Myelodysplastic Myelodysplastic SyndromesSyndromes

Jennifer Rogers MS, FNPJennifer Rogers MS, FNP

Cancer Center of the CarolinasCancer Center of the Carolinas

Greenville, SCGreenville, SC

The Myelodysplastic SyndromesThe Myelodysplastic SyndromesOverviewOverview

Clonal disorder characterized by Clonal disorder characterized by hypercellularhypercellularmarrows, peripheral cytopenias, and cell marrows, peripheral cytopenias, and cell functional abnormalitiesfunctional abnormalities

Dominant feature: Ineffective Dominant feature: Ineffective hematopoiesishematopoiesiswith peripheral blood cytopeniaswith peripheral blood cytopenias

Bone marrow failureBone marrow failure–– Majority succumb to infection or bleedingMajority succumb to infection or bleeding–– Transformation to acute leukemia in 35Transformation to acute leukemia in 35--40% range40% range

High mortality rateHigh mortality rate

Supportive Care has been the standard Supportive Care has been the standard treatmenttreatment Kurzrock R. Semin Hematol. 2002 Jul;39(3 Suppl 2):18-25.

Miller KB. Curr Treat Options Oncol. 2000 Apr;1(1):63-9.

The Myelodysplastic SyndromesThe Myelodysplastic SyndromesEpidemiologyEpidemiology

15,000 new cases/year in US (Adults)15,000 new cases/year in US (Adults)

More common than AMLMore common than AML

Median survival 1Median survival 1--3 years3 years

Predominantly a disease of the elderlyPredominantly a disease of the elderly–– Median age > 60Median age > 60–– Incidence greater in Males than FemalesIncidence greater in Males than Females–– Incidence increases with ageIncidence increases with age

Kurzrock R. Semin Hematol. 2002 Jul;39(3 Suppl 2):18-25.Steensma DP, Tefferi A. Leuk Res. 2003 Feb;27(2):95-120..

MDS DefinitionMDS Definition

The myelodysplastic syndromes (MDS) are a group The myelodysplastic syndromes (MDS) are a group of diseases in which the production of blood cells is of diseases in which the production of blood cells is severely disrupted.severely disrupted.In MDS, bone marrow is “injured”.In MDS, bone marrow is “injured”.–– Defect occurs in one of the stem cells within the bone marrow.Defect occurs in one of the stem cells within the bone marrow.–– All cells produced from that point forward carry the same defectAll cells produced from that point forward carry the same defect..–– Defective stem cells crowd out and overwhelm normal, Defective stem cells crowd out and overwhelm normal,

healthy cells.healthy cells.

Defect in normal differentiation (dysplasia).Defect in normal differentiation (dysplasia).

KurzrockKurzrock R. R. SeminSemin HematolHematol. 2002. Jul;39(3 . 2002. Jul;39(3 SupplSuppl 2):182):18--25.25.Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: PathobiologyPathobiology and and Clinical Management. New York: MarcelClinical Management. New York: Marcel DekkerDekker Inc.; 2002. Inc.; 2002. http:// www.http:// www.hmdshmds.org..org.ukuk//mdsmds.html.html

MDS DefinitionMDS Definition

Marrow is less able to produce normal Marrow is less able to produce normal blood cells, leading to low blood counts.blood cells, leading to low blood counts.–– Characterized by 1 or more peripheral blood Characterized by 1 or more peripheral blood

cytopenias secondary to bone marrow cytopenias secondary to bone marrow dysfunction.dysfunction.

Secondary MDS has poorer prognosis.Secondary MDS has poorer prognosis.

KurzrockKurzrock R. R. SeminSemin HematolHematol. 2002. Jul;39(3 . 2002. Jul;39(3 SupplSuppl 2):182):18--25.25.Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: PathobiologyPathobiology and Clinical and Clinical Management. New York: MarcelManagement. New York: Marcel DekkerDekker Inc.; 2002. Inc.; 2002. http:// www.http:// www.hmdshmds.org..org.ukuk//mdsmds.html.html

EtiologyEtiology

–– Environmental Environmental ExposureExposure

BenzeneBenzenePetrochemicalsPetrochemicalsCigarette smoking Cigarette smoking Insecticides Insecticides Organic SolventsOrganic Solvents

