1

Assessment and Grading of Assessment and Grading of Oral Mucositis after Stem Cell Oral Mucositis after Stem Cell

TransplantationTransplantation

Corey Cutler, MD MPH FRCP(C)Corey Cutler, MD MPH FRCP(C)

DanaDana--Farber Cancer Institute Farber Cancer Institute Brigham and WomenBrigham and Women’’s Hospital s Hospital

Harvard Medical SchoolHarvard Medical School

Boston, MassachusettsBoston, Massachusetts

NEJMNEJM. 1990;322:704.. 1990;322:704.

StomatitisStomatitisA fish hook lodges in my throat.A fish hook lodges in my throat.Spittle, kindergarten paste, thickens everything Spittle, kindergarten paste, thickens everything –– even vision.even vision.Mouth, pocked with sores & blisters, swollen ulcerated tongue.Mouth, pocked with sores & blisters, swollen ulcerated tongue.Topside, sandpapered with number 7 coarsest grade.Topside, sandpapered with number 7 coarsest grade.Taste buds, saliva glands, seared.Taste buds, saliva glands, seared.Cool water, corrosive acid now.Cool water, corrosive acid now.The tongue rests; teeth become enemies.The tongue rests; teeth become enemies.Coiled steel Coiled steel razoredrazored wire atop dentate prison walls.wire atop dentate prison walls.Only moans escape my lips. I cannot eat or speak.Only moans escape my lips. I cannot eat or speak.Inside a howl festers.Inside a howl festers.Pain lengthens time.Pain lengthens time. –– Anita Hart Anita Hart BalterBalter

Oral MucositisOral Mucositis

♦♦Side Effect of Standard Side Effect of Standard CytotoxicCytotoxic ChemotherapyChemotherapy–– Effect on tissues with rapid cell turnoverEffect on tissues with rapid cell turnover

–– Bone Marrow Bone Marrow -- MyelosuppressionMyelosuppression–– Hair Follicles Hair Follicles -- AlopeciaAlopecia–– GI system GI system -- DiarrheaDiarrhea

-- EsophagitisEsophagitis-- Oral mucositisOral mucositis

Mouth

Esophagus

Stomach

SmallIntestineColon

RectumAnal Canal

and Anus

2

Close to 400,000 Patients Per Year Suffer From Close to 400,000 Patients Per Year Suffer From Mucositis During Cancer TherapyMucositis During Cancer Therapy

Source: Mattson Jack Database 2003; NCI; Note: 400,000 patients in the US

Colorectal21%

Breast14%

NHL5%

NSCLC41%

Stem Cell Transplant

4%

Head and Neck15%

Adapted from Bellm LA et al,Support Care Cancer. 2000;8:33-39.

Oral Mucositis: The Worst Complication of Oral Mucositis: The Worst Complication of MyeloablativeMyeloablative TransplantationTransplantation

Res

pond

e nts

(%)

Most Debilitating Side Effects4540

35

30

25

20

15

10

5

0Oral

MucositisNausea and

VomitingWeakness

and LethargyDiarrhea

Elting, et al; Cancer 2003

For Every 55 Patients with Severe Mucositis For Every 55 Patients with Severe Mucositis and and MyelosuppressionMyelosuppression……

41 will develop infection …

and 5 will die.

3

Relationship of Mucositis to Outcomes in BMT

Health OutcomeIncrease in Days:Mucositis vs. No Mucositis

Injectable narcotics 4.80 (<0.01)TPN days 5.34 (<0.01)Febrile days 1.59 (<0.02)Significant infection 2.55 (<0.05)Hospital days (autos) 11.02 (<0.01)Hospital days (allos) 6.92 (<0.02)

Pathobiology of Mucositis

Normal Epithelium

Phase IInitiation

Phases II & IIIMessaging, Signaling,

& Amplification

Phase IVUlceration (Mucositis)

