Clinical Epidemiology and First-Line Treatment in Immune Thrombocytopenia Adults. Results of the Carmen Prospective Cohort

Abstract Background: The clinical epidemiology of immune thrombocytopenia (ITP) is not well known. Some issues (bleeding events at diagnosis, association to other autoimmune diseases, rate of infection prior to ITP onset) are not well described in adults. Little is known as regards first-line treatment choice in the real-life practice. Aim: The aims of this study were to assess i) the clinical epidemiology of incident ITP adults; ii) the use of first-line treatments in this population; and iii) the factors associated with the initial use of intravenous (IV) corticosteroids (CS) and of intravenous immunoglobulin (IVIg) in a real-life setting. This study was carried out on behalf of the French national center for autoimmune cytopenia and the French national center for rare diseases in immunohematology. Methods: Study population was the patients included between June 2013 and December 2014 in the CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) multicenter registry. This multicenter registry is carried out on behalf of the French national center for autoimmune cytopenia and the French national center for rare diseases in immunohematology. The originalities of this registry are: the prospective follow-up of newly diagnosed ITPs, aimed at completeness of recording in the French Midi-Pyrénées region, South of France (3 million inhabitants), and the detailed recording of ITP treatment exposures. All the physicians in charge of ITP patients in the region, belonging to the netwotk of the regional center for autoimmune cytopenia, prospectively follow every patient newly diagnosed for ITP during routine visit or hospital stay. ITP is defined in accordance with French guidelines: platelet count <150 x 109/L and exclusion of other causes of thrombocytopenia. In this study, we assessed the clinical epidemiology at ITP onset, as well as ITP treatment use during the week following the diagnosis. Logistic regression models were performed to assess the factors associated with the use of IV CS and of IVIg. The following covariates were included: age, gender, Charlson's comorbidity score, secondary vs. primary ITP, bleeding score and platelet count. Results: Out of 121 newly diagnosed ITP, 113 patients were followed in the region and gave informed consent. Median age was 65 years (range: 18-95). Half of the patients were female, 24 (21.3%) had a secondary ITP, 57 (50.4%) had a Charlson's score ≥1, median platelet count was 17 x109/L (range: 1-126); 57 (50.9%) had bleeding symptoms, including 2 severe gastro-intestinal tract and 1 intracranial bleeding. Median Khellaf's bleeding score was 5 (range: 0-35). Twenty-five (21.4%) patients had another autoimmune disease (mostly: Hashimoto's thyroiditis, n=6, Sjögren syndrome, n=5, Evans syndrome, n=3) and 23 (20.3%) experienced an infection within the six weeks before ITP onset (including 8 influenza-like and 3 gastro-enteritis like syndromes, the others being various bacterial infections). Sixty-eight (60.2%) patients were treated during the week following the diagnosis. Among them, 66 (98.5%) received CS (median dose: 0.99 mg/kg/d), including 21 (31.3%) IV CS, 29 (43.3%) IVIg, 8 (11,9%) platelet transfusion, 2 romiplostim and 1 rituximab. The factors associated with the use of IV CS were secondary ITP (OR: 5.91; 95% CI: [1.78-19.71]) and Khellaf's bleeding score >8 (OR: 4.09; 95% CI [0.96-17.35]). Those associated with the use of IVIg were Khellaf's bleeding score >8 (OR: 7.30; 95% CI [1.36-32.27]) and platelet count <10 x 109/L (OR: 3.95; 95% CI [1.77-13.29]). Conclusions: This prospective cohort of newly diagnosed ITP adults confirms that severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections are frequent. IVIg and IV CS were frequently used, particularly in case of severe bleeding. Disclosures Godeau: Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adoue:LFB: Other: Symposium presentations ; OCTAPHARMA: Other: Symposium presentations ; ACTELION: Other: Symposium presentations ; PFIZER: Other: Symposium presentations ; AMGEN: Other: Symposium presentations ; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Other: Symposium presentations.

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Incidence of Adverse Drug Reactions Related to Immune Thrombocytopenia Drugs. A Prospective Cohort Study

Blood ◽

10.1182/blood.v126.23.1056.1056 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1056-1056

Author(s):

Salim Mezaache ◽

Thibault Comont ◽

Johanne Germain ◽

François Montastruc ◽

Natacha Brun ◽

...