–– Treatment RelatedTreatment Related•• Ionizing RadiationIonizing Radiation•• Chemotherapeutic Chemotherapeutic

AgentsAgentsalkylating agentsalkylating agentsCisplatinCisplatinetoposideetoposide

List AF, et al. The Myelodysplastic Syndromes. In: List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’sWintrobe’s Hematology 2003Hematology 2003

• Primary (de novo) MDS (unknown cause)

• Secondary MDS

Pathophysiology: Contributing FactorsPathophysiology: Contributing Factors

With Permission of J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic Foundation

MDSStemCell

Changes

AngiogenicMolecules

Epigenetic Immunologic

Environmental

Molecular Gain of FunctionGenetic –

Loss of Signal

Apoptosis

Pathophysiology of MDSPathophysiology of MDS

LeukemiaImmune system?

HGF

Cytokine Receptors - Nl

CD95Aberrant

TNF−αTGF-−βIL-1−βγ-interferon

Apoptosis

…

Differentiation

Microenvironment

SignalPathwayStem

Cell

Cytokines

Silverman, LR. The Oncologist. 2001;6(suppl 5):8-14.

Pathologic CorrelatesPathologic Correlates

ApoptosisApoptosisHallmark of MDSHallmark of MDSDifference b/t MDS Difference b/t MDS and AMLand AMLDecreases as blast % Decreases as blast % increasesincreases

MicrovesselMicrovesseldensity MVDdensity MVDIncreased in MDSIncreased in MDSHighest in RAEBHighest in RAEB--T T and CMMLand CMMLIncreased TNFIncreased TNF--ααIncreased VEGFIncreased VEGF

Clinical PresentationClinical Presentation

Patients in early stages are most likely Patients in early stages are most likely asymptomatic.asymptomatic.Most often discovered by accident on routine Most often discovered by accident on routine exam or blood test.exam or blood test.Lab evaluation often prompted by signs or Lab evaluation often prompted by signs or symptoms. symptoms. –– Fatigue (anemia)Fatigue (anemia)–– Infections (neutropenia)Infections (neutropenia)–– Bleeding (thrombocytopenia)Bleeding (thrombocytopenia)

Bennett J, et al. Int J Hematol. 2002 Aug;76 Suppl 2:228-38.

Clinical PresentationClinical PresentationCytokine release (Occurring within the Bone Cytokine release (Occurring within the Bone Marrow environment) may result in Marrow environment) may result in constitutional symptoms such as:constitutional symptoms such as:

AnorexiaAnorexiaWeight lossWeight lossLowLow--grade feversgrade fevers

Basic Diagnostic EvaluationBasic Diagnostic EvaluationPeripheral blood Peripheral blood counts + reticulocyte counts + reticulocyte countcountBone marrow biopsy Bone marrow biopsy and aspirationand aspiration–– CytogeneticsCytogenetics

Auxiliary testsAuxiliary tests–– Iron saturation, Iron saturation,

ferritinferritin–– B12, B12, folatefolate levelslevels–– EPO levelEPO level

Establish diagnosis of Establish diagnosis of MDS & AssessMDS & Assess–– FAB/WHO FAB/WHO

ClassificationClassification–– IPSS scoreIPSS score

http://www.hmds.org.uk/mds.htmlhttp://www.nccn.org/professionals/physician_gls/PDF/mds.pdf

Usually Usually hypercellularhypercellular, although can be , although can be hypocellularhypocellular–– Degree of cellularity may interfere with diagnosisDegree of cellularity may interfere with diagnosis

DysplasiaDysplasiaRinged sideroblasts (RARS)Ringed sideroblasts (RARS)Excess blasts (> 5%) (RAEB, RAEBExcess blasts (> 5%) (RAEB, RAEB--T, CMMoL)T, CMMoL)

http://www.hmds.org.uk/mds.htmlhttp://www.nccn.org/professionals/physician_gls/PDF/mds.pdf

Bone Marrow Findings CytogeneticCytogenetic Features Features

Normal Normal karyotypekaryotype may be present may be present Most common abnormalities:Most common abnormalities:–– 5q5q--–– MonosomyMonosomy 77–– 7q 7q --–– Trisomy 8Trisomy 8

Complex abnormalities (3 or more Complex abnormalities (3 or more abnormalities)abnormalities)

Bennett J, et al. Int J Hematol. 2002 Aug;76 Suppl 2:228-38.