Phase VHealing

Epithelial Layer

Submucosa FibroblastBasal Cell Blood Vessel Inflammatory Cell

Bacteria

Chemotherapy

Radiation

Clinical Features of MucositisClinical Features of Mucositis♦♦ErythemaErythema

♦♦UlcerationUlceration

♦♦PseudomembranePseudomembrane formationformation

♦♦ConsequencesConsequences–– PainPain–– Difficulty in swallowing/chewing foodDifficulty in swallowing/chewing food

–– Decreased nutritionDecreased nutrition–– Requirement for IV nutritionRequirement for IV nutrition

–– Infectious riskInfectious risk–– Breakdown of mucosal barrier Breakdown of mucosal barrier –– Risk of Risk of bacteremiabacteremia secondary to TPNsecondary to TPN

4

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Reasons to Reasons to ‘‘MeasureMeasure’’ MucositisMucositis

♦♦Toxicity description and assessmentToxicity description and assessment

♦♦Medical management Medical management

♦♦Research Research –– Descriptive studiesDescriptive studies–– Intervention studiesIntervention studies

Ideal Mucositis ScaleIdeal Mucositis Scale

♦♦Accurately reflects severity and course of Accurately reflects severity and course of objective and subjective clinical changes.objective and subjective clinical changes.

♦♦Easy to teach and use, with minimal interEasy to teach and use, with minimal inter--observer variability. observer variability.

♦♦Does not require lesion measurement.Does not require lesion measurement.

♦♦Sensitive enough to discriminate treatment Sensitive enough to discriminate treatment efficacy.efficacy.

♦♦Clinically meaningful and easily interpretable Clinically meaningful and easily interpretable end points for clinicians, patients, and FDA.end points for clinicians, patients, and FDA.

Mucositis Research InstrumentsMucositis Research Instruments

♦No uniformity in end points.

♦Wide range of complexity.

♦Provide tight, comparable data, but meaningfulness of end points may be difficult to convey in general clinical settings, ie. How important is a difference between 1.62 vs. 0.77?

♦Major value in phase 2 trials and outcome analyses, but of limited value in phase 3 trials.

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WHONCI CTCUndefinedCollaborative studyRTOGBearmanOther

Mucositis Scale FrequencyMucositis Scale Frequency

Mucositis Scales to be ReviewedMucositis Scales to be Reviewed

WHO Oral Toxicity Scale (WHO Score)WHO Oral Toxicity Scale (WHO Score)

NCINCI--CTC v3 Mucositis ScaleCTC v3 Mucositis Scale

Clinical ScoreClinical Score

Functional/Symptomatic ScoreFunctional/Symptomatic Score

OMASOMAS

WHO ScoreWHO Score♦♦ Based on a combination of subjective, objective and Based on a combination of subjective, objective and

functional outcomes:functional outcomes:

♦♦ SubjectiveSubjective–– Soreness as described by the patientSoreness as described by the patient

♦♦ ObjectiveObjective –– Presence of erythema and ulcerationsPresence of erythema and ulcerations

♦♦ FunctionalFunctional–– Ability to eat solids, liquids or nothing by Ability to eat solids, liquids or nothing by mouthmouth

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WHO ScoreWHO Score♦♦ Grade 0 Grade 0 –– No objective findings, function irrelevantNo objective findings, function irrelevant

♦♦ Grade 1 Grade 1 –– EErythema rythema plus painplus pain, function irrelevant, function irrelevant

–– May include mucosal scalloping with or without erythema or May include mucosal scalloping with or without erythema or sorenesssoreness

♦♦ Grade 2 Grade 2 –– UlcerationUlceration, ability to eat solids, ability to eat solids

♦♦ Grade 3 Grade 3 –– UlcerationUlceration, ability to eat liquids, ability to eat liquids

♦♦ Grade 4 Grade 4 –– UlcerationUlceration, nothing by mouth, nothing by mouth

GradeGrade

MucositisMucositisto the extent that to the extent that alimentation is not alimentation is not possiblepossible

