immunotherapy: dose matters!tsaai.org/assets/tankersley-it.pdfd. farinae d. pteronyssinus age...

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Immunotherapy:Dose Matters!

Mike Tankersley, MD, MBA

FAAAAI, FACAAI, FAAP

Col(ret), USAF, MC

Professor

Departments of Medicine and Pediatrics

Memphis, TN

Disclosures: ALK

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Objectives:

Upon completion of the session, participants should be able to

1. Discuss and expand upon the optimal dosing necessary topromote maximal outcomes for their immunotherapy patients2. Describe and discuss cross-reactive allergens and those withproteolytic enzymes and how this impacts dosing3. Identify creative ways to streamline the onboarding of newSCIT patients which will improve efficiency and effectiveness4. Discuss coding and other administrative aspects of animmunotherapy practice.

All Quotes from 2011 IT and2017 Venom Practice

Parameters

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No Deep Dives

1. Cluster and rush immunotherapy

2. Local and systemic reactions

3. Dose adjustments for seasons, reactions and time lapses

4. Immunologic mechanisms

5. Cross-reactivity

6. Standardization methodology

7. Build-up schedules• “Choose a buildup dose schedule for optimal safety and convenience.”

Dosing Thoughts to Ponder

1. Does dose really matter?

2. Does one dose fit all?

3. Are ANY and ALL doses effective?

4. What is a placebo dose?

5. Is it possible to give a placebo dose?

6. How do I calculate the effective dose?

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Effective Doses

1. Right patient, right drug, RIGHT DOSE, right route, righttime, right reason and right documentation

2. Amoxicillin 500 mg po bid

3. Acetaminophen 325 mg po q 4-6 hours

4. Cetirizine 10 mg po qday

5. Montelukast 10 mg po qday

6. Benralizumab 30 mg SQ q 8 weeks

7. Is immunotherapy any different?

Effective Dose Ranges

1. Amoxicillin 40-80 mg/kg

2. Prednisone 1-2 mg/kg

3. Albuterol 2-6 puffs

4. Epinephrine 0.3-0.5 mg

5. Acetaminophen 325-1000 mg

6. Omalizumab 150-300 mg

7. Is immunotherapy any different?

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Specificity and Dosing• Specificity of AIT

• Treatment with ragweed has little or no effect on grass pollen-induced symptoms

• Optimum dosing of AIT

• High>moderate>low dose

• 5-20 mcg of major allergen = effective dose

• Major allergen: antigen that binds to IgE sera from 50% or more ofa clinically allergic group of patients

• Efficacy and systemic reaction rate increase with increasingallergen content

Labeling Treatment Vials

• 1:1 v/v Red

• 1:10 v/v Yellow

• 1:100 v/v Blue

• 1:1,000 v/v Green (safe starting concentration)

• 1:10,000 v/v Silver

• Labeled with name, ID (e.g. DOB), vial #,dilution, allergens, expiration date

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Vial Number

VialConcentration

Vial Contents

Expiration Date

PatientIdentifiers

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Effective Doses

1. Sublingual immunotherapy (SLIT)

2. Venom immunotherapy (VIT)

3. Imported fire ant (IFA) immunotherapy

4. Aeroallergen immunotherapy

SLIT

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SLIT EfficacyORALAIR® GRASTEK® RAGWITEK® ODACTRA®

Components

Sweet VernalOrchard

Perennial RyeTimothy

Kentucky Blue

Timothy Short ragweedD. farinae

D. pteronyssinus

Age Indications 5-65 years 5-65 years 18-65 years 18-65 years

Initiation16 wks prior tograss season

12 wks prior tograss season

12 wks prior toragweed season

Can be startedanytime

FDA-approved 2014 2014 2014 2017

SLIT Effective Doses

• Total combined daily symptom/medication score (TCS)

• Daily symptom score (DSS)

• Daily medication score (DMS)

Creticos PS, et al. Randomized controlled trial of a ragweed allergy immunotherapy tablet in N Americanand European adults. J Allergy Clin Immunol 2013;131:1342-9.

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Question 2

Which of the following ragweed doses have been shown to beeffective in adjusted mean TCS, adjusted mean DSS andadjusted mean DMS?

A. 1.5 Amb a 1 units

B. 6 Amb a 1 units

C. 12 Amb a 1 units

Question 2

Which of the following ragweed doses have been shown to beeffective in adjusted mean TCS, adjusted mean DSS andadjusted mean DMS?