MDS Risk Group & PrognosisMDS Risk Group & Prognosis

Scoring systems identify the risk group of Scoring systems identify the risk group of the patient.the patient.The risk group helps predict disease The risk group helps predict disease progression.progression.Determine patient’s risk group to decide Determine patient’s risk group to decide on best course of treatment.on best course of treatment.

Bennett J, et al. Int J Hematol. 2002 Aug;76 Suppl 2:228-38.

MDS Classification SystemsMDS Classification Systems

French American British (FAB)French American British (FAB)World Health Organization (WHO)World Health Organization (WHO)International Prognostic Scoring System International Prognostic Scoring System (IPSS)(IPSS)

Bennett J, et al. Int J Hematol. 2002 Aug;76 Suppl 2:228-38.

MDS Classification SystemsMDS Classification Systems

FAB ClassificationFAB ClassificationIn use for approximately In use for approximately 20 years.20 years.Requires morphologic Requires morphologic findings of findings of dysplasticdysplasticchanges in cell lines.changes in cell lines.Classification has been Classification has been shown to be predictive shown to be predictive of prognosis.of prognosis.–– Primarily based on % Primarily based on %

blastsblasts–– AML > 30% blastsAML > 30% blasts

WHO ClassificationWHO ClassificationRecently introduced Recently introduced Attempt to address Attempt to address deficiencies with MDS deficiencies with MDS especially with RAEB and especially with RAEB and CMMoLCMMoLReRe--classified RAEBclassified RAEB--T as T as AML AML ≥≥20% blasts20% blasts

MDSMDSFAB ClassificationFAB Classification

ClassificationClassification BM BlastsBM Blasts

Refractory anemia Refractory anemia (RA)(RA)RA with ringed sideroblasts RA with ringed sideroblasts (RARS)(RARS)

<5%<5%

RA with excess blasts RA with excess blasts (RAEB)(RAEB) 55--20%20%

RAEB in transformation RAEB in transformation (RAEB(RAEB--T)T) 2121--30%30%

Chronic myelomonocytic leukemia Chronic myelomonocytic leukemia (CMMoL)(CMMoL) <20%<20%

List, AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.

MDS MDS -- WHO ClassificationWHO ClassificationRefractory AnemiaRefractory Anemia–– with ringed sideroblastswith ringed sideroblasts–– without ringed sideroblastswithout ringed sideroblasts

Refractory Refractory cytopeniacytopenia multilineage dysplasia (RCMD)multilineage dysplasia (RCMD)Refractory Anemia with Excess Blasts (RAEB I and II)Refractory Anemia with Excess Blasts (RAEB I and II)–– RAEB I:5RAEB I:5--9% blasts; RAEB9% blasts; RAEB--II: 10II: 10--19% blasts19% blasts

5q5q-- syndromesyndromeMDS unclassifiableMDS unclassifiableRAEBRAEB--TT AMLAMLMDS/Myeloproliferative disease (MPD)MDS/Myeloproliferative disease (MPD)–– CMMoLCMMoL–– Atypical CMLAtypical CML–– Juvenile Myelomonocytic leukemiaJuvenile Myelomonocytic leukemia

Steensma DP, et al. Leukemia Research. 2003;27:95-120Brunning RD, et al. Pathology and genetics of tumors of hematopoietic and lympoid tissues. IARC Press, Lyon, France, 2001.

International Prognostic Scoring International Prognostic Scoring System (IPSS):System (IPSS):

The most commonly used system to score a The most commonly used system to score a patient’s disease in terms of risk (shortened life patient’s disease in terms of risk (shortened life expectancy & chances of transformation to expectancy & chances of transformation to AML). Based on three items:AML). Based on three items:–– CytogeneticCytogenetic findingfinding-- The The karyotypekaryotype (profile of (profile of

chromosomal abnormalities)chromosomal abnormalities)–– Blood cell countBlood cell count-- Extent of cytopenias (deficiencies in Extent of cytopenias (deficiencies in

blood)blood)–– BlastsBlasts-- Percentage of marrow blasts (immature blood Percentage of marrow blasts (immature blood

cells)cells)

Greenberg P, et al. Blood. 1997;89(6):2079-88.