Keyword(s):

Diabetes Mellitus ◽

Platelet Count ◽

Board Of Directors ◽

Immune Thrombocytopenia ◽

Real Life ◽

Newly Diagnosed ◽

Drug Reactions ◽

Advisory Committees ◽

Factors Associated

Abstract Background: The incidence ofadverse drug reactions (ADRs) related to immune thrombocytopenia (ITP) drugs is not well known in the real-life practice. Aim: The principal aim of this study was to assess the incidence of ADRs related to ITP drugs. The secondary aims were to compare the incidence of ADRs depending on the drugs, and to assess the factors associated to corticosteroids-related ADR occurrence. Methods: Study population was the patients included between June 2013 and December 2014 in the CARMEN (Cytopénies Auto-immunes: Registre Midi-PyréneEN) registry. This multicenter registry is carried out on behalf of the French national center for autoimmune cytopenia and the French national center for rare diseases in immunohematology. It is aimed at the prospective follow-up of all newly diagnosed ITP adults in the French Midi-Pyrénées region (3 million inhabitants). Each investigator prospectively follows every patient newly diagnosed for ITP in routine visit or hospital stay, providing informed consent was received. ITP is defined in accordance with French guidelines: platelet count <150 x 109/L and exclusion of other causes of thrombocytopenia. CARMEN is dedicated to pharmacoepidemiological studies, with detailed recording of treatment exposure and prospective reporting of every ADR that the investigator judge significant. All ADRs are analyzed by two independent investigators at the Midi-Pyrénées Center for Pharmacovigilance. Only ADRs with a World Health Organization causality score at least "possible" were included in this study. For incidence calculations, the denominator was the period of exposure to ITP drugs. To assess the factors associated with corticosteroids-related ADRs, we performed univariate and multivariate (backward procedure) Cox models. The variables included were: age, gender, secondary vs.primary ITP, bleeding score and platelet count at diagnosis, diabetes mellitus, Charlson's comorbidity score, and number of concomitant drugs. Results: Out of 116 patients, 81 were exposed to at least one ITP drug and had at least one follow-up visit. At diagnosis, median age was 64 years (range: 18-95), 48.1% were female, 74.1% had primary ITP, 69.1% had bleeding symptoms and median platelet count was 7 x109/L. Eighty patients (98.8%) of the patients were exposed to corticosteroids, 46 (56.8%) to intravenous immunoglobulin (IVIg), 11 (13.6%) to thrombopoietin receptor agonists (TPO-RA), 7 (8.6%) to danazol and 7 to dapsone, 6 (7.4%) to rituximab. Thirty-nine patients (48.1%) experienced at least one significant ADR (58 ADRs in total). The most frequent ADRs were infections (25.0%) and endocrinal diseases (18.5%). Twenty-two (37.9%) ADRs were serious (leading to hospitalization, necessitating a new drug) and 2 were lethal. The overall incidence of ADRs related to ITP drugs was 4.2/100 persons-weeks (95% confidence interval - 95% CI: 3.2-5.2). Corticosteroids showed the highest incidence of ADR (5.2/100 persons-weeks; 95% CI: 3.6-6.8). In multivariate analysis, the 2 remaining variables associated with corticosteroids-related ADR occurrence were an age >60 years (hazard ratio - HR: 1.79, 95% CI: 0.77-4.15) and diabetes mellitus (HR: 2.73, 95% CI: 1.08-6.87). Conclusion: This first study assessing the incidence of ADRs related to ITP drugs in a real-life setting showed that they are frequent. Corticosteroids were the first drug responsible for ADRs, stressing the need of second-line treatments, particularly in older and diabetic patients. Disclosures Godeau: Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adoue:AMGEN: Other: Symposium presentations; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Other: Symposium presentations; OCTAPHARMA: Other: Symposium presentations; PFIZER: Other: Symposium presentations; LFB: Other: Symposium presentations; ACTELION: Other: Symposium presentations.

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Treating Acute Leukemia during the COVID-19 Pandemic: A Multicenter Latin American Registry

Blood ◽

10.1182/blood-2020-139018 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Roberta Demichelis ◽

Martha Alvarado ◽

Jule F Vasquez ◽

Nancy Delgado ◽

Cynthia Gómez ◽

...

Keyword(s):

