding increased risk for thrombosis. Current management guidelines lack supporting evidence regarding the utilization of phlebotomy in such cases. We describe presenting features, treatment strategies and follow-up events involving 41 consecutive cases seen at our institution. Methods Study patients were recruited from our institutional laboratory and clinical Hgb variant database. Initial evaluation for Hgb variants was conducted by capillary electrophoresis and high-performance liquid chromatography. Additional testing which included mass spectrometry and isoelectric focusing was pursued as necessary. Since the majority of variants were difficult to identify by protein studies, DNA sequencing of HBB, or HBA1, HBA2 genes was performed for confirmation. Symptoms and thrombosis, both at presentation and during follow up, were recorded. Therapeutic interventions were based on physician discretion and mostly included phlebotomy and/or aspirin therapy; a careful response assessment was performed to determine the impact of each therapy on symptoms and/or thrombosis. Results A total of 41 patients with HOA Hgb variant-associated erythrocytosis (median age 39 years, range 1-81; 54% males) were seen at our institution between January 1973 and February 2020. The majority of the patients carried β-chain variants (n=34; 83%), common variants being Hgb Malmo (n=13), Olympia (n=4), San Diego (n=3), and Wood (n=2). Among the 7 patients with α-chain variants, Hgb Dallas was the most frequent (n=4). Presenting median values (range) for Hgb/Hct, serum erythropoietin and p50 were 18 g/dl/52.9%(16-21.9g/dl/48-66%) 10.4 mIU (4-36.3 mIU), and 20 mmHg (12-25 mmHg), respectively. Family history was documented in 34 patients, of which 24 (71%) reported one or more affected family members. Family history of thrombosis was documented in 7 patients (21%). CV risk factors were present in half of the patients; by contrast, history of thrombosis prior to or at diagnosis was documented in only two patients (5%). Of 23 pregnancies reported in 12 women, live birth rate was 78% (n=18); none of the fetal losses were attributed to erythrocytosis. Active therapies at the time of initial referral consisted of phlebotomy (n=12), aspirin (n=11) and systemic anticoagulation (n=1). At a median follow-up of 10 years (range; 0.04-44), 23 patients had reported one or more symptoms, attributed to hyper-viscosity, such as headaches, fatigue, and lightheadedness. Neither Hct level at diagnosis (p=0.32) nor phlebotomy (p=0.16; 75% patients on vs 52% not on phlebotomy) or aspirin therapy (p=0.75; 55% patients on vs 60% not on aspirin) appeared to influence the occurrence of symptoms. Phlebotomy relieved symptoms in 7 (42%) symptomatic patients; however, 7 (30%) of 23 patients on phlebotomy reported one or more adverse symptoms that were attributed to phlebotomy-induced iron deficiency. Ten patients (24%) experienced thrombosis prior to or following diagnosis: 6 arterial and 4 venous. Median age at thrombotic event was 51 years and median hematocrit 52%; active therapies at the time of event included phlebotomy in 5 patients, aspirin in 4, and systemic anticoagulation in 2. Hct level at diagnosis (p=0.10) or the time of event (p=0.67) did not correlate with occurrence of thrombosis. Additionally, the incidence of thrombosis was no different among patients receiving or not receiving phlebotomy (5/23(22%) vs 5/18(28%), respectively; p=0.66). The presence of CV risk factors was predictive of arterial events (p=0.002). Two of the 4 venous events developed in the context of concomitant thrombophilia. Eight patients (20%), median age 28 years, without CV risk factors, were observed without therapy for a median of 9.5 years (range; 0.4-21) and have not experienced any thrombosis to date. Conclusions We found no association between Hct level and either thrombotic or non-thrombotic symptoms in HOA hemoglobinopathy-associated erythrocytosis; furthermore, implementation of aggressive phlebotomy did not provide a clear benefit with respect to thrombosis risk reduction. Figure 1 Figure 1. Disclosures Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding.