International Prognostic Scoring System International Prognostic Scoring System (IPSS)(IPSS)

Greenberg P, et al. Blood. 1997;89(6):2079-88.

Score ValueScore Value

Prognostic Prognostic VariableVariable

00 0.50.5 1.01.0 1.51.5 2.02.0

BM Blasts (%)BM Blasts (%) <5<5 55--1010 —— 1111--2020 2121--3030

KaryotypeKaryotype** GoodGood IntermInterm.. PoorPoor

CytopeniasCytopenias 0/10/1 2/32/3

Scores:Scores:

Low:Low: 00

IntInt--1:1: 0.5 0.5 -- 1.01.0

IntInt--2:2: 1.5 1.5 -- 2.02.0

High:High: ≥≥ 2.52.5

CytogeneticsCytogenetics::

Good: Good: NormalNormal-- YYdel (5q)del (5q)del (20q)del (20q)

Poor:Poor: Complex (Complex (≥≥ 3 3 abnabn))ChrChr. 7 . 7 abnabn

Int.:Int.: OtherOther

Use of International PrognosticUse of International PrognosticScoring SystemScoring System

Median Median ScoreScore IPSS Survival % LeukemiaIPSS Survival % Leukemia00 LowLow 5.75.7 19190.50.5--1.0 Int1.0 Int--11 3.53.5 30301.51.5--2.0 Int2.0 Int--22 1.21.2 3333>2.0 High 0.4>2.0 High 0.4 4545

The Myelodysplastic SyndromesThe Myelodysplastic SyndromesFAB ClassificationFAB Classification

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 101112131415161718

years

perc

ent

A Survival

125 pts294 pts126 pts208 pts

61 pts

RARSRACMMoLRAEBRAEB-T

B AML Evolution100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 101112131415161718

years

perc

ent

109 pts272 pts118 pts198 pts

60 pts

RARSRACMMoLRAEBRAEB-T

Greenberg P, et al. Blood. 1997;89(6):2079-88.

Sample Patient #1Sample Patient #164 y/o female64 y/o femaleLabs reveal: WBC 4.5, HGB 6.0, ANC 2600, Labs reveal: WBC 4.5, HGB 6.0, ANC 2600, plat 200,000. plat 200,000. BMbxBMbx hypercellularhypercellular, 3% blasts, , 3% blasts, cytogeneticscytogenetics--5Q(del)5Q(del)IPSS Score?IPSS Score?

–# of cytopenias…(1) score = 0

–% of blasts…(<5%) score = 0–cytogenetics…(good) score = 0

Total Score = 0 Prognosis = Good

Sample Patient #2Sample Patient #2

70 y/o male with 70 y/o male with hxhx: CAD. : CAD. Presents with c/o fatigue, SOB X 3 mos. WBC 1.2, Presents with c/o fatigue, SOB X 3 mos. WBC 1.2, HGB 7.0, ANC 500, Plat. 50,000. HGB 7.0, ANC 500, Plat. 50,000. BMbxBMbx reveals reveals hypercellularhypercellular marrow, 15% blasts, Cytogenetics: 46 marrow, 15% blasts, Cytogenetics: 46 xyxy abnabn. 7 in 5 metaphases.. 7 in 5 metaphases.IPSS Score?IPSS Score?

–# of cytopenias (3) score = .5–% marrow blasts (15%) score=1.5

– Cytogenetics (poor) score =1.0

Total Score = 3.0 Prognosis = Poor

Clinical CourseClinical CourseTransformation is usually fatalTransformation is usually fatal–– Durable remissions are rareDurable remissions are rare–– Toxic death rate of chemotherapy is equal Toxic death rate of chemotherapy is equal

to or exceeds response rateto or exceeds response rateMorbidity and mortality due to marrow Morbidity and mortality due to marrow failure or AML, infection.failure or AML, infection.