High Risk ◽

Maintenance Therapy ◽

Acute Leukemia ◽

Board Of Directors ◽

Latin American ◽

Refractory Disease ◽

Newly Diagnosed ◽

Advisory Committees ◽

Factors Associated ◽

Latin American Countries

Introduction The COVID-19 pandemic has affected the entire world. Health systems have been affected in such a way that patients with diseases other than COVID-19 have suffered serious consequences. In Latin America, the disease has emerged in a fragile system with more disparities, making our patients more vulnerable. Acute leukemia patients have a high risk of severe COVID-19 disease. Various expert recommendations have emerged with the aim of minimizing the risk of COVID-19 without affecting leukemia-related outcomes. However, multiple logistical issues tangentially associated with the pandemic have also appeared, potentially limiting the quality of management of these patients. The objective of this study was to register treatment modifications associated with the COVID-19 pandemic and its short-term consequences in Latin American countries. Methods We included patients older than 14 years, from 14 centers of 4 Latin American countries (Mexico, Peru, Guatemala and Panama), with the diagnosis of acute leukemia, who were on active treatment since the first case of COVID-19 was documented in each country. We documented their baseline characteristics and followed the patients prospectively until July 15, were data-cutoff for this pre-planned analysis was performed. The primary outcome was the incidence of COVID-19 disease and its complications. Secondary outcomes included treatment and consult modifications, and cause of death during the study period. Logistic regression was performed to determine factors associated with COVID-19 and all-cause mortality. Results We recorded the information of 635 patients: 58.1% Ph-negative ALL, 25.7% AML, 9% APL and 7.2% Ph+ALL. The median age was 35 years (14-90 years); 58.8% were consideredf high-risk patients. The majority were on CR (68.3%) receiving consolidation or maintenance therapy, while 14.5% were newly diagnosed and 17.2% with relapsed/refractory disease. The majority (91.8%) were treated in centers that were also receiving COVID-19 patients, 40.2% in centers were patients could not be electively hospitalized for leukemia treatment because of the COVID-19 pandemic. The COVID-pandemic led to treatment-modifications in 40.8% of the cases. Reasons for modifications were associated with logistical issues (22.4%), medical decisions (15.1%) or patient choice (3.3%). The most frequent modification was chemotherapy delay (17.3%) followed by regimen modification (13.4%) and dose-reductions (10.1%). (Figure 1) 83 patients (13.1%) developed COVID-19 disease, the majority mild-moderate disease (54.2%), 27.7% severe disease and 18.1% critically ill; 27.7% required mechanical ventilation and 37.7% died from COVID-19 disease, representing 4.9% of the entire cohort. We identify as risk factors for COVID-19 disease the presence of active leukemia (newly diagnosed or relapsed) (OR 3.46 [95% CI: 2.16-5.5], p<0.001), high-risk leukemia (OR 1.63 [95% CI: 1.54-4.52], p<0.001) and being treated in a center were elective hospitalization was possible (OR 2.17 [95% CI 1.29-3.67], p=0.004). Treatment modifications, appointment prolongations or the use of virtual consultation were not associated with a reduction in the risk of COVID-19. On the other hand, 16.7% of patients died during period analyzed due to leukemia (57.5%), COVID-19 (29.2%) or treatment related-mortality (13.2%). Independent factors associated with mortality were AML vs. ALL (OR 1.89 [95% CI: 1.12-3.18], p=0.016), relapsed-refractory disease (OR 8.34 [95% CI: 4.83-14.41], p<0.001), induction/consolidation vs. maintenance therapy (OR 2.20 [95% CI: 1.25-3.18], p<0.001) and the use of virtual consultation (OR 0.35 [95% CI: 0.13-0.94] p=0.037). (Table 1) Discussion/Conclusions The COVID-19 pandemic led to significant modifications in the standard of care treatment of patients with acute leukemia. The incidence of COVID-19 disease in acute leukemia patients was considerable and more than a third of the patients with acute leukemia and COVID-19 disease died. Despite a short-follow up, 16.7% of the patients died and leukemia-related deaths were the most frequent. In low- and middle-income countries with fragile health systems, the collateral damage for patients with acute leukemia may be just as important as the direct consequences of COVID-19. Disclosures Alvarado: Roche: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau. De la Peña-Celaya:Amgen: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Perez:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Gomez-Almaguer:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Hypovitaminosis D Influences the Clinical Presentation of Immune Thrombocytopenia in Children with Newly Diagnosed Disease

Journal of Clinical Medicine ◽

10.3390/jcm8111861 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1861

Author(s):

Petrovic ◽

Benzon ◽

Batinic ◽

Culic ◽

Roganovic ◽

...

Keyword(s):

Immune Thrombocytopenia ◽

Clinical Presentation ◽

Coastal Region ◽

Autoimmune Disorder ◽

Hypovitaminosis D ◽

Severe Bleeding ◽

Newly Diagnosed ◽

Randomized Controlled Studies ◽

Bleeding Score ◽

D Values

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia defined as platelet count in peripheral blood <100 × 109/L. Hypovitaminosis D is very common in children with autoimmune diseases. To analyze whether hypovitaminosis D is associated with the clinical presentation of ITP in children, medical records of 45 pediatric patients with newly diagnosed immune thrombocytopenia in the coastal region of Croatia were evaluated. The severity of bleeding was assessed using two bleeding scores. Children with lower 25-hydroxyvitamin D (25(OH)D) values had higher values of the skin-mucosa-organ-gradation (SMOG) bleeding score and respectively more severe bleeding on diagnosis of ITP. With further analysis of the main domains of that score, we found that patients with a lower 25(OH)D value had more severe bleeding in the skin and organs. When 25(OH)D and ITP Bleeding Scale (IBLS) score were analyzed, a negative correlation was found, but it was not significant. Our findings suggest that hypovitaminosis D influences the severity of the clinical presentation of ITP in children on initial diagnosis of the disease. Therefore, therapy with 25(OH)D could be a new potential option for treatment of ITP. To investigate the connection between 25(OH)D and the incidence and severity of ITP, further studies, especially randomized controlled studies, are needed.