A. 1.5 Amb a 1 units

B. 6 Amb a 1 units

C. 12 Amb a 1 units

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Effective Doses

• Primary efficacy end point: total combined dailysymptom/medication score (TCS) during peak ragweed season

• Three daily sublingual doses (1.5, 6 and 12 Amb a 1 units)

• 1.5 Amb a 1-U reduced TCS by 9% (-0.76; P = 0.22)

• 6 Amb a 1-U reduced TCS by 19% (-1.58; P = 0.01)

• 12 Amb a 1-U reduced TCS by 24% (-1.58; P = 0.01)


Effective Doses


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The Nashville Times

The arrest of Nashville medical provider Dr. Rip MOff on charges that he took 2800 BAU Timothy grasssamples, created a suspension, diluted it 10-fold and

sold it as sublingual drops to his self-paying patients toincrease profits has divided the community and left

many community members in a state of"disbelief, outrage and fear”.

DOSE MATTERS!

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Venom IT

Placebo VIT Dosing

A Controlled Trial of Immunotherapy in Insect Hypersensitivity

Kevin J. Hunt, M.D., Martin D. Valentine, M.D., Anne K. Sobotka, Ph.D.,Allen W. Benton, Ph.D., Frank J. Amodio, M.D.,

and Lawrence M. Lichtenstein, M.D.July 27, 1978

N Engl J Med 1978; 299:157-161

Placebo and whole-body extract gave similar results and weresignificantly less effective than venom immunotherapy (P<0.01)We conclude that venom immunotherapy is clinically superior

to therapy on whole-body extract or placebo.

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Venom Immunotherapy Dosing

• 1:1 v/v Red vial 100 mcg/mL

• 1:10 v/v Yellow vial 10 mcg/mL

• 1:100 v/v Blue vial 1 mcg/mL

• 1:1,000 v/v Green vial 0.1 mcg/mL

• 1:10,000 v/v Silver vial 0.01 mcg/mL

• 1:100,000 v/v Silver Jr vial 0.001 mcg/mL


• Starting dose• Package insert: 0.001-0.01 mcg

• 2017 Practice Parameter: 1 mcg

• Effective dose• “The full dose of 100 mcg/mL must be achieved to ensure optimal clinical

protection (50 mcg may be considered in children)”

• Mixed vespid would be 300 mcg (100 mcg of each insect)• Yellow jacket

• Yellow hornet

• White-faced hornet

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• Dosing frequency• “The interval between maintenance dose injections can be increased to 4-week

intervals during the first year of VIT and eventually to every 6 to 8 weeksduring subsequent years.”

• Recurrent anaphylaxis• “If the insect is the same as that causing the initial reaction, an increase in

venom dose of up to 200 mcg per injection might provide protection.”

• “If the culprit is unknown, further testing might be needed to determinewhether there is a new or untreated venom sensitivity before considering anincrease in the venom dose.”

• “Consider measuring basal serum tryptase because failure of VIT can berelated to underlying mast cell disorders.

Venom Immunotherapy Dosing• Injection frequency

• “Continue the maintenance dose monthly for at least 12 to 18 months, thenconsider extending the interval to 6 or 8 weeks during several years oftreatment. For patients who continue VIT for longer than 4 years, a 12-weekinterval is safe and effective”

• Operationalizing the recommendation• Year 1: every 4 weeks

• Year 2: every 6 weeks

• Year 3-4: every 8 weeks

• Year 5 and beyond: every 12 weeks

• Option: stay every 4 weeks and the patient’s frequency will be dictated by lifeevents with dose adjustments liberalized (shared decision making)

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DOSE MATTERS!

Imported Fire Ant IT

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IFA Immunotherapy Dosing

• Starting dose• “…dosage schedule…less well defined in terms of starting dose and rapidity

of buildup.”

• Effective dose• “Although most experts recommend a maintenance dose of 0.5 mL of a 1:100

wt/vol concentration and there is increasing evidence that this dose isprotective a 1:10 wt/vol maintenance concentration has been recommended bysome.”

• Red vial recipe for 1:100 wt/vol• 1 mL of 1:10 wt/vol manufacturer vial in 9 mL of diluent

• 0.5 mL of 1:10 wt/vol manufacturer vial in 4.5 mL of diluent

Aeroallergen IT

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Placebo SCIT Dosing

A 23 page publication, 1 page of references

Placebo SCIT Dosing

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Effective SCIT Dosing

• “Allergen immunotherapy is effective when appropriatedoses of allergens are administered.”

• “Effective subcutaneous allergen immunotherapy appears tocorrelate with administration of an optimal maintenance dosein the range of 5 to 20 mcg of major allergen for inhalantallergens.”

• What is 5-20 mcg of major allergen?

