Du är nu på väg att lämna en GSK-hemsida

Denna länk leder till en hemsida som inte tillhör GSK. GSK tar inget ansvar för innehållet på tredje parts hemsidor.

Fortsätt

Tillbaka

Eosinophils as markers for treatment

Go To Close Top

Evaluating blood eosinophil levels to guide treatment

Together with clinical symptoms, high blood eosinophil counts can identify a severe asthma patient as having severe asthma with eosinophilic inflammation.

  • Using blood eosinophil counts to guide treatment decisions

    The DREAM study, which evaluated mepolizumab i.v. over 52 weeks, determined that the biomarker of blood eosinophil counts ≥150 cells/µL at screening, or ≥300 cells/µL in the past 12 months, predicted patients who would benefit most from mepolizumab therapy.1-2

    Baseline FeNO was also measured, but was found to have a lower association than blood eosinophil count when identifying patients who would respond to mepolizumab.1

    Screening eosinophils is predictive of the eosinophil count in the following year3

    Graph showing eosinophils at screening following changes in levels at the end of 1 year.

    The solid blue line represents the predicted geometric mean eosinophil count after screening in patients receiving placebo only. The pink line represents the line of identity, which indicates where the values would fall if there was no change between eosinophil count at screening (X-axis) and at Week 56 (Y-axis). The graph is divided into quadrants, with the perpendicular line representing the cell counts ≥150 cells/µL or <150 cells/µL at screening. The horizontal line represents the geometric mean after screening of ≥150 cells/µL or <150 cells/µL.2

    The figure indicates that eosinophil counts are unlikely to change between screening and Week 56, because the data points are clustered close to the line of identity.3Katz, et al. 2014.3

  • Using a single blood eosinophil count to predict the response to mepolizumab

    On the basis of data obtained from patients who received placebo in the DREAM clinical trial, a single blood eosinophil count of ≥150 cells/μL predicted subsequent average measurements of ≥150 cells/μL in 85% of patients in this population.3Using the average of two, three or four blood eosinophil counts of ≥150 cells/μL, the proportion of patients with post-screening averages was 85%, 90% and 92%, respectively. These data indicate that taking multiple measurements is unlikely to increase sensitivity compared with taking a single measurement, and therefore is not necessary.3

  • The rationale for two different eosinophil thresholds

    There are two different eosinophil thresholds to inform patient eligibility for mepolizumab. These were determined using a data-driven approach, based on the findings of the DREAM study where mepolizumab treatment was associated with clear clinical benefits in patients with an eosinophil count of ≥150 cells/μL at screening or ≥300 cells/μL in the prior 12 months.3The results of the Phase III clinical trials, MENSA and SIRIUS, have confirmed that this is an appropriate criterion for selecting a patient population most likely to respond to mepolizumab.45

Which patients are eligible for mepolizumab treatment?

Anti-IL-5 treatment can reduce the blood eosinophil count in patients with elevated blood eosinophil counts.1IL-5 plays a key role in eosinophil production and recruitment and is related to eosinophilic inflammation.6

Historically, the blood eosinophil threshold that defines severe asthma with eosinophilic inflammation has been a subject of debate within the asthma community. At present, no definitive threshold exists.
Data from the DREAM clinical trial have driven the blood eosinophil threshold for mepolizumab treatment eligibility.1These levels best predicted exacerbation reduction with mepolizumab treatment:

Patients with severe asthma and two or more exacerbations in the past 12 months despite high-dose ICS and additional controllers, with or without OCS, and blood eosinophils ≥150 cells/μL at treatment initiation or ≥300 cells/μL in the past 12 months. 1

 

Mepolizumab is indicated as add-on treatment for severe refractory eosinophilic asthma in adult patients, at a dose of 100 mg s.c. 2

These blood eosinophil count thresholds were prospectively tested in the MENSA and SIRIUS studies and confirmed the patients responding best to mepolizumab therapy.4-5

  • Early clinical studies with mepolizumab

    An early study with mepolizumab was conducted in a population of moderate asthma patients who received moderate doses of ICS (maximum dose of beclomethasone: 1000 µg/day).7Patients were required to have FEV1 50–80% predicted value and reversibility of ≥12% with salbutamol, but were not required to meet a predefined eosinophil threshold (blood or sputum) or have a history of frequent exacerbations.7Patients were excluded if they had used OCS in the previous 4 weeks or had poorly controlled asthma that meant they had been hospitalised or visited the emergency department in the previous 6 weeks.7

    The primary endpoint was change from baseline in morning PEF at Weeks 12 and 20 with either mepolizumab or placebo.7Based on the results of this earlier study, the inclusion criteria for future studies were modified to require a history of exacerbations in order to determine whether exacerbation reduction may be the primary benefit of treatment with mepolizumab.7