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A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.613.613 ◽

2009 ◽

Vol 114 (22) ◽

pp. 613-613 ◽

Cited By ~ 17

Author(s):

Antonio Palumbo ◽

Meletios A. Dimopoulos ◽

Michel Delforge ◽

Martin Kropff ◽

Robin Foa ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Primary Endpoint ◽

Interim Analysis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Time To Progression ◽

First Line ◽

Advisory Committees

Abstract Abstract 613 Background: Lenalidomide (Revlimid®) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to progression (TTP) and overall survival (OS) in comparison with dexamethasone alone. In newly diagnosed MM patients, the current study compares the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) with that of MP alone. Methods: Key inclusion criteria were: ≥65 years of age, newly diagnosed and symptomatic MM. 459 patients were randomly assigned to receive MPR followed by lenalidomide maintenance therapy or MPR followed by placebo maintenance therapy or MP followed by placebo maintenance therapy (Figure 1). The study induction and maintenance phases were followed by an open label lenalidomide extension and a follow-up phase. All patients received aspirin 100 mg/day as thrombo-prophylaxis. The primary endpoint of the study is progression free survival (PFS). The secondary endpoints are OS, time-to-progression, response rate, time to response, response duration, time-to-next anti-myeloma therapy, safety, quality of life and exploratory assessment of cytogenetic abnormalities. Primary comparison is based on the intent-to-treat population comparing PFS between MPR followed by lenalidomide with MP followed by placebo; secondary comparisons are between MPR followed by lenalidomide and MPR followed by placebo, and between MPR followed by placebo and MP followed by placebo. Results: The first patient was enrolled in February 2007. A pre-planned interim analysis to evaluate the efficacy and safety was performed at 50% information. An independent central adjudication committee determined the assessment and timing of progressive disease prior to the interim analysis. At the interim analysis, it was determined by the Data Monitoring Committee (DMC) that the study had crossed the O'Brien Fleming superiority boundary for the primary endpoint, demonstrating a highly statistically significant improvement in PFS for patients treated with MPR compared with MP as first-line treatment for MM patients. The topline results will be availabel at the time of the meeting. Conclusions: MPR is an effective and safe regimen for front-line use in MM. PFS was significantly improved in patients who received MPR followed by lenalidomide maintenance compared with those who received MP followed by placebo maintenance. MPR followed by lenalidomide maintenance is a new therapeutic option and can be considered a new standard for patients older than 65 years old. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Dimopoulos:Celgene: Honoraria. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Honoraria, Speakers Bureau. Kropff:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Foa:Celgene: Membership on an entity's Board of Directors or advisory committees. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Catalano:Celgene: Research Funding.

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The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2016.2016 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2016-2016

Author(s):

Tomer M Mark ◽

Peter Forsberg ◽

Ihsane Ouansafi ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Management of newly diagnosed immune thrombocytopenia: can we change outcomes?

Blood Advances ◽

10.1182/bloodadvances.2017009860 ◽

2017 ◽

Vol 1 (24) ◽

pp. 2295-2301 ◽

Cited By ~ 16

Author(s):

Cindy E. Neunert

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Newly Diagnosed ◽

First Line ◽

Current Standard ◽

First Line Therapy ◽

Line Therapy ◽

Remission Rates ◽

Treatment Naïve ◽

Treatment Paradigm

Abstract Immune thrombocytopenia resulting from antibody-mediated platelet destruction combined with impaired platelet production is a common cause of thrombocytopenia. The decision to treat newly diagnosed patients is based on several factors including ceasing hemorrhagic manifestations, increasing the platelet count, prevention of bleeding, and inducing remission. Current standard first-line therapy is a course of corticosteroids. Although this treatment paradigm increases the platelet count in the majority of patients, a high percentage relapse after discontinuation of corticosteroid therapy. For this reason, intensification of first-line therapy that results in superior long-term remission rates would be desirable. This manuscript focuses primarily on adults with idiopathic thrombocytopenic purpura (ITP), highlighting pediatric data and practice when applicable. The primary aim is to outline upfront strategies for treatment-naive patients with ITP to enhance remission rates, taking into account assessment of the risks and benefits of these approaches.