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Reversible Cardiotoxicity Associated with Carfilzomib Use in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.2126.2126 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2126-2126 ◽

Cited By ~ 1

Author(s):

Tania Jain ◽

Hemalatha Narayanasamy ◽

Joseph Mikhael ◽

Craig B. Reeder ◽

P. Leif Bergsagel ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Cardiac Dysfunction ◽

Research Funding ◽

Systolic Dysfunction ◽

Effective Therapy ◽

Calcium Isotopes ◽

History Of ◽

Initial Drop

Abstract Background: Proteasome inhibition with carfilzomib (CFZ) has shown to be effective therapy in relapsed refractory multiple myeloma (MM).1 Cardiac toxicity induced by CFZ has been reported in a small subset of patients treated in phase 3 clinical trials, including congestive heart failure (CHF) in approximately 2-5% of patients. The natural history or reversibility of cardiac dysfunction with CFZ has not been fully reported. The myocardium constantly contracts in adults and thus, adequate protein metabolism may be essential; and hence, effective proteasome degradation may pose a risk for contractility. Methods and results: We identified 12 patients, who received CFZ at Mayo Clinic in Arizona, and had a drop in ejection fraction (EF) attributable to the use of CFZ. Medical records were reviewed for baseline cardiovascular (CV) risk factors, CV disease reversibility and mortality resulting from CFZ induced cardiac dysfunction. Patients who had a drop in EF attributed to other causes, were not included in this count. The median age at the time of initiation of therapy with CFZ was 62.5 years (range, 55-70 years), median body mass index was 27.65 (range, 21 - 40), with 4 (33%) patients being obese and 6 (50%) in the overweight range. Two (17%) patients had history of coronary artery disease while 9 (75%) had hypertension, and were on medical treatment prior to CFZ initiation. Six (46%) patients had a previous history of CHF. Two of these had symptomatic systolic dysfunction, however at the time of CFZ initiation, EF had improved. The other 4 with prior CHF had sub-normal EFs noted on echocardiograms done prior to initiation of CFZ (median EF of these 4 was 49%). Overall, baseline EF was available for 10 out of these 12 patients and median EF at baseline was 55% (range, 45 - 67%). Other risk factors predisposing to cardiac dysfunction were smoking in 1 patient and history of radiation to the chest in 2 (17%) patients. No patient had received cardiotoxic dose of anthracyclines prior to starting CFZ. Myeloma therapies: All patients had received multiple lines of therapy for MM (median 4, range, 2-7). Ten (83%) patients had previous received bortezomib and 10 (83%) had received autologous stem cell transplant. Cardiac events and CFZ use: Median duration of CFZ therapy received prior to documented systolic dysfunction was 4 months (range, 0.5 - 20 months), with 3 episodes happening with less than one month of total CFZ therapy. Five out of the 12 (42%) patients had previously discontinued CFZ for other reasons when the systolic dysfunction was noted. However they were included since CHF occurred shortly after treatment (median of 2 months, range, 0.5 - 3). The median drop in EF was 22% (range, 9 - 45%). Recovery/ outcomes: Follow-up echocardiograms were available in 8 patients and all of these showed some improvement in EF (table 1). Median improvement in EF noted by the time of last follow up was 16% (range, 7-30%). Median best EF noted after the initial drop was 48% (range, 35 - 67%). Two patients never discontinued CFZ and EF improved spontaneously, to 67% and 64% respectively, after an initial drop. Another patient was rechallenged with CFZ due to progression of MM, 8 months after initial discontinuation, and did not have recurrence of systolic dysfunction. No patients succumbed to CHF. Six (50%) out of these 12 patients had died by the time of last follow-up. Cause of death was progressive MM in 4 (67%) and sepsis secondary to immunosuppression resulting from chemotherapy in 2 (33%). Conclusions: Our data, although with limited number of patients, suggests using caution when treating patients who have underlying cardiac risk factors with CFZ. Nevertheless, the cardiotoxicity was mostly reversible, with the minimal EF after recovery of 35%. In the setting of a life threatening malignancy, the impact and reversibility of cardiotoxicity needs to be understood so as not to prevent the utilization of otherwise effective therapy such as CFZ. Larger studies are needed to confirm these findings. References: 1. Stewart et al. Carfilzomib, Lenalidomide and Dexamethasone for relapsed multiple myeloma. NEJM 2015;372:142-52. Disclosures Mikhael: Celgene: Research Funding; Abbvie: Research Funding; Sanofi: Research Funding; Onyx: Research Funding. Reeder:Novartis, Millennium, BMS and Celgene: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Fonseca:Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Millennium, a Takeda Company: Consultancy; Novartis: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Celgene: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy.

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