Ulcers, extensive Ulcers, extensive erythemaerythema

Patients cannot Patients cannot swallow solid dietswallow solid diet

ErythemaErythema, , ulcersulcers

Patients can Patients can swallow solid swallow solid dietdiet

Soreness +/Soreness +/––erythemaerythema

No ulcerationNo ulceration

NoneNone

4433221100

Severeoral mucositis

WHO Oral Mucositis ScaleWHO Oral Mucositis Scale

Diet Assessment Diet Assessment –– Food DefinitionsFood Definitions♦♦SolidsSolids

–– Foods that have to be chewedFoods that have to be chewed–– Chunky soups, meats, grains, pasta or whole Chunky soups, meats, grains, pasta or whole

vegetablesvegetables

♦♦LiquidsLiquids–– Foods that take the shape of their containerFoods that take the shape of their container–– Pureed soups, JellPureed soups, Jell--OO®®, pudding, mashed potatoes, , pudding, mashed potatoes,

baby food, Ensurebaby food, Ensure®® or other liquid supplementor other liquid supplement

♦♦Nothing Per OsNothing Per Os–– No eating or drinking, except enough liquid to allow for No eating or drinking, except enough liquid to allow for

taking of medicationstaking of medications

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WHO Scale Grading NuancesWHO Scale Grading NuancesPain in the absence of objective findings = 0Pain in the absence of objective findings = 0

Erythema without pain = 0Erythema without pain = 0

Ulcers, automatically Ulcers, automatically ≥≥ 22

Extent or size of ulcers is not a driverExtent or size of ulcers is not a driver

WHO Grading TipsWHO Grading TipsGrade 1Grade 1 : If there is an ulcer, it: If there is an ulcer, it’’s not Grade 1 s not Grade 1

: May include mucosal scalloping with or : May include mucosal scalloping with or without without erythemaerythema or soreness.or soreness.

Grade 2Grade 2 : Can: Can’’t be a Grade 2 unless there is an t be a Grade 2 unless there is an ulcer. Solid diet.ulcer. Solid diet.

Grade 3Grade 3 : Ulcers. Liquid diet. No solids.: Ulcers. Liquid diet. No solids.

Grade 4Grade 4 : Mucositis of such severity that : Mucositis of such severity that eating/drinking is impossible. eating/drinking is impossible.

:: PO meds donPO meds don’’t countt count

WHO Grading ExamplesWHO Grading ExamplesSubject has a Subject has a fetanylfetanyl patch, large ulceration, patch, large ulceration, no no erythemaerythema, can eat , can eat JelloJello®® and puddingand pudding

Subject is taking an NSAID (within the last 24 Subject is taking an NSAID (within the last 24 hrs) for mouth pain, is now not sore and has hrs) for mouth pain, is now not sore and has erythemaerythema

Subject has no Subject has no erythemaerythema, no soreness, can , no soreness, can eat solids and has an ulcereat solids and has an ulcer

Subject has severe erythema, mouth pain Subject has severe erythema, mouth pain and can only tolerate liquidsand can only tolerate liquids

4

0

2

1

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NCINCI--CTC v3 ScoringCTC v3 Scoring

♦♦ Two ComponentsTwo Components

1.1. Clinical Score Clinical Score –– Objective findingsObjective findings

2.2. Functional/Symptomatic Score Functional/Symptomatic Score ––Functional findingsFunctional findings

CTC Clinical ScoreCTC Clinical Score♦♦ 0 = No oral mucositis0 = No oral mucositis

♦♦ 1 = Erythema1 = Erythema

♦♦ 2 = Patchy ulceration or pseudomembrane 2 = Patchy ulceration or pseudomembrane formationformation

♦♦ 3 = Confluent ulceration or pseudomembrane, 3 = Confluent ulceration or pseudomembrane, confluent ulceration occupies >50% of the confluent ulceration occupies >50% of the mucosal surface of the designated anatomic mucosal surface of the designated anatomic sitesite

♦♦ 4 = Tissue necrosis4 = Tissue necrosis

CTC Functional/Symptomatic ScoreCTC Functional/Symptomatic Score♦♦1 = Ability to eat solids1 = Ability to eat solids

♦♦2 = Requires liquid diet2 = Requires liquid diet

♦♦3 = Not able to tolerate a solid or liquid diet3 = Not able to tolerate a solid or liquid diet

♦♦4 = Symptoms associated with life4 = Symptoms associated with life--threatening threatening consequencesconsequences

♦♦NOTE: If diet is limited for reasons other than mucositis, the NOTE: If diet is limited for reasons other than mucositis, the CTC Functional/Symptomatic Score is based on what the CTC Functional/Symptomatic Score is based on what the subject feels he/she could eat.subject feels he/she could eat.