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Thrombopoietin Receptor Agonist Use, Efficacy and Toxicity in Children with Immune Thrombocytopenia: Data from an Italian Multicenter Survey

Blood ◽

10.1182/blood-2018-99-110652 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4997-4997

Author(s):

Paola Giordano ◽

Giuseppe Lassandro ◽

Marco Spinelli ◽

Momcilo Jancovic ◽

Paola Saracco ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Immunosuppressive Agents ◽

Real Life ◽

Complete Response ◽

Clinical Use ◽

First Line ◽

Thrombopoietin Receptor ◽

Multicenter Survey

Abstract Background: Immune Thrombocytopenia (ITP) is one of the most common conditions encoutered by the pediatric hematologist. Current first-line therapy includes: observation without drug therapy, corticosteroids and intravenous immune globulin. A minority of patients are refractory to first-line approaches. Second-line treatment options are: immunosuppressive agents and thrombopoietin receptor agonists (TPO-RA). Eltrombopag and Romiplostin are TPO-RA licensed for clinical use. Eltrombopag is, actually, the only TPO-RA approved in Italy (since two years ago) for children, over one year old, with a chronic and/or refractory ITP. Real life data of Eltrombopag are limited. Methods: We performed an Italian multicenter retrospective survey to study the clinical on-label use of TPO-RA, focus on Eltrombopag, in pediatric ITP. Our aims were, primarily, to bring out the prevalence of the use in clinical practice and secondarily to collect data on efficacy and toxicity. Results: We enrolled 69 pediatric ITP subjects from 15 Italian treatment centers (TC). 4 patients received Romiplostin as TPO-RA and were excluded by the analysis. 36/65 patients weer female (55%). Median age at ITP diagnosis: 6 years + 6 months (min 1 y + 2 m; max 16 y + 7 m). Median age at first Eltrombopag assumption: 11 years + 5 months (min 2 y + 0 m; max 17 y + 8 m). Accounting in 344 the total number of chronic ITP subjects treated by TC in the same observation period (July 2016-June 2018), we observed an Eltrombopag clinical use prevalence of 0.19 (95% CI 0.15 to 0.26). We underlined a "no response" to Eltrombopag (platelet count persistently less than 30000 per microliter) in 16/65 (25%); a "partial response" (platelet count between 30000 and 100000 per microliter) in 14/65 (21%) and a "complete response" (platelet count persistently up than 100000 per microliter) in 35/65 (54%). The overall response (partial or complete) was described in 49/65 (75%) children. During the follow up was seen in 16/49 (33%) subjects with initial response a platelet rise that waned to no response. There was no evidence of significant adverse events (clinicians are obliged, to monthly surveillance, by Italian drug agency for hypertransaminasemia and peripheral smear cell abnormalities). Conclusions: Our results demonstrate that Eltrombopag is a therapeutic option quite considered by Italian clinicians. Moreover, according with the percentages of clinical trials, Eltrombopag is safe and effective to rise platelet count. Further studies need to emphasize how factors favor a complete response and to know the incidence of long-term adverse effects. A prospective study designed and driven by Italian Association of Pediatric Hematology Oncology (AIEOP) Coagulation Disorders Working Group is, already, in progress. Disclosures No relevant conflicts of interest to declare.

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First-Line Second Generation Tyrosine Kinase Inhibitors in Newly Diagnosed Accelerated Phase Chronic Myeloid Leukemia Patients.

Blood ◽

10.1182/blood-2018-99-113058 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 48-48 ◽

Cited By ~ 2

Author(s):

Marie Balsat ◽

Vincent Alcazer ◽

Gabriel Etienne ◽

Gaelle Fossard ◽

Francoise Huguet ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Free Survival

