MANAGEMENT OF APLASTIC ANEMIA

Presentor – Dr. Ritika KhuranaModerator – Dr. Sunil Gomber

APLASTIC ANEMIA

One of the types of bone marrow failure syndromes presenting with reduced hematopoeitic cells of all 3 lineages

BM failure syndromes Single cytopenia1. RBC’sDiamond blackfann syndromeCongenital dyserythropoetic anemiaPearson syndromeTransient erythroblastopeniaChronic parvovirus B19 infection2. WBC’sShwachman diamond syndromeKostmann’s syndromeReticular dysgenesis3. PLATELETSCongenital amegakaryocytic thrombocytopeniaThrombocytopenia absent radii syndrome Generalized BM failure

Classification

Inherited - 30%Acquired - 70%

InheritedFanconi’s Anemia – MCDyskeratosis congenitaShwachman diamond syndromeAmegakaryocytic ThrombocytopeniaDiamond blackfann syndromeFamilial Aplastic AnemiasNon-hematolog syndromes Down’s Dubowitz Seckel syndrome

Acquired Idiopathic – MC

Secondary• Radiation• Drugs & chemicals• Infections – EBV, Hep virus, HIV, CMV• Immune diseases - Eosinophilic

fascitis, hypoimmunoglobinemia, SLE• Thymoma• GVHD• PNH• Myelodysplasia

Camitta’s ClassificationMild/Mod(hypoplastic anemia) ANC 500-1500 Platelet count - 20k-1lacSevere aplastic anemia* ANC < 500 Platelet count - <20kVery severe* ANC < 200

*in addition <25% bone marrow cellularity

Pathogenesis

Overproduction of cytokines

progenitor cells shortened telomeresImmune susceptibilityPoor microenvironment (seed and soil theory)

Clinical EvaluationHistory Recent illnesses Medications Exposure to toxins/ Radiation Family h/o bleeding disorders,

malignancies, congenital anomaliesO/E Vitals Ht & Wt Congenital anomalies

InvestigationsCBC, DLCReticulocyte countBM aspiration n biopsySkeletal surveyOthers – LFT, serologic test, flow

cytometry, DEB/ Mitomycin test(chromosome breakage analysis), comet assay, Autoimmune disease evaluation

MANAGEMENT

SUPPORTIVE

DEFINITIVETransfusio

nsTreatment of infections

Bone Marrow TransplantationImmunosupp- ressive Therapy Others 1) Alemtuzumab 2) Hematopoietic

GF’s3) Androgens4) Corticosteroids5) Anti IL2 –

Daclizumab, Eculizumab

TransfusionsPlatelet transfusion if <10000 or Visceral bleedingPlateletpheresis(Single donor platelets)

to be preferredAvoid transfusion from related donor

Role of antibioticsNo role of prophylactic antibioticsFever or documented infection with

severe neutropenia <500

Immunosuppressive therapy

ATG/ALG

Cyclosporine

Combined IST

ATG- antithymocyte globulin

2 types – horse and rabbit ATGImmunization of both by

human thoracic duct lymphocytes or thymocytes

Mechanism – act against T- lymphocytes, downregulating production of IFN gamma, IL2

PrerequisitesSkin testing to be done for

hypersensitivityDouble lumen central catheter Platelet count to be maintained

above 20kDrugs like ß-blockers to be

avoidedAvoid starting on weekends or

late during day

How to administer?DOSE –40mg/kg over 4hrs daily

for 4daysPrednisone 1 mg/kg started on

day1, continued for 2 weeks (prophylaxis for serum sickness)

Premedications – diphenhydramine, acetaminophen

Hydration n supplemental oxygen

Side effects n managementSerum sickness- steroidsRash, fever- diphenhydramine,

acetaminophenRigors- mepiridineInc transaminases – regular

monitoring

Monitoring responseResponse – within first 3 monthsEarliest response – appearance of

granulocytes and nucleated RBC’s

Order of rise – 1. RBC’s ( inc HbF)2. WBC’s3. Platelets

Horse vs Rabbit ATGRabbit ATG more lymphocytotoxicHematologic response to rabbit ATG

(37%) about half that observed with standard horse ATG (68%),

Inferior survival noted in the rabbit ATG arm

Scheinberg P,et al. Horse versus rabbit antithymocyte globulin in acquired aplastic

anemia. N Engl J Med 2011;365(5):430-438.

Cyclosporine Fungal cyclic undecapeptideInhibits T-cell - IL-2, IFN-gammaCyclosporine alone lower response rates n

higher risk of disease progressionBest results seen as combined IST(with

ATG)5yr survival rate- 70%

Rosenfeld SJ, et al.Intensive immunosuppression with antithymocyte globulin and cyclosporine as

treatment for severe acquired aplastic anemia. Blood 1995;85(11):3058-3065

How to administer?Twice daily to maintain trough levels 100-

250ng/mlStarting dose 15mg/kg/dayResponse takes weeks to monthsMinimum trial period should be 3-6mthsIdeally ATG×4days n cyclosporine×6-

12mthsCyclosporine should be gradually tapered

Scheinberg P,  Horse versus rabbit antithymocyte globulin

in acquired aplastic anemia. N Engl J Med 2011;365(5):430-438

Adverse effects n managementHypertension – amlodipineHirsutism Gingival hyperplasia – azithromycinInc creatinine levels – monitoring and

adjusting dose if creat > 2mg/ml – temp cessation n

reintroduction at lower dosesP.carinii pneumonia- monthly

aerosolized pentamidineDev of Clonal hematopoeitic disorders

Definitions Complete response- transfusion

independence, neutrophil count >1500/L, platelet count>1lac n Hb>10g/dl

Partial remission- transfusion independence, Hb by atleast 2g/dl n actual value>8, granulocytes by atleast 500/L, platelets>30k

No response- continued severe aplastic anemia

Refractory SAA – severe pancytopenia 6mths after initiation of IST

Chandra J, et al. Antithymocyte globulin and

cyclosporin in children with acquired aplastic anemia. Indian J Pediatr. 2008 Mar;75(3):229-33

Treatment Failure

20-40% fail to respond to combined IST

Give second course – 77% respond

Patients failing to respond to 2 courses- unlikely to respond to third course

Give trial of androgens, eltromopag, g-csf

Role of steroidsHigh dose steroids not

recommended as 1st lineMethylprednisolone in the dose

2mg/kg/day as 0.5mg/kg/dose 6hrly

Prednisone taper following 8 day course of IV methylprednisolone over total of 15 days

Role of G-CSFG-CSFincreases neutrophil recoveryno increase in trilineage responseFlu like symptomsInc risk of clonal evolutionSeiji Kojima, et al concluded, G-CSF

therapy did not modify long-term hematopoietic recovery and survival in patients with severe and very severe AA

Role of eltromopagThrombopoeitin mimeticIdeally should be ineffective- already high

levelsIn contrast – 40% responded

(bilineage/trilineage)Inc Hb n BM cellularity transfusionsSE – risk of progression to MDS

Young NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology Am Soc Hematol

Educ Program. 2013;2013:76-81

Role of cyclophosphamideUsed in pastEfficacy similar to horse ATGFewer relapse rateBut excessively toxic and inc risk

of fungal infectionsNot recommended anymore

Tisdale JF, et al.High-dose cyclophosphamide in severe aplastic

anaemia: a randomised trial. Lancet 2000;356(9241):1554-1559

Haematopoetic stem cell transplantation<20yrs n HLA matched donors 5yr survival rate 88-97%Matched unrelated donors, unrelated cord blood

survival rate <50%Gupta V, et al.Impact of age on outcomes

after bone marrow transplantation for acquired aplastic anemia using HLA

matched sibling donors.Hematologica. 2010;95(12):2119-2125

StepsHLA matchingPreoperative conditioning regimen

ATG + cyclophosphamide + cyclosporine

Transplantation

ComplicationsGVHDSecondary solid tumorsEffect on growth n developmentEffect on endocrine functionEffect on gonadal functionPreexisting anti HLA antibodies affect

outcome Zhu H, et al. Pre-existing anti-HLA

antibodies negatively impact survival ofpediatric aplastic anemia patients undergoing

HSCT. Clin Transplant. 2014 Aug 14

Keys to a successful transplant

Level of HLA matchingGood conditioning regimen exposure to blood productsUse of leukocyte free productsFludarabine conditioningUse of BM stem cell plants rather than

peripheral blood

Schