High Incidence of Bleeding Found with Direct Oral Anticoagulant Use in Myeloproliferative Neoplasm Patients

Abstract BACKGROUND: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are at increased risk of arterial (ATE) and venous thromboembolism (VTE). There are no clear guidelines regarding selection of anticoagulation (AC) in MPN patients. Direct oral anticoagulants (DOACs) are increasingly used in the general population to treat a variety of conditions including VTE, ATE, and atrial fibrillation (AF). Data on the safety and efficacy of DOACs in MPNs limited. We conducted a multi-center, retrospective analysis of DOAC use in MPN patients to characterize real-world practice patterns and evaluate thrombosis and bleeding risks. METHODS: We retrospectively analyzed 133 MPN patients prescribed DOACs across the Massachusetts General Brigham / Dana Farber Harvard Cancer Center system from 1995 to 2020. Patients were identified using ICD-9 and 10 codes in the electronic medical record. Patient and treatment characteristics were described with summary statistics. We calculated cumulative incidence functions of VTE and ATE, and major and clinically relevant non-major bleeding (CRNMB) by ISTH criteria, using death on DOAC as a competing risk. A Gray's test was used to compare cumulative incidence between groups. Analysis of risk factors associated with bleeding/thrombosis was carried out by univariate and multivariable Fine-Gray models. RESULTS: Baseline characteristics are displayed in Table 1. Seventy-five (56.4%) MPN patients were prescribed DOAC for VTE, 46 (34.6%) for AF, 7 (5.3%) for stroke, and 5 for other ATE (3.8%). The median age at DOAC initiation was 71; the AF population was significantly older than patients with VTE (75 vs 59, p<0.001). Fifty-seven percent of patients (N = 76) had a diagnosis of PV, with 89% (N = 118) of patients carrying a JAK2 driver mutation. Apixaban was the most commonly prescribed DOAC (N = 83, 62.4%). Nearly half (N = 59, 45%) of patients had a prior VTE/ATE at DOAC initiation, and 23% (N = 31) of patients were switched from warfarin. Among the VTE-treated patients, 43% of events were deep vein thrombosis (N = 39), 31% (N = 28) were pulmonary embolism, 21% (N = 19) were splanchnic vein thrombosis (SVT), and 4.4% (N=4) were other VTE. Table 2 displays practice patterns of DOAC use in MPN patients. The median duration of AC was 37.0 months for all patients, with no difference (p=0.01) between patients treated for AF (42.3 months) and VTE (37.0 months). Twenty-one percent of VTE-treated patients completed a finite course of AC of 6 months median duration. Fifteen percent (N = 11) of VTE-treated and 4.3% (N = 2) of AF patients had reduction to prophylactic dosing. Fifty percent (N = 66) of patients took aspirin and AC concurrently; 83% (N = 110) of patients took cytoreduction with AC. After a median follow-up of 37 months, we found 12 thrombotic (7 arterial, 3 venous, 2 TIPS occlusions) and 28 bleeding (6 major with 4 contributing to patient death, 2 CRNMB) events on DOAC. The estimated 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5%-9.5%) and 12.3% (6.4%-18.2%), respectively (Figure 1). Thrombosis and bleeding rates were not significantly different between patients treated for VTE versus AF. Prior history of thrombosis and use of dabigatran or edoxaban were significantly associated with increased thrombosis on both univariate and multivariable analysis (p<0.05). Age ≤ 65 also emerged as a risk factor for recurrent thrombosis in multivariate analysis (p=0.04). Use of dabigatran or edoxaban trended toward increased bleeding, but otherwise we found no significant risk factors for bleeding at α=0.05 level, including concomitant aspirin use. DISCUSSION: DOACs are increasingly prescribed in MPN patients for a wide range of indications, with heterogeneity in practice patterns. In our cohort, 1-year thrombosis and bleeding incidence rates on DOAC were 5.5% and 12.3%, respectively. While our 5.5% thrombosis rate is similar to recurrent thrombosis rates reported in MPN patients on DOACs and VKA, our 12.3% bleeding rate appears much higher. This may be related to the complexity of patients seen at our tertiary referral center. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population, with the gold standard being randomized controlled trials comparing DOAC with warfarin. Figure 1 Figure 1. Disclosures Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hobbs: Bayer: Research Funding; Merck: Research Funding; AbbVie.: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Incyte Corporation: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding. Connors: Abbott: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Alnylam: Consultancy; Pfizer: Honoraria; CSL Behring: Research Funding.

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

Blood ◽

10.1182/blood.v120.21.3480.3480 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3480-3480

Author(s):

Gérard Socié ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Jeffrey Szer ◽

Alvaro Urbano-Ispizua ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Advisory Committees ◽

Significant Protective Effect ◽

Rbc Transfusion

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

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The Risk of Central Nervous System (CNS) Relapses in Patients with Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.4153.4153 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4153-4153 ◽

Cited By ~ 1

Author(s):

Dai Chihara ◽

Michelle A Fanale ◽

Roberto N. Miranda ◽

Mansoor Noorani ◽

Jason R. Westin ◽

...

Keyword(s):

Risk Factors ◽

T Cell ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Advisory Committees ◽

Cns Relapse ◽

One Year

Abstract Background: CNS relapse is a rare but fatal complication of patients with peripheral T-cell lymphoma (PTCL). Several large studies have identified risk factors for CNS relapse in PTCL, such as elevated serum lactate dehydrogenase (LDH), >1 extranodal sites of involvement and high International Prognostic Index (IPI) score. We performed an analysis of histologic type of PTCL to identify additional risk factors for CNS relapse. Patients and Methods: A total of 616 patients with PTCL diagnosed between 1999 and 2014 were analyzed retrospectively including: 174 not otherwise specified (NOS), 144 angoimmunoblastic T-cell lymphoma (AITL), 76 ALK+ anaplastic large cell lymphoma (ALCL), 103 ALK-ALCL, 55 nasal type T/NK cell lymphoma (NK/T), 23 hepatopslenic T-cell lymphoma (HSTL), 16 enteropathy-type T-cell lymphoma (EATL), 13 adult T-cell leukemia/lymphoma (ATLL), and 12 subcutaneous panniculitis-like T-cell lymphoma (SPTL). Patients with CNS involvement at diagnosis (n=15) were excluded from this study. Progression-free survival (PFS) and overall survival (OS) were calculated and pretreatment characteristics were evaluated for association with survival outcomes by hazard ratio (HR). Cumulative incidence of CNS relapse was calculated by competing risk (death without CNS relapse) regression analysis. Results: The median age of the patients was 56 years (range, 17-93 years). With a median follow up of 57 months, 15 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 NK/T, and 2 ATLL) experienced CNS relapse, and 321 patients (52%) died without having had CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.8% (95%CI: 1.0-3.1%), 2.4% (95%CI: 1.3-3.8%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.3% in ALK+ALCL, 2.1% in ALK-ALCL and 3.6% in NK/T (Figure). All patients with CNS relapse eventually died, with median OS duration from CNS relapse of 1.6 months. Extranodal sites of involvement >1 (HR: 6.0, 95%CI: 2.0-17.4) and higher IPI score (HR: 1.8, 95%CI: 1.1-3.1, by one increase in IPI score) were risk factors of CNS relapse by univariate analysis. ALK+ALCL patients who had > 1 extranodal site of involvement (N=19) had very high risk of CNS relapse with one year cumulative incidence of 15% (95%CI: 3.7%-33.5%), with all occurring within six months after diagnosis. Summary: CNS relapse in patients with PTCL is rare as reported previously. However, the risk varies by histologic type. Specifically ALK+ALCL patients with > 1 extranodal site of involvement have a very high risk of CNS relapse in early phase of treatment, and CNS evaluation at the time of diagnosis and possibly CNS targeted prophylaxis may be appropriate. Figure Figure. Disclosures Westin: ProNAi: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fayad:Seattle Genetics: Consultancy, Research Funding. Wang:BeiGene: Research Funding; Kite Pharma: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding; Dava Oncology: Honoraria; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Acerta: Consultancy, Research Funding; Juno Therapeutics: Research Funding. Fowler:Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding; Infinity: Consultancy, Research Funding; TG Therapeutics: Consultancy. Oki:Novartis: Research Funding.

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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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High Incidence of Venous Thromboembolism in Patients with Chronic Graft-Versus-Host Disease

Blood ◽

10.1182/blood-2020-136337 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 44-46

Author(s):

Najla El Jurdi ◽

Heba Elhusseini ◽

Todd E. DeFor ◽

Grigori Okoev ◽

Aleksandr Lazaryan ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Advisory Committees ◽