    This early study showed limited clinical benefits of mepolizumab on pulmonary function endpoints and symptoms. However, among the relatively small number of exacerbations recorded, a difference towards a reduction in the frequency of exacerbations was noted in the highest dose group (750 mg i.v.) compared with placebo. This observation was not statistically significant.7

  • Using blood versus sputum eosinophil counts to predict the response to mepolizumab

    The international ERS/ATS guidelines on definition, evaluation and treatment of severe asthma identifies sputum eosinophil count as one measure to identify patients with an eosinophilic phenotype.8

    Both blood and sputum eosinophil levels were measured in the DREAM clinical trial.1However, only blood counts were used as an entry requirement in the MENSA and SIRIUS clinical trials with mepolizumab.1457Blood eosinophil counts were performed for all patients at all study visits, whilst sputum eosinophil counts were performed in a subset of 94 patients from sites with previous experience in sputum collection and processing, and only at baseline or screening, and Weeks 4,6and 52.1The figure below shows that baseline blood eosinophils correlated with response to mepolizumab in terms of exacerbation reduction; sputum eosinophils did not.13

  • Example blood eosinophil level calculation

    Step 1: Convert eosinophils % into a decimal.

    • % Eosinophil ÷ 100

    Step 2: Convert white blood cell (WBC) count into cells/µL, if not already in these units.

    • WBC count (in K/µL or GI/L or x 103 cells/µL) x 1000 = WBC in cells/µL

    Step 3: Multiply eosinophils by WBC count in cells/µL.

  • Considerations for blood eosinophil measurements

    There are a number of conditions and medications that can affect blood eosinophil counts, including medications used to treat severe asthma.6It is vital to consider the patient’s history when determining whether they have severe asthma associated with eosinophilic inflammation, so that both the longitudinal blood eosinophil response to treatment and exacerbation history are taken into account.6

  • Oral corticosteroids

    Corticosteroids are a strong eosinophil suppressant, for both their activation and their survival.6They prevent production of many inflammatory mediators, including IL-3, IL-4, IL-5 and GM-CSF, which are vital to eosinophil production and survival.6

    As a common treatment for severe asthma, therefore, OCS can reduce blood eosinophil counts,6and their usage should be taken into account when considering eligibility for an anti-IL-5 treatment.2

  • Montelukast

    Montelukast is a leukotriene receptor antagonist indicated for the treatment of asthma, exercise-induced bronchoconstriction and allergic rhinitis.9Clinical trials have shown a suppressant effect of montelukast treatment on blood eosinophil counts, comparable to increasing budesonide dose.10Montelukast inhibits leukotriene receptors, which are expressed on eosinophils and other inflammatory and airway cells, and block the induction of oedema, smooth muscle contraction and inflammatory cell modulation by leukotriene D4.9
    This indicates that montelukast therapy should be taken into account when assessing blood eosinophil counts.

  • Omalizumab

    Omalizumab is an anti-IgE antibody used for the treatment of severe allergic asthma and does not have a MoA directly related to eosinophil production.11However, a pooled analysis found an association between the reduction of IgE and significant decreases in blood eosinophil counts in patients with moderate-to-severe persistent allergic asthma.12

     

  • Anti-IL-5 agents

    Anti-IL-5 agents are a new class of asthma treatment. They are biologics targeted against IL-5, which is a key cytokine responsible for eosinophil proliferation and maturation in the bone marrow.6

    Anti-IL-5 agents have been shown to reduce the number of eosinophils in peripheral blood.  

  • Medication-independent factors

    Eosinophils are primarily responsible for the body’s antiparasitic defences. Parasitic infection can elevate blood eosinophil count and present a confounding factor when diagnosing severe asthma.6

    In countries where parasitic diseases are prevalent, parasite infection should always be considered as a differential diagnosis when using blood eosinophils as a diagnostic or treatment biomarker.6

    Severe asthma should not be diagnosed on the basis of blood eosinophil counts alone. Other differential diagnoses for high blood eosinophil counts should include allergy, symptoms of cancer, Churg-Strauss syndrome, hypereosinophilic syndrome and a hypersensitivity reaction resulting from drug ingestion.61314The table below shows examples of diseases associated with high blood eosinophil levels.