Abstract Introduction Up to 10% of patients (pts) with chronic myeloid leukemia (CML) are already in accelerated phase (AP) at diagnosis and despite treatment advances in the field of tyrosine kinase inhibitors (TKIs), management of these pts is challenging. This study aims to examine the benefit of second generation BCR-ABL tyrosine kinase inhibitors (TKI2) as first-line treatment for newly diagnosed AP-CML. Methods Pts meeting criteria for AP-CML at diagnosis and treated with first-line TKI2 (i. e. Nilotinib or Dasatinib) were included in this retrospective multicenter observational national study. AP-CML were defined according to the ELN (Baccarani, Blood 2013) as hematological acceleration (HEM-AP, any of the following features: blasts in PB or marrow 15-29%, or blasts+promyelocytes in PB or marrow >30% with blasts <30%, basophils in PB ≥20%, or persistent thrombocytopenia <100×109/L (unrelated to therapy) and/or chromosomal abnormalities in addition to the Ph at diagnosis (ACA-AP). Pts initiated nilotinib at 6-800 mg BID or dasatinib at 100-140 mg QD with further dose adaptations according to toxicities or response. Overall survival (OS), progression-free survival (PFS) and failure-free survival [FFS= progression to blast crisis, death, loss of any previous response (CHR, CCyR, or MMR) discontinuation of TKI2 for toxicity], were analysed since TKI2 initiation in intention-to-treat. Results Sixty-six pts were analysed: 45 males (68%) and 21 females (32%) with a median age at diagnosis of 49 (15-78.5) years. The median follow-up of the cohort was 43.5 (1.7-117) months. We segregated the pts in HEM-AP (n=33) and ACA-AP (n=33) for further analyses. Nine pts with HEM-AP harboured ACA and were analysed in the HEM-AP group. Fusion transcripts were of the Major BCR in 57 pts, 6 pts had atypical BCR-ABL transcripts (2 e19a2, and 1 e1a2 in the HEM-AP group and 2 e19a2 and 1 Ma3 in the ACA-AP group), and 3 transcripts unknown. Not surprisingly, spleen enlargement was significantly greater in the HEM-AP group [10 (5-14.75) vs. 3 (0-10)cm, p=0.014]. PB basophils [median 10 (6-16) vs. 3 (2-5)%, p <0.001], PB blasts [median: 12.05 (7.5-15) vs. 1.5 (0-4)%, p<.001], as well as PB blasts+promyelocytes [median 14 (11-20) vs. 4 (1-7)%, p<.001]. Hemoglobin levels were significantly lower in the HEM-AP group [median 93 (6-113.5) vs 120 (100-134) g/L, p<0.001]. Neither WBC counts, platelets counts, nor BCR-ABL/ABL load differed significantly between the 2 groups. In the ACA-AP group, 10 (30%) pts harbored major route ACA and 23 (70%) pts harbored minor route ACA of whom 3 pts with i(17q) and 1 with 7q abnormalities. In the ACA-AP group, Sokal score was low in 42%, intermediate in 32% and high in 26% of pts (2 pts unknown). Dasatinib was initiated in 19/33 pts (57.5%) in the HEM-AP group and in 8/33 pts (24%) in the ACA-AP group. Treatment responses did not significantly differ between ACA-AP and HEM-AP group, regardless of the TKI2 administered, with 33/33 (100%) vs 31/33 (94%) pts achieving a CHR, 2/33 (6%) pts vs 0/33 (0%) pts achieving a MCyR, 5/33 (15%) pts vs 5/33 (15%) pts achieving CCyR, 9/33 (27%) pts vs 4/33 (12%) pts achieving a MMR respectively. However, 11/33 (33%) HEM-AP vs 22/33 (66%) ACA-AP pts achieved a deep molecular response (p=0.013, Fisher test). Median times to CHR and MMR were not significantly different between ACA-AP group and HEM-AP group with 1.05 vs 1.25 months (p=0.088) for CHR and 6 vs 7 months (p=0.156) for MMR, respectively. Overall, the estimated 7-yr FFS rate was 56.92% (95%CI: 40-81), 7-yr PFS was 83.42% (95% CI: 69.6-100%) and 7-yr OS was 87.14% (95%CI: 73.5-100%) (Figure 1.) with no significant differences between ACA-AP vs HEM-AP pts [7-yr FFS: 57.7 vs. 62%, p=0.739; 7-yr PFS: 84.7% vs. 84%, p=0.185; 7-yr OS: 88.9% vs 86.6%, p=0.132] respectively. There was also no difference in FFS, PFS and OS according to the type of TKI2. The only factors influencing negatively OS were the % of BM blasts (HR=1.17, 95%CI: 1.1-1.28, p<0.001) and the % of BM blasts+promyelocytes (HR=1.14, 95%CI: 1.06-1.22, p<0.001). We identified too few significant factors in univariate analysis to perform a multivariate analysis. Conclusion The initiation of a TKI2 in newly diagnosed AP-CML pts induces excellent response and survival rates, probably superior to that of Imatinib first-line, and counterbalances the negative impact of this advanced disease, particularly in HEM AP subgroup. Disclosures Etienne: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Berger:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau. Rea:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Pfizer: Honoraria. Nicolini:BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau; Sun Pharma Ltd: Consultancy.

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French Observatory of Adult' Chronic Immune Thrombocytopenia (ITP) Treated By Thrombopoietin Receptor Agonists (TPO-RAs)

Blood ◽

10.1182/blood.v126.23.2250.2250 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2250-2250

Author(s):

Marc Michel ◽

Daniel Adoue ◽

Stéphane Cheze ◽

Paul Coppo ◽

Soraya Leclerc-Teffahi ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Immune Thrombocytopenia ◽