High Incidence ◽

Independent Association ◽

Very High ◽

Fund Research

Background: Limited studies report a wide range of venous thromboembolism (VTE) incidence among allogeneic hematopoietic cell transplant (alloHCT) recipients. Chronic GVHD (cGVHD) is an immune mediated complication after alloHCT associated with vascular endothelial damage and prolonged systemic inflammation. We hypothesized that patients developing cGVHD are a subgroup at particularly high risk for VTE. Aims: To assess VTE incidence, sites of involvement, and risk factors in patients with cGVHD and to examine the impact of VTE on clinical outcomes after alloHCT. Methods: We performed a retrospective cohort study of all 145 patients who developed cGVHD after a matched sibling (MSD) and umbilical cord blood (UCB) donor alloHCT from 2010 to 2018. VTE was defined as a new confirmed event by imaging at any time after cGVHD diagnosis. VTE sites were categorized as upper extremity (UE), lower extremity (LE) deep vein thrombosis (DVT) or pulmonary embolus (PE). We assessed the cumulative incidence of VTE treating non-VTE mortality as a competing risk. Multivariate regression was used to evaluate the independent association of risk factors with the incidence of VTE using predefined factors in our model including gender, age, DRI, cGVHD severity, days to cGVHD from transplant and platelet level. We accounted for multiple events of VTE using PWP regression. Cox and Fine and Gray regressions were used to evaluate the independent association of time-dependent VTE on overall survival (OS) and non-relapse mortality (NRM), respectively using propensity scoring to control for confounding.. Results: Median age at time of cGVHD diagnosis was 52 years (range 19-74). 104 (72%) patients received MSD and 41 (28%) UCB alloHCT. Of the 145 patients with cGVHD, 32 (22%) developed either 1 or 2 VTE events and 14 (10%) developed 2 VTE events. The first VTE events were PE (n=6, 19%), and DVT (n=26, 81%; n=17 LE, n= 8 UE and n=5 catheter related UE DVT); one patient developed an IVC thrombus. The second VTE events were PE (n=2, 14%), and DVT (n=12, 86%; n=5 LE, n= 7 UE and n=4 catheter related UE DVT). Most patients were on corticosteroids at the first (n=28, 88%) and second (n=10, 71%) VTE with a median dose of (0.3 and 0.2 mg/kg/day, respectively) ± additional immunosuppression therapies. The cumulative incidence of VTE through 5 years post cGVHD diagnosis was estimated at 22% (95% CI: 15-29%) with median time from cGVHD diagnosis to VTE of 234 days (IQR 85-599). Median time to the development of LE DVT or PE was shorter than UE DVT (107 vs 450 days, respectively). Incidence was higher in males (24% vs 18%), and was not significantly different by age (< or ≥50), BMI (< or ≥30), HCT- comorbidity index, donor type, conditioning regimen and GVHD prophylaxis. Cumulative incidence was higher (50%) in patients with high/very high risk DRI compared to 19% in those with low and intermediate risk DRI. VTE incidence was highest in patients with de novo cGVHD (25%) compared to quiescent (20%) and progressive type (17%). Cumulative incidence was 9%, 17% and 38% in those with mild, moderate and severe GVHD respectively. Patients with lung, gastrointestinal, genitourinary and liver cGVHD had a higher incidence of VTE. Patients developing cGVHD >6 months from HCT had a higher incidence of VTE (24% vs 19%). In multivariate analysis, high/very high risk DRI was associated with higher risk of VTE (HR 2.5; 95% CI; 1.2-5.3) (Figure 2). VTE was not associated with a significantly higher 2-year NRM (HR 1.2; 95% CI; 0.4-3.6) or 5 year OS (HR 1.4; 95% CI; 0.7-3.0). Conclusion: Patients who develop cGVHD after alloHCT have a high incidence VTE. Identifying a subgroup at a particularly high risk for VTE could inform thromboprophylaxis and other supportive care strategies for prevention of such events. Disclosures Bachanova: Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Blazar:Tmunity: Other: Co-founder; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding. Brunstein:Astex: Research Funding; AlloVir: Other: Advisory board; Magenta: Research Funding; Gamida: Research Funding. Holtan:CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy; Generon: Consultancy; Incyte: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Gangaraju:Sanofi Genzyme, Consultant for Cold Agglutinin Disease: Consultancy. MacMillan:Talaris Therapeutics, Inc: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Fate Therapeutics, Inc.: Consultancy; Mesoblast: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Pharmacyclics: Research Funding; Fate Therapeutics: Consultancy; Kadmon: Research Funding; Syndax: Research Funding.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽

10.1182/blood-2020-139253 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 51-52

Author(s):

Sung-Eun Lee ◽

Joon Seong Park ◽

Young Rok Do ◽

Sung-Hyun Kim ◽

Dae Young Zang ◽

...

Keyword(s):

Prospective Study ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Kinase Inhibitor ◽

Molecular Response ◽

Close Monitoring ◽

Advisory Committees ◽

Deep Molecular Response ◽

Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

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Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽

10.1182/blood.v128.22.3306.3306 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3306-3306

Author(s):

Yi L. Hwa ◽

Qian Shi ◽

Shaji Kumar ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Research Funding ◽

Beta Blockers ◽

Multivariable Analysis ◽

Advisory Committees ◽

Risk Of Death ◽

Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset

Blood ◽

10.1182/blood.v124.21.3339.3339 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3339-3339 ◽

Cited By ~ 4

Author(s):

Ciara Louise Freeman ◽

Mark Dixon ◽

Richard Houghton ◽

Kathryn Humphrey ◽

Gunter Fingerle-Rowson ◽

...