Diseases associated with high blood eosinophil levels

Type of disease
Potential disease cause
Infectious
Invasive helminth infection
Respiratory
Eosinophilic pneumonitis; asthma; allergic bronchopulmonary aspergillosis; chronic eosinophilic pneumonia; subset of COPD patients
Gastrointestinal
Inflammatory bowel disease; eosinophilic gastroenteritis; allergic colitis
Allergic
Allergic rhinoconjunctivitis; asthma; eczema; atopic dermatitis
Systemic Idiopathic hypereosinophilic syndrome; vasculitis; Churg-Strauss syndrome/eosinophilic granulomatosis with polyangitis
Iatrogenic Drug reaction; cytokine infusions
Malignant Lymphoma; colonic carcinoma; Langerhans cell histiocytosis; myeloid or stem cell neoplasms

COPD, chronic obstructive pulmonary disease.

Adapted from Rothenberg 1998 and Valent, et al. 2012.14

References:

  1. Pavord ID, et al. Lancet 2012;380:651–9.
  2. Mepolizumab SmPC; GlaxoSmithKline 2016
  3. Katz LE, et al. Ann Am Thorac Soc 2014;11:531–6.
  4. Ortega HG, et al. N Engl J Med 2014;371,1198–207.
  5. Bel EH, et al. N Engl J Med, 2014;371:1189–97.
  6. Rothenberg M. N Engl J Med 1998;338:1592–600.
  7. Flood-Page P, et al. Am J Respir Crit Care Med 2007;176:1062–71.
  8. Chung KF, et al. Eur Respir J 2014;43:343–73.
  9. Montelukast SmPC; Accord Healthcare 2016
  10. Price DB, et al. Thorax 2003;58:211–6.
  11. Omalizumab SmPC; Novartis 2016
  12. Massanari M, et al. Resp Med 2010;104:188–96.
  13. Bochner B, et al. J Allergy Clin Immunol 2012;130:587–96.
  14. Valent P, et al. Expert Rev Hematol 2012;5:157–76.

NUCALA (mepolizumab), 100 mg pulver till injektionsvätska, lösning, 100 mg injektionsvätska, lösning i förfylld spruta, 100 mg injektionsvätska, lösning i förfylld penna. Medel vid obstruktiva luftvägssjukdomar, övriga systemiska medel för obstruktiva lungsjukdomar
Rx (F), ATC kod: R03DX09.
Terapeutiska indikationer: Nucala är indicerat som tilläggsbehandling vid svår refraktär eosinofil astma hos vuxna patienter, ungdomar och barn från 6 års ålder. (För barn 6 till 11 år är endast Nucala 100 mg pulver till injektionsvätska godkänd). Dosering: Rekommenderad dos för mepolizumab hos vuxna och ungdomar från 12 års ålder är 100 mg administrerat subkutant en gång var fjärde vecka. Rekommenderad dos för mepolizumab hos barn från 6 till 11 år är 40 mg administrerat subkutant en gång var fjärde vecka. Nucala är avsett för långtidsbehandling. Behovet av fortsatt behandling ska omprövas minst en gång om året baserat på läkarens bedömning av sjukdomens svårighetsgrad och patientens kontroll över exacerbationer. Ytterligare information: I kliniska studier visades effekt hos följande subpopulation: aktuell standardbehandling som minst inkluderade högdosbehandling med inhalerade kortikosteroider (ICS) plus ytterligare en underhållsbehandling, två eller fler exacerbationer under de senaste 12 månaderna eller beroende av systemiska kortikosteroider samt blodeosinofilvärde minst 150 celler/μl vid behandlingsstart eller minst 300 celler/μl under de senaste 12 månaderna. Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne. Varningar och försiktighet: För att underlätta spårbarheten av biologiska läkemedel ska den administrerade produktens namn och batchnummer tydligt anges i patientjournalen. Mepolizumab ska inte användas för att behandla akuta astmaexacerbationer. Astmarelaterade biverkningar eller exacerbationer kan förekomma under behandling. Abrupt utsättning av kortikosteroider efter behandlingsstart med mepolizumab rekommenderas ej. Akuta och fördröjda systemiska reaktioner, inklusive överkänslighetsreaktioner (t.ex. anafylaxi, urtikaria, angioödem, hudutslag, bronkospasm, hypotoni), har förekommit efter administrering av mepolizumab. Patienter med befintliga maskinfektioner ska behandlas innan behandling med mepolizumab påbörjas. Om patienten blir infekterad under behandling med Nucala och inte svarar på maskmedel ska temporär utsättning av Nucala övervägas. 
Subventionsbegränsning: Subventioneras endast för patienter med svår eosinofil astma som är otillräckligt kontrollerade trots standardbehandling och antingen behandling med perorala kortikosteroider (OCS) i doser som ger ökad risk för biverkningar eller när OCS är kontraindicerat.

För fullständig förskrivningsinformation och pris, se www.fass.se. Datum för översyn av produktresumén: 2021-06-15. 
GlaxoSmithKline AB, Box 516, 169 29 Solna. Tel 08-638 93 00, www.se.gsk.com.