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Anatomic SiteAnatomic Site--Directed ScoringDirected Scoring

♦♦ Inner aspect of upper lipInner aspect of upper lip

♦♦ Inner aspect of lower lipInner aspect of lower lip

♦♦Right cheek mucosaRight cheek mucosa

♦♦Left cheek mucosaLeft cheek mucosa

♦♦Right bottom and side of tongueRight bottom and side of tongue

♦♦Left bottom and side of tongueLeft bottom and side of tongue

♦♦Floor of mouth and Floor of mouth and frenulumfrenulum

♦♦Soft palateSoft palate

Oral Mucositis Assessment Scale Oral Mucositis Assessment Scale (OMAS)(OMAS)

Sonis et al, Cancer 1999

Febrile daysFebrile days 0.130.13

SigSig infectioninfection 0.26*0.26*

TPN daysTPN days 0.39*0.39*

InjectableInjectable--narcotic daysnarcotic days 0.36*0.36*

Total hospital daysTotal hospital days 0.28*0.28*

Total hospital chargesTotal hospital charges 0.48*0.48*

Correlations Between Peak OMAS Score and Correlations Between Peak OMAS Score and Selected Clinical and Economic OutcomesSelected Clinical and Economic Outcomes

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How Frequently How Frequently Should Evaluations Be Done?Should Evaluations Be Done?

♦♦ Depends on the reason for the assessment.Depends on the reason for the assessment.

♦♦ Mucosal condition in chemotherapy responds Mucosal condition in chemotherapy responds relatively acutely.relatively acutely.

♦♦ Consequently, accuracy of assessment tracks well Consequently, accuracy of assessment tracks well with frequency of evaluation.with frequency of evaluation.

♦♦ Since duration of significant mucositis is the most Since duration of significant mucositis is the most important driver of untoward outcomes of mucositis, important driver of untoward outcomes of mucositis, less than daily assessment is risky, especially in less than daily assessment is risky, especially in clinical trials.clinical trials.

Why Does Mucositis MatterWhy Does Mucositis Matter

♦♦ BMT CTN 0401 BMT CTN 0401 –– Will intervention make mucositis Will intervention make mucositis worse???worse???

♦♦ BMT CTN 0402 BMT CTN 0402 –– Will intervention make mucositis Will intervention make mucositis better???better???

♦♦ New interventions exist New interventions exist -- PaliferminPalifermin

0401: 0401: BexxarBexxar--BEAM BEAM vsvs BEAMBEAM

♦♦ AutologousAutologous transplantation transplantation –– standard for relapsed standard for relapsed nonnon--HodgkinHodgkin’’s Lymphomas Lymphoma

–– Usual regimen: HighUsual regimen: High--dose chemotherapy dose chemotherapy –– BEAM or BEAM or equivalent.equivalent.

–– 0401 0401 –– Tests hypothesis that the addition of Tests hypothesis that the addition of 131131II--Tositumomab to highTositumomab to high--dose chemotherapy will dose chemotherapy will increase response rate increase response rate survivalsurvival

–– BUT: Addition of radioBUT: Addition of radio--immunotherapy may increase immunotherapy may increase mucositismucositis

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Pathobiology of Mucositis

Normal Epithelium

Phase IInitiation

Phases II & IIIMessaging, Signaling,

& Amplification

Phase IVUlceration (Mucositis)