Skeel R. Handbook of Cancer Chemotherapy. 5th Edition: 472

Goals of TherapyGoals of Therapy

Select therapy best suited for the Select therapy best suited for the individualindividualMinimize toxicityMinimize toxicityImprove blood countsImprove blood counts–– Decrease transfusionsDecrease transfusions–– Decrease infectionsDecrease infectionsImprove quality of lifeImprove quality of lifeProlong survivalProlong survival

ChesonCheson BD, et al. Blood. 2000;96:3671BD, et al. Blood. 2000;96:3671--4.4.http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf

Treatment OptionsTreatment OptionsObservationObservation

Best Supportive Care (BSC)Best Supportive Care (BSC)–– Transfusions (RBC, platelets)Transfusions (RBC, platelets)–– AntibioticsAntibiotics–– Colony stimulating factors Colony stimulating factors

EPO +/EPO +/-- GG--CSF (or GMCSF (or GM--CSF)CSF)

Bone marrow transplant Bone marrow transplant

Chemotherapy Chemotherapy

Approved therapiesApproved therapies

Investigational therapiesInvestigational therapies

Bennett JM (ed). MDS: Pathobiology and Clinical Management. New York: Marcel Dekker Inc.; 2002.http://www.nccn.org/professionals/physician_gls/PDF/mds.pdfGordon MS. Semin Hematol. 1999 Oct;36(4 Suppl 6):21-4.

TransfusionsTransfusionsMajority of patients require transfusion Majority of patients require transfusion support support Thresholds based on symptoms, coThresholds based on symptoms, co--morbidities:morbidities:–– PLTsPLTs 1010--20K may be well tolerated in absence 20K may be well tolerated in absence

of bleeding.of bleeding.Degree of dysfunction may require higher threshold.Degree of dysfunction may require higher threshold.

Multiple transfusions lead to complicationsMultiple transfusions lead to complications–– AlloAllo--sensitization.sensitization.–– Iron overload.Iron overload.

ChelationChelation for > 25U for > 25U pRBCpRBC..Iron absorption may be seen in RARS.Iron absorption may be seen in RARS.

Gordon MS. Gordon MS. SeminSemin HematolHematol. 1999 Oct;36(4 . 1999 Oct;36(4 SupplSuppl 6):216):21--4.4.Tricot GJ, et al. Tricot GJ, et al. SeminSemin OncolOncol. 1987 Dec;14(4):444. 1987 Dec;14(4):444--53.53.http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf

Bone Marrow TransplantBone Marrow TransplantAllogeneic transplantAllogeneic transplant: when the patient receives stem : when the patient receives stem

cells from another person or donor. cells from another person or donor. NonNon--myeloablativemyeloablative transplanttransplant: is a stem cell transplant : is a stem cell transplant

from a donor (allogeneic) that uses a less toxic from a donor (allogeneic) that uses a less toxic regimen of chemotherapy and/or radiation to regimen of chemotherapy and/or radiation to prepare the patient for the transplantprepare the patient for the transplantGenerally not an option for majority of patients with Generally not an option for majority of patients with MDS because of age and lack of suitable donorMDS because of age and lack of suitable donorAllogeneic Allogeneic hematopoietichematopoietic stem cell transplant stem cell transplant (HSCT) remains the only potential curative option(HSCT) remains the only potential curative option

Anderson, JE. Allogeneic Bone Marrow Transplantation in the Myelodysplastic Syndromes.In: Bennet, JM (ed). MDS: Pathobiology and Clinical Management. New York. Marcel Dekker, Inc. 2002Aplastic Anemia & MDS International Foundation, Myelodysplastic Syndromes Basic Explanations, 2003

ChemotherapyChemotherapy

Intensive chemotherapy or standard Intensive chemotherapy or standard induction/remission chemotherapy similar to induction/remission chemotherapy similar to AML AML Patient selectionPatient selection–– Advanced disease (RAEB, RAEBAdvanced disease (RAEB, RAEB--T) or high risk T) or high risk –– Younger Younger

Associated with significant treatment related Associated with significant treatment related morbidity and mortality in the elderly morbidity and mortality in the elderly (prolonged (prolonged hypoplasiahypoplasia))

deWitte, TM. Intensive Chemotherapy, Including Autologous Stem Cell Transplantation, in the Myelodysplastic SyndroIn: Bennet, JM (ed). MDS: Pathobiology and Clinical Management. New York. Marcel Dekker, Inc. 2002.