Standardized US Allergen Extracts

• D. farinae and pteronyssinus AU• Short ragweed AU• Cat hair and cat pelt BAU• Grasses BAU

• Bermuda• Northern grasses (7 of them)

• June (KY blue), orchard, timothy, rye• Fescue, Red top, Sweet vernal

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• “These parameters also provided specific recommendationsfor immunotherapy maintenance doses for some standardizedallergens and a suggested dosing range for nonstandardizedallergen extracts.”

• “The term maintenance concentrate should be used to identifythe allergen immunotherapy extract that contains atherapeutic effective dose for each of its individualconstituents.”

SCIT Starting Dose

• “In general, the starting immunotherapy dose is 1,000- (greenvial) to 10,000-fold (silver vial) less than the maintenancedose. For highly sensitive patients, the starting dose might belower.”

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• “These parameters also provided specific recommendationsfor immunotherapy maintenance doses for some standardizedallergens and a suggested dosing range for nonstandardizedallergen extracts.”

• “The term maintenance concentrate should be used to identifythe allergen immunotherapy extract that contains atherapeutic effective dose for each of its individualconstituents.”


• “For nonstandardized extracts, a suggested maintenance doseis…0.5 mL of a 1:100 or 1:200 wt/vol dilution ofmanufacturer’s extract.”

• House dust mite: 500-2000 allergy units (AU)

• Cat: 1000-4000 bioequivalent allergy units (BAU)

• Grass: 1000-4000 bioequivalent allergy units (BAU)

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• “The effective therapeutic dose or maintenance dose is thedose that provides therapeutic efficacy without significantadverse local or systemic reactions.”

• “The effective therapeutic dose might not be the initiallycalculated projected effective dose (eg, 500 BAU [highesttolerated dose] vs 2000 BAU [projected effective dose] forcat)”

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• “The maintenance goal (or projected effective dose) is theallergen dose projected to provide therapeutic efficacy. Notall patients will tolerate the projected effective dose, andsome patients experience therapeutic efficacy at lowerdoses.”

• “If clinical improvement is not apparent after 1 year ofmaintenance therapy, possible reasons for lack of efficacyshould be evaluated.”


• “The intervals between maintenance immunotherapyinjections generally range from…every 2 to 4 weeks forinhalant allergens but can be advanced as tolerated if clinicalefficacy is maintained.”

• If pregnancy occurs during the build-up phase and the patientis receiving a dose unlikely to be therapeutic, discontinuationof immunotherapy should be considered.”

• This means there are doses unlikely to be therapeutic

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• “The most commonly used schedule is for increasing doses ofallergen immunotherapy extract to be administered 1 to 3times per week.”

• “If there are recurrent systemic reactions at the maintenancedose, one management consideration would be to decreasethe maintenance dose provided the dose is still high enoughto benefit the patient.”


• “Consideration of the following principles is necessary whenmixing allergen extracts:

(1) cross-reactivity of allergens,

(2) optimization of the dose of each constituent, and

(3) enzymatic degradation of allergens”

• “The maintenance concentrate should be formulated todeliver a full projected therapeutic dose of each of itsconstituent components.”

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• “Because a full dose-response curve has not been determinedfor most allergens, it is possible (and supported by expertopinion) that therapeutic response can occur with doses lowerthan those that have been shown to be effective in controlledstudies. In general, however, low doses are less likely to beeffective, and very low doses usually are ineffective.”

DOSE

IMMUNOGENICITY

ALLERGENICITY


• “The allergist/immunologist might need to prepare more than1 maintenance concentrate to provide a therapeutic dose ofeach of the allergens for the polysensitized patient.”

• “Cockroach and mold/fungi extracts are generally of lowpotency and vary considerably in composition. Onlyglycerinated cockroach or mold/fungi extracts should beused, and they should be used at higher doses than thenonstandardized pollens.”

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Proteolytic Enzymes and Mixing

• “Studies designed to investigate the effect of combining extractswith high proteolytic activity, such as cockroach and mold/fungi,with extracts such as pollen, dander, and dust mite, havedemonstrated a significant loss of potency with some of theseextracts. Separation of extracts with high proteolytic enzymeactivities from other extracts is recommended. It might benecessary to prepare 2 or more vials to provide allergenimmunotherapy containing an optimal dose of each componentwhile avoiding allergen extract combinations that might result indegradation of some or all of the components.”

Proteolytic Enzymes and Mixing

• “Preparing allergen immunotherapy extracts that contain anoptimal dose of each allergen extract, a determinant of efficacy,which does not contain allergen extract combinations that resultin degradation of some of all or all of the components, mightrequire preparation of 2 or more vials. Therefore 2 or moreinjections might be needed to be given at each patient’s visitdepending on whether all of the relevant extracts can be mixedinto a single vial and still deliver an optimal dose of eachallergen.”