Phase VHealing

Epithelial Layer

Submucosa FibroblastBasal Cell Blood Vessel Inflammatory Cell

Bacteria

Chemotherapy

Radiation

0402: Effect of 0402: Effect of MethotrexateMethotrexate EliminationEliminationRetrospective cohort analysis (2001Retrospective cohort analysis (2001--2003)2003)

Cohorts designated by GVHD prophylaxis:Cohorts designated by GVHD prophylaxis:Sirolimus/Tacrolimus vs. Tacrolimus/MethotrexateSirolimus/Tacrolimus vs. Tacrolimus/MethotrexateCyCy--TBI MRD PBSCT TBI MRD PBSCT

Oral MucositisOral MucositisMucositis assessed 2Mucositis assessed 2--3x/week by members of the Oral 3x/week by members of the Oral Medicine serviceMedicine serviceOMAS scaleOMAS scale

Other OutcomesOther OutcomesTotal Total ParenteralParenteral Nutrition Nutrition

Total number of days of use recordedTotal number of days of use recorded

Narcotic useNarcotic useConversion of all narcotics to intravenous mg morphine Conversion of all narcotics to intravenous mg morphine equivalents (MME) using accepted conversion factorsequivalents (MME) using accepted conversion factors

Duration of HospitalizationDuration of HospitalizationFrom day of transplantation to 1From day of transplantation to 1stst dischargedischarge

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0.160.166 (25%)6 (25%)3 (10%)3 (10%)GrGr IIII--IV GVHDIV GVHD

6.56.5

15 (1115 (11--25)25)5 (21%)5 (21%)3 (13%)3 (13%)16 (67%)16 (67%)

11 (46%)11 (46%)43 (2443 (24--58)58)

2424TacroTacro / Mtx/ Mtx

0.360.3655Mucositis Mucositis

AssessmentsAssessments

0.040.0414 (1114 (11--17)17)Time To ANC > 500Time To ANC > 5000.520.528 (27%)8 (27%)NHL/ALLNHL/ALL

7 (23%)7 (23%)CMLCML15 (50%)15 (50%)AML/MDSAML/MDS

MalignancyMalignancy0.780.7816 (53%)16 (53%)Male GenderMale Gender0.460.4642 (1942 (19--54)54)Median AgeMedian Age

3030Sample SizeSample SizeppSiroSiro / / TacroTacro

DataData

010

2030

4050

60

Peak Mucositis Score

Muc

ositi

s In

cide

nce

(%)

0-1 2-3 4-5

ST groupTM group

Mucositis Incidence

05

1015

2025

30

ST group TM group

Dur

atio

n of

Ulc

erat

ive

Muc

ositi

s (d

ays)

Duration of Mucositis

p = 0.0002 p = 0.008

020

4060

80

Patie

nts

Req

uirin

g TP

N(%

)

TPN usage

010

2030

ST group TM group

Dur

atio

n of

TPN

Usa

ge

Days of TPN requiredST groupTM group

p = 0.08 p = 0.005

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Narcotic Utilization

Narcotic Days MME/Day

Nar

cotic

Day

sM

ME/

day

MM

E/ n

arco

tic d

ay

0

200

400

600

800

1000

1200

1400

Total MME

MM

E

p = 0.08 p = NS p = NS

MME = mg Morphine Equivalents

0

20

40

60

80

100

MME/NarcoticDay

p = NS20

3040

5060

70

**

*

*

ST group TM group

Dur

atio

n of

Hos

pita

lizat

ion

(day

s)

Duration of Hospitalization

p = 0.07

MethotrexateMethotrexate ConclusionsConclusions♦♦ GVHD prophylaxis with SirolimusGVHD prophylaxis with Sirolimus--Tacrolimus is Tacrolimus is

associated with less oral mucositis than with a associated with less oral mucositis than with a MethotrexateMethotrexate--containing regimencontaining regimen

♦♦ Patients who do not receive Methotrexate require less Patients who do not receive Methotrexate require less TPN and less narcoticsTPN and less narcotics

♦♦ Hospitalization duration is shortened in patients not Hospitalization duration is shortened in patients not treated with Methotrexatetreated with Methotrexate

♦♦ The improved mucositis outcomes with nonThe improved mucositis outcomes with non--Methotrexate Methotrexate containing regimens may be associated with substantial containing regimens may be associated with substantial cost savings.cost savings.