Malignant Tumors ◽

Real Life ◽

Autoimmune Disorder ◽

Current Data ◽

Line Treatment ◽

Antiplatelet Antibody ◽

Advisory Committees

Abstract Immune Thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated low platelet count (<100x109/L) with a variable risk of bleeding. The prevalence of ITP in France is 25/100000. While drug therapy is indicated in patients with platelet count less than 30x109/L and or with bleeding symptoms, discussions remain about therapeutic strategy to be implemented. The SATURNE study aimed to describe the current therapeutic management of adult ITP patients, to focus on TPO-RAs treated patients, and to assess changes in real life treatment strategy since TPO-RAs' approval. This study was carried out in referral and non-referral centersby hematologists and internists from hospitals or clinics in France. Enrolled patients were adults suffering from persistent (3 to 12 months after diagnosis) or chronic (>12 months) ITP. Patients with a newly diagnosed ITP (<3 months) and patients with secondary ITP (viral infection, lupus, etc.) were excluded. Data were collected online by investigators through an eCRF at inclusion (M0). A subgroup of patients initiating a TPO-RAs treatment during the study period was followed up at M3, M6, M12, M18 and M24. Only M0 data are presented in this abstract as interim analysis. Overall, 48 investigators included 333 patients (278 with chronic ITP and 55 with persistent ITP) over a 19 months period (2012 to 2013). Figure 1 displays the main characteristics including comorbidities and laboratory tests performed at diagnosis. Half ofthe patients (53%) had bleeding manifestations at ITP diagnosis; 10% at time of inclusion. ITP was mainly diagnosed by a hematologist (53%) or an internist (32%) and less frequently by a general practitioner (11%). Patients completed a median of 2 treatment lines before entering the study. Figure 2 shows treatment-lines distribution according to the ITP phase. Most patients had been treated with corticosteroids ± intravenous immunoglobulin (IVIG) (83%) as 1st line treatment. Rituximab was the preferred 2nd line option, far prior to splenectomy (44% vs 14%). A total of 144 patients (123 chronic/ 21 persistent ITP) received TPO-RAs (39% romiplostim/ 33% eltrombopag / 15% both / 13% non specified): 6%, 20%, 34%, 28% and 12% respectively as a 1st line treatment, 2nd, 3rd, 4th, 5th and beyond. At inclusion 75% were still on TPO-RAs. Recently diagnosed patients received 2nd line TPO-RAs in higher proportions: 40% (of 46 patients diagnosed <2 years) vs 15% (of 65 patients diagnosed 2-5 yrs ago) and 7% (of 72 patients diagnosed >5 yrs). TPO-RAs became the 3rd line most used treatment (over 76% for diag. <2 yrs). In parallel, the use of splenectomy decreased from 31% (diag. >5 yrs) to 9% (<2 yrs) in 2nd line, and from 16% to 5% in 3rd line. TPO-RAs treated patients had a more severe ITP, in particular at diagnosis. More patients in this group showed platelet counts less than 30.109/L (71% vs 51%, p<0.0001 at diagnosis / 23% vs 10%, p<0.001 at inclusion), and bleeding manifestations (64% vs 44%, p<0.001 at diagnosis/12% vs 8%, p=0.24 at inclusion). They received an average of 3.2 lines of treatment (against 1.7 in TPO-RAs' non-treated patients, p<0.0001). The SATURNE study supports epidemiological trends observed in current practice in terms of patients and ITP characteristics, and provides current data on comorbidities. The results highlight the increasing use of TPO-RAs as 2nd and 3rd lines for ITP treatment and the decrease of splenectomy use over time. Initiated in 2012, respectively 1 and 2 years after eltrombopag and romiplostim approval, the SATURNE study points out the changes of the management of adult ITP in France. Table 1. N=333 Age 57 ± 20yr Women 190 (57%) Main ITP characteristics Chronic/Persistent ITP 278 (84%)/55 (16%) Mean ITP duration* 6 ±8yr Platelet count* - diagnosis - inclusion 33±31.109/L 100±83.109/L Hemorrhagic manifestations- diagnosis- baseline 176 (53%) 32 (10%) White blood cell* 8±3.109/L Hemoglobin* 14±5g/dl Globular volume* 90±6fl Comorbidities since ITP diagnosis At least once 36% Hypertension 17% Diabetes 8% Benign/malignant tumors 8% Cardiovascular disease 6% Diagnostic tests performed at ITP onset Viral serology tests 96% Blood smear 93% Blood coagulation 93% Marrow aspirate 78% Antiplatelet antibody 52% ITP treatment (at least once since diagnosis all lines combined) Corticosteroids and/or IVIG 275 (83%) Rituximab 146 (44%) TPO-RAs- eltrombopag- and/or romiplostim 144 (43%) 69 (48%) 78 (54%) Splenectomy 59 (18%) *mean ± SD Figure 1. Figure 1. Disclosures Michel: Roche: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Adoue:GSK: Other: Symposium presentations; AMGEN: Other: Symposium presentations; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; OCTAPHARMA: Other: Symposium presentations; LFB: Other: Symposium presentations; PFIZER: Other: Symposium presentations; ACTELION: Other: Symposium presentations. Cheze:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Coppo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leclerc-Teffahi:Novartis: Employment. Fernandes:Novartis: Other: CRO. Texier:Novartis: Other: CRO.