ChemotherapyChemotherapy

AML treatmentAML treatmentLow dose ARALow dose ARA--CCTopotecanTopotecanCombo of ARACombo of ARA--C/C/TopotecanTopotecan

Other treatmentsOther treatments

ATG (ATG (AtgamAtgam))-- HypoplasticHypoplastic marrowmarrowCyclosporine Cyclosporine ––HypoplasticHypoplastic marrowmarrowAmifostineAmifostine ((EthyolEthyol))Steroids, androgens, and pyridoxineSteroids, androgens, and pyridoxine

VIDAZA VIDAZA VIDAZA is believed to exert its antineoplastic effects VIDAZA is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the cytotoxicity on abnormal hematopoietic cells in the bone marrow.bone marrow.Hypomethylation of DNA may restore normal Hypomethylation of DNA may restore normal function to genes that are critical for differentiation function to genes that are critical for differentiation and proliferation.and proliferation.Direct cytotoxicity on abnormal hematopoietic cells in Direct cytotoxicity on abnormal hematopoietic cells in the bone marrow causes death of rapidly dividing the bone marrow causes death of rapidly dividing cells, including cancer cells that are no longer cells, including cancer cells that are no longer responsive to normal growth control mechanisms. responsive to normal growth control mechanisms. NonNon--proliferating cells are relatively insensitive to proliferating cells are relatively insensitive to VIDAZA.VIDAZA. VIDAZATM (azacitidine for injectable suspension)

Dosing RegimenDosing Regimen

75 mg/m75 mg/m2 2 azacitidine for 7 days every 28 azacitidine for 7 days every 28 daysdaysDoses greater than 4 Doses greater than 4 mLmL should be divided should be divided into into 2 syringes and administered in different sites 2 syringes and administered in different sites Patients should be prePatients should be pre--medicated for nausea medicated for nausea & vomiting& vomiting

VIDAZATM (azacitidine for injectable suspension)

VIDAZA AdministrationVIDAZA AdministrationDose may be increased to 100 mg/mDose may be increased to 100 mg/m22 if no if no beneficial effect is seen beneficial effect is seen after two treatment after two treatment cyclescycles, and no toxicity other than nausea and , and no toxicity other than nausea and vomiting vomiting Recommend that patients be treated for a Recommend that patients be treated for a minimum minimum of 4 cycles. CR or PR may require more than 4 of 4 cycles. CR or PR may require more than 4 treatment cycles.treatment cycles.Treatment may be continued as long as the patient Treatment may be continued as long as the patient continues to benefit. continues to benefit.

VIDAZATM (azacitidine for injectable suspension)

Nursing Implications of Therapy Nursing Implications of Therapy With VIDAZA™With VIDAZA™

Most common adverse events:Most common adverse events:Nausea and vomiting Nausea and vomiting MyelosuppressionMyelosuppressionInjection site reactionInjection site reactionConstipationConstipation

Nursing Implications of Therapy With Nursing Implications of Therapy With VIDAZAVIDAZA

Nausea and VomitingNausea and Vomiting1/3 will not experience 1/3 will not experience N/VN/V2/3 will2/3 willPremedicatePremedicate with 5with 5--HTHT3 3 ((e.g. e.g. ZofranZofran 8mg 8mg popo x1)x1)30 min prior to dose or 30 min prior to dose or immediately before the immediately before the dosedose95% effective95% effectiveNo delayed N/VNo delayed N/VBreakthrough N/V rareBreakthrough N/V rare

MyelosupressionMyelosupressionPlatelet Nadir: Platelet Nadir:

~Day 7~Day 7--1414ANC Nadir:ANC Nadir:

~Day 14~Day 14--2828HgbHgb Nadir:Nadir:

~Day 7~Day 7--1414

Nursing Implications of Therapy With Nursing Implications of Therapy With VIDAZA™: VIDAZA™: Injection Site ReactionInjection Site Reaction

PruritusPruritusErythema Erythema EcchymosisEcchymosis

Grade 1 (pain or itching Grade 1 (pain or itching or erythema) or erythema)

Grade 2 (pain or swelling Grade 2 (pain or swelling w/inflammation)w/inflammation)