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Prevention of Oral MucositisPrevention of Oral Mucositis

♦♦““Many are called, but few are chosenMany are called, but few are chosen””–– Multiple agents failed in randomized trials;Multiple agents failed in randomized trials;–– Until recently, no standard Until recently, no standard

♦♦PaliferminPalifermin

♦♦VelaferminVelafermin

PaliferminPalifermin

♦♦ The mouth is covered in specialized epithelium The mouth is covered in specialized epithelium called called keratinocyteskeratinocytes

♦♦ PaliferminPalifermin is a recombinant Nis a recombinant N--terminal truncated terminal truncated version of version of KeratinocyteKeratinocyte Growth Factor (KGF) with Growth Factor (KGF) with same biological activity but increased stabilitysame biological activity but increased stability

♦♦ KGF is a 28kD, heparinKGF is a 28kD, heparin--binding member of the binding member of the fibroblast growth factor familyfibroblast growth factor family

♦♦ Ameliorates mucositis in Ameliorates mucositis in murinemurine modelmodel

PaliferminPalifermin--Induced Thickening of Normal Induced Thickening of Normal Tongue MucosaTongue Mucosa

Ventral surface of rodent tongue mucosa in absence or presence of palifermin (rHuKGF) 5 mg/kg/day for 3 days

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PaliferminPalifermin

♦♦Phase I (Phase I (MeropolMeropol et al,et al, JCO 1993): JCO 1993): –– Doses of 80 Doses of 80 ugug /kg x 3 d appeared safe/kg x 3 d appeared safe

♦♦Phase II (Phase II (SonisSonis et al,et al, Cancer 1995) Cancer 1995) –– EtoposideEtoposide, , CytarabineCytarabine, , MelphalanMelphalan preparative preparative

regimenregimen–– Reduced mucositis and weight lossReduced mucositis and weight loss

♦♦Phase III (Phase III (SpielbergerSpielberger et alet al, NEJM 2004) , NEJM 2004) –– PaliferminPalifermin vs. placebo in XRTvs. placebo in XRT--containing containing

preparative regimen for preparative regimen for autologousautologous transplanttransplant

PaliferminPalifermin vs. Placebo vs. Placebo -- DesignDesign

♦♦InclusionInclusion–– > 18 > 18 yoyo–– KPS KPS >> 70%70%–– AutotransplantAutotransplant planned for planned for hemeheme malignancymalignancy

♦♦Treatment Treatment –– Etoposide/Cytoxan/TBIEtoposide/Cytoxan/TBI preparative regimenpreparative regimen–– PaliferminPalifermin @ 60 @ 60 ugug/kg x 3d iv prior to XRT/kg x 3d iv prior to XRT–– PaliferminPalifermin @ 60 @ 60 ugug/kg x 3d iv d0, 1, 2/kg x 3d iv d0, 1, 2–– Double blindDouble blind–– GG--CSF given from d0 to recoveryCSF given from d0 to recovery

PaliferminPalifermin vs. Placebo vs. Placebo -- EndpointsEndpoints

♦♦Mucositis assessment daily, multiple scalesMucositis assessment daily, multiple scales–– WHOWHO–– RTOGRTOG–– WCCNRWCCNR

♦♦PatientPatient--reported outcomesreported outcomes–– Sore throatSore throat–– ADL participationADL participation

♦♦Narcotic useNarcotic use

♦♦TPN useTPN use

♦♦Primary endpoint: duration of WHO gr3/4 mucositisPrimary endpoint: duration of WHO gr3/4 mucositis

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Spielberger, R. et al. N Engl J Med 2004;351:2590-2598

PaliferminPalifermin vs. Placebo vs. Placebo -- PatientsPatients

Spielberger, R. et al. N Engl J Med 2004;351:2590-2598

PaliferminPalifermin vs. Placebo vs. Placebo -- ResultsResults

98% 9d

63%3d

Spielberger, R. et al. N Engl J Med 2004;351:2590-2598

PaliferminPalifermin vs. Placebo vs. Placebo ––PatientPatient--Reported OutcomesReported Outcomes

18

♦♦Lower dose of Lower dose of opioidsopioids administered (morphine administered (morphine equivalents): 212 vs. 535 mgequivalents): 212 vs. 535 mg

♦♦Lower duration of Lower duration of opioidopioid administration: 7 vs. 11dadministration: 7 vs. 11d

♦♦Lower incidence of febrile Lower incidence of febrile neutropenianeutropenia: 75 vs. 92%: 75 vs. 92%

♦♦Lower incidence of bloodLower incidence of blood--borne infections: 15 vs. borne infections: 15 vs. 25%25%

♦♦Lower incidence of TPN use : 31 vs. 55%Lower incidence of TPN use : 31 vs. 55%

PaliferminPalifermin vs. Placebo vs. Placebo -- ResultsResults

♦♦Rarely discontinuedRarely discontinued

♦♦Most events with > 5% frequency in Most events with > 5% frequency in paliferminpalifermin group group (and not in placebo group) were due to effect of drug on (and not in placebo group) were due to effect of drug on skin and oral epitheliumskin and oral epithelium

♦♦SAE: Rash; HypotensionSAE: Rash; Hypotension

♦♦Deaths: 1 in each groupDeaths: 1 in each group

♦♦12 month PFS is similar in both groups 12 month PFS is similar in both groups

♦♦No excess of cancer deaths in either group (No excess of cancer deaths in either group (ieie KGF KGF does not protect tumors)does not protect tumors)

PaliferminPalifermin vs. Placebo vs. Placebo -- SafetySafety

♦♦PaliferminPalifermin was effective in reducing the incidence was effective in reducing the incidence and duration of severe and lifeand duration of severe and life--threatening threatening mucositismucositis

♦♦Reduction in Reduction in opioidopioid and TPN use probably and TPN use probably beneficial for ptsbeneficial for pts

♦♦Other Questions:Other Questions:–– Role in Role in AlloAllo transplant transplant –– not effective as GVHD not effective as GVHD

prophylaxisprophylaxis

PaliferminPalifermin vs. Placebo vs. Placebo -- ConclusionsConclusions

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VelaferminVelafermin

♦♦Recombinant Human FibroblastRecombinant Human Fibroblast--Growth FactorGrowth Factor--2020

♦♦Promotes Epithelial and Promotes Epithelial and MesenchymalMesenchymal cell cell proliferation proliferation –– prevents mucositis in animal modelsprevents mucositis in animal models

♦♦Being tested in Ph II trials in people undergoing Being tested in Ph II trials in people undergoing autologousautologous transplantationtransplantation

VelaferminVelafermin TrialTrial

Schuster et al, ASCO 2006

VelaferminVelafermin –– Patient PopulationPatient Population

Schuster et al, ASCO 2006

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VelaferminVelafermin -- OutcomesOutcomes

Schuster et al, ASCO 2006

* Non-Dose Dependent Pharmacology suggested in animal studies

VelaferminVelafermin

♦♦Primary Endpoint not met in this trial Primary Endpoint not met in this trial ––

♦♦Safety establishedSafety established

♦♦Further studies planned at optimal dose Further studies planned at optimal dose

SummarySummary

♦♦ Mucositis Mucositis -- An important complication of An important complication of myeloablativemyeloablative transplantationtransplantation

♦♦ Scoring Scoring –– Important for research and patient careImportant for research and patient care

♦♦ New agents may change incidence and severityNew agents may change incidence and severity

♦♦ New agents may prevent mucositis New agents may prevent mucositis –– need to be need to be tested furthertested further

21

♦♦ AcknowledgementsAcknowledgements–– Nathaniel Nathaniel TreisterTreister, DMD , DMD –– Stephen Stephen SonisSonis, DMD, DMD–– Richard Stone, MDRichard Stone, MD