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Fig 1. Combinations producing low (X), moderate or risky (Ø), and favorable (+)compatibilities when allergenic extracts are mixed with protease-containinginsect, fungal, and mite extracts are shown.

Esch JACI 2008;122:659-660

Effect of Dilution on Dose• “Preparing allergen immunotherapy extracts that contain an

optimal dose of each allergen extract, a determinant of efficacy,which does not contain allergen extract combinations that resultin degradation of some of all or all of the components, mightrequire preparation of 2 or more vials. Therefore 2 or moreinjections might be needed to be given at each patient’s visitdepending on whether all of the relevant extracts can be mixedinto a single vial and still deliver an optimal dose of eachallergen. Once the diluent is all replaced, addition of furtherallergens will result in undesirable dilution of all allergens in themaintenance mixture.”

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Maintenance Dosing Frequency

• “Once a patient who is receiving inhalant allergenimmunotherapy reaches a maintenance dose, an interval of 2to 4 weeks between injections is recommended, providedclinical improvement is maintained. Some subjects mighttolerate longer intervals between maintenance doseinjections.”

Dog Dosing

• “The major allergen content of most dog extracts is too lowto allow effective dosing, even with undiluted manufacturers’extracts.”

• “However, in one study using an extract containingapproximately 161 mcg/mL Can f 1 (Hollister-StierLaboratories, Spokane, Wash), there was a significant doseresponse of immunologic parameters similar to thatdemonstrated with other allergens.”

• Use AP Dog if you want an effective dose!

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Math Free?

Math Free?

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The 10% Rule

Assumption: 0.5 mL maintenance dose

The Allergist’s “Tithe”

• Each relevant allergen should be 10% of the totalvolume of the maintenance vial

• Example for a 10 mL vial• Oak 1 mL

• Sweetgum 1 mL

• Johnson 1 mL

• Ragweed 1 mL

• Df 1 mL

• Alternaria 1 mL

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3 Exceptions to the Rule

• 5% northern grasses (e.g. Timothy)• 15% (AP dog)• 20% (cat)• Example for a 10 mL vial

• Timothy 0.5 mL

• AP dog 1.5 mL

• Cat 2 mL

Summary 5-10-15-20%

• 5% northern grasses (e.g. Timothy)• 10% everything but the 3 exceptions• 15% (AP dog)• 20% (cat)• Example for a 10 mL vial:

• Timothy 0.5 mL

• AP dog 1.5 mL

• Cat 2 mL

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Tree Example

+ Skin Test Results

• Alder

• Ash

• Birch

• Box Elder/Maple mix

• Elm

• Mountain Cedar

• Oak

IT Prescription (10 mL)

• Alder

• Ash 1 mL

• Birch 1 mL

• Box Elder/Maple 1 mL

• Elm 1 mL

• Mountain Cedar 1 mL

• Oak 1 mL

• Diluent 4 mL

Grass Example

+ Skin Test Results

• Bahia

• Bermuda

• Johnson

• Rye

• Timothy


•

• Bermuda 1 mL

• Johnson 1 mL

•

• Timothy 0.5 mL

• Diluent 7.5 mL

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Weed Example

+ Skin Test Results

• Dock/Sorrel mix

• Lambs quarters

• Marshelder/Poverty mix

• Ragweed GSW

• Russian Thistle

• Sagebrush/Mugwort mix


• Dock/Sorrel 1 mL

•

• Marshelder/Poverty 1 mL

• Ragweed GSW 1 mL

• Russian Thistle 1 mL

• Sagebrush/Mugwort 1 mL

• Diluent 5 mL


• Dosing used in the remote practice of allergy

• “Dose” is found 298 times in the 2011 IT PP

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Tank’s Tips

• Skin test with cross-reactive allergens• Limit your skin testing panel to 75 allergens• Use effective doses with 10% rule and 3 exceptions• Take cross-reactivity into consideration for treatment kit

• Pick 1 representative allergen for each cross-reactive group

Tank’s Tips

• Use a 4 vial kit (green, blue, yellow and red)• Use 5 mL green, blue and yellow vials and 10 mL red vial• Use a 40 visit build-up in 0.05 mL increments• Offer 2-dose cluster in green and blue vials• Don’t be afraid to give 4 injections in polysensitized patient

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Summary

DOSE MATTERS!

Questions or Comments?

Mike [email protected]

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Addendum

Venom Dosing Schedules

15 visit build-up

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Venom Dosing Schedules

20 visit build-up

IFA Dosing Schedules

28 visit build-up

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IFA Dosing Schedules

25 visit build-up

immunotherapy: dose matters!tsaai.org/assets/tankersley-it.pdfd. farinae d. pteronyssinus age...

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