Grade 3 is extremely Grade 3 is extremely rarerare

PruritusPruritus: /grade 1 : /grade 1 (mild or localized)(mild or localized)Antihistamine (OTC) Antihistamine (OTC) cream/lotioncream/lotionOral Antihistamines if Oral Antihistamines if necessarynecessaryCold/warm compress Cold/warm compress 24 hrs post 24 hrs post CaladrylCaladryl cream, Tylenolcream, Tylenol

PruritusPruritus: Generalized: GeneralizedAtaraxAtarax

Nursing Implications of Therapy With Nursing Implications of Therapy With VIDAZA™: VIDAZA™: Injection Site ReactionInjection Site Reaction

ErythemaErythemaMay beMay be mild to mild to moderatemoderate (similar to (similar to a first degree burn)a first degree burn)Skin dries up and Skin dries up and peels offpeels offGets better over Gets better over timetimeApply cool/warm Apply cool/warm compress 24hrs postcompress 24hrs post

EcchymosisEcchymosisDue to Due to thrombocytopeniathrombocytopenia

Patients may applyPatients may applycool compresscool compress

Hold the injection Hold the injection site for 10site for 10--1515minutesminutes

Nursing Implications of Therapy Nursing Implications of Therapy With VIDAZA™:With VIDAZA™:

Allergic ReactionAllergic Reaction1% have had allergic drug 1% have had allergic drug reactionreactionGeneralized Generalized maculopapularmaculopapularrash, rash, pruriticpruritic on trunk, on trunk, arms, legsarms, legsPrednisone 10mg QD x7 Prednisone 10mg QD x7 days each cycledays each cycleGoes away with Goes away with antihistamine and/or antihistamine and/or steroids steroids RechallengedRechallenged all with all with VIDAZA™ VIDAZA™ -- no problemsno problems

ConstipationConstipation50% of patients 50% of patients have constipationhave constipationStart bowel regimenStart bowel regimenIncrease intake of Increase intake of fluids and fiberfluids and fiberStool softener Stool softener ((ColaceColace 100mg 100mg popoTID)TID)

ThalidomideThalidomide

Approved for leprosyApproved for leprosy11stst antiangiogenicantiangiogenic agent evaluated for MDSagent evaluated for MDSPotent inhibitor of angiogenesis through Potent inhibitor of angiogenesis through action of VEGFaction of VEGFMajority of responders are patients with low Majority of responders are patients with low risk diseaserisk diseaseErythroidErythroid responsesresponses

Arsenic TrioxideArsenic Trioxide

FDA approved for relapsed/refractory APLFDA approved for relapsed/refractory APLOrphan drug status for many Orphan drug status for many diseases/MDSdiseases/MDSResponses as single agent Responses as single agent Responses with ARAResponses with ARA--C, ThalidomideC, ThalidomideResponses seen in all cell linesResponses seen in all cell linesFollow ECG (QT prolongation), Potassium, Follow ECG (QT prolongation), Potassium, MagnesiumMagnesium

Agents Under InvestigationAgents Under Investigation

AntiangiogenicAntiangiogenic Compounds:Compounds:CC5013 (CC5013 (RevlimidRevlimid™)™)BevacizumabBevacizumab (Avastin™)(Avastin™)Arsenic trioxide (Trisenox™)Arsenic trioxide (Trisenox™)Receptor tyrosine kinase (RTK) Receptor tyrosine kinase (RTK)

inhibitors (inhibitors (GleevecGleevec))

Agents Under InvestigationAgents Under Investigation

ImmunomodulatoryImmunomodulatory Drugs (Drugs (IMiDIMiD™ ) ™ ) CC5013 (CC5013 (RevLimidRevLimid™)™)COXCOX--2 induction inhibitors (mRNA 2 induction inhibitors (mRNA destabilization)destabilization)

DNA Methylation InhibitorsDNA Methylation InhibitorsDecitabine Decitabine

LenalidomideLenalidomide

New New ––IMID (analog of thalidomide)IMID (analog of thalidomide)5q5q-- syndromesyndromeHigh responsesHigh responsesLow risk patients/FemalesLow risk patients/FemalesFew patients transform to AMLFew patients transform to AMLNeutropenia/thrombocytopenia major side Neutropenia/thrombocytopenia major side effecteffectWaiting for approval by FDAWaiting for approval by FDA