Keyword(s):

Risk Factors ◽

Monoclonal Antibodies ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukaemia ◽

Signs And Symptoms ◽

Leukemic Cells ◽

Tumour Burden ◽

Advisory Committees ◽

Anti Cd20

Abstract Background: The administration of anti-CD20 monoclonal antibodies (mAb) in patients with B-cell lympho-proliferative disorders is frequently accompanied by a constellation of signs and symptoms that have been labelled as infusion-related reactions (IRR). The pathophysiology of IRR remains poorly understood as do predictors of risk, which may relate to the mechanism of action of the anti-CD20, disease-related factors such as tumour burden or host factors such as polymorphisms of Fc gamma receptor 3A (FcγRIIIA). In the CLL11 trial (NCT01010061), patients with previously untreated chronic lymphocytic leukaemia and comorbidities were randomised to receive either rituximab (type I anti-CD20 mAb) or obinutuzumab (type II and glycoengineered anti-CD20 mAb) in combination with chlorambucil for six cycles. Obinutuzumab led to faster depletion of B cells and achieved an improvement in outcome parameters such as response and progression-free survival compared with the rituximab arm, but was also associated with a higher rate and increased severity of IRR. To better understand the profile of risk for IRR in patients with CLL, we performed an exploratory analysis on data obtained from patients treated with either one of the two antibodies given in combination with chlorambucil. Methods: Patients from the prospective, randomized Phase III CLL11 study who received a first infusion of obinutuzumab (N=331) or rituximab (N=326) were included. Baseline pre-treatment risk factors thought to play a possible role in the development of IRR were identified a priori and included patient demographics, concurrent conditions and premedications, parameters of disease burden, prognostic factors, laboratory variables and FcγR genotype. Baseline values for mean fluorescence intensity (MFI) of CD20, gated on the circulating CLL clone, and MFI of CD16, gated on the natural killer (NK) cell population (CD56+16+) in peripheral blood were also available for N=510 patients. The primary outcome, development of an IRR with the first infusion, was defined as the occurrence of related signs and symptoms during or within 24 hours of administration of antibody. Due to the short-term nature of the initial IRR a multivariate logistical regression analysis was performed rather than a time to event analysis. Internal validation of this model, derived from a single dataset, was conducted using the established resampling technique of bootstrapping. This assessed the proportion of times each variable retained significance at α=0.10 when the model was fitted to bootstrapped samples of the dataset. Results: Patients that appeared to be at greater risk of developing any grade of IRR with the first infusion of rituximab or obinutuzumab were those treated with obinutuzumab, those with higher surface expression CD20 on CLL cells (MFI CD20) and greater FcγRIIIA (MFI CD16) on NK cells in peripheral blood, those with higher affinity FcγRIIIA genotype (VV), more pronounced neutropenia and splenomegaly at baseline (Table 1). Higher baseline absolute lymphocyte count and the presence of respiratory comorbidity also appeared to increase risk. All variables significant for inclusion in the model are shown in Table 1. Looking at those patients treated with obinutuzumab only, the most important determinant of risk was MFI CD20 (OR 3.6 95% CI 1.6-7.9). The impact of glucocorticoid premedication in reducing risk in obinutuzumab treated patients was not sufficient to reach significance, however, patients were not randomised to this intervention. Conclusion: This work identifies novel disease- and patient-specific biological variables that appear to play a role in the development of IRR in patients with CLL treated with anti-CD20 mAb, although the treatment received (obinutuzumab >rituximab) confers greatest risk. In addition to parameters of tumour burden, target antigen expression and gene polymorphisms of FcγR also appear to contribute to the risk of developing an IRR. Our results support the hypothesis that higher rates of IRR seen with the administration of obinutuzumab may result from stronger activation upon binding to CD20 on leukemic cells and subsequent enhanced cross-linking between CD20 expressing leukemic cells and FcγRIIIA bearing effector cells. Further studies involving obinutuzumab in this patient population will be needed to externally validate the results of this exploratory analysis. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Humphrey:Roche: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Kreuzer:Roche Pharmaceuticals: Research Funding. Engelke:Roche: Travel grants Other. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Goede:Bristol Myers Squibb: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

Blood ◽

10.1182/blood.v116.21.1244.1244 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1244-1244

Author(s):

Géraldine Salmeron ◽

Raphaël Porcher ◽

Anne Bergeron ◽

Marie Robin ◽

Regis Peffault de Latour ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Risk Of Death ◽

First Line Treatment

Abstract Abstract 1244 Background. Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods. We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results. Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below. The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions. The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures: Bergeron: Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

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