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Bleeding Manifestations and Management of Children with Persistent and Chronic Immune Thrombocytopenia (ITP): Data From the Intercontinental Cooperative ITP Study Group.

Blood ◽

10.1182/blood.v114.22.1315.1315 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1315-1315 ◽

Cited By ~ 2

Author(s):

Cindy Neunert ◽

George R. Buchanan ◽

Paul A. Imbach ◽

Paula HB Bolton-Maggs ◽

Carolyn M. Bennett ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Threshold Value ◽

Acute Onset ◽

Additional Patient ◽

Severe Bleeding ◽

Study Group ◽

Advisory Committees ◽

Fatal Hemorrhage

Abstract Abstract 1315 Poster Board I-339 ITP during childhood is generally characterized by acute onset of thrombocytopenia and bleeding in an otherwise well child. While the platelet count has traditionally been viewed as a marker of disease severity, additional patient characteristics such as bleeding severity have not been well defined. The Intercontinental Cooperative ITP Study Group (ICIS) Registry II was designed to characterize the location, frequency, timing, and severity of bleeding in children with ITP (Blood, 2008;112: 4003-8). We report here data from Registry II with a focus on bleeding symptoms reported at 6 and 12 months. Patients enrolled on Registry II had research visits at diagnosis, and 28 days, 6 months, 12 months, and 24 months following diagnosis. Bleeding manifestations were retrospectively recorded at 6 and 12 months capturing all sites of bleeding (e.g skin, epistaxis, and gastrointestinal) since the last research visit. Of the 1318 children enrolled at diagnosis, 891 were evaluated at 6 months and 718 at 12 months. Mean platelet counts were 198 × 109/l (s.d. 130) and 195 × 109/l (s.d.122) at 6 and 12 months respectively. At 6 months 29% (261/891) of patients still had a platelet count <100 × 109/l; of these 45% (118/261) were <30 × 109/l. At 12 months these values were 28% (203/718) and 40% (82/203) respectively. Number of bleeding sites reported since the last research visit at 6 months and 12 months are outlined in Table 1. There were no reports of intracranial hemorrhage (ICH) or fatal hemorrhage. The most common bleeding site reported at both 6 and 12 months was skin, followed by epistaxis. 4 children with a platelet count <30 × 109/l at both 6 and 12 months were reported as having undergone splenectomy. Red cell transfusions were infrequent (3 reported) and administered only in children with bleeding from ≥ 3 sites. The percentage of patients with a platelet count <30 × 109/l who received platelet count enhancing therapy (including platelet transfusions) is outlined in Table 2. Table 1 Number of bleeding sites reported since last research visit at 6 and 12 months 6 month visit 12 month visit Number of sites Platelet count <100 × 109/l (n= 261) Platelet count <30 × 109/l (n= 118) Platelet count <100 × 109/l (n= 203) Platelet count <30 × 109/l (n= 82) None 60 (23%) 10 (9%) 74 (36%) 16 (19%) 1 110 (42%) 44 (37%) 82 (40%) 33 (40%) 2 61 (23%) 39 (33%) 32 (16%) 21 (26%) 33 30 (12%) 25 (21%) 15 (7%) 12 (15%) Table 2 Patients with platelet count <30 × 109/l reported as having received platelet count enhancing therapy Number of bleeding sites reported between research visits Treatment reported between 28 days and 6 months (n = 118) Treatment reported between 6 and 12 months (n = 82) None 1/10 (10%) 4/16 (8%) 1 29/44 (66%) 19/33 (58%) 32 58/64 (91%) 26/33 (78%) In summary, approximately 30% of children with ITP enrolled on ICIS Registry II remain thrombocytopenic 6 and 12 months later, many still having a platelet count <30 × 109/l, a threshold value sometimes used to determine drug treatment and enrollment in prospective intervention studies. This cut-off may be appropriate since bleeding was more common when the platelet count was <30 × 109/l. However, even below this threshold life-threatening hemorrhage was uncommon, few patients required packed red blood cell transfusions, and approximately half the patients reported no more than one site of bleeding. Treatment was infrequently used in patients in this group if they had no bleeding, and platelet enhancing therapy was often employed if more bleeding sites were involved. These data suggest a trend towards reserving treatment for patients with more severe bleeding manifestations rather than because of a specific platelet count. Disclosures Buchanan: AMG 531: Research Funding. Bolton-Maggs:Baxter: Travel support to meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; United Kingdom Immune Thrombocytopenic Pupura Support Association: Research Funding; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blanchette:AMG 531: Membership on an entity's Board of Directors or advisory committees. Kuehne:F. Hoffman-La Roche Ltd: Research Funding; Amgen: Research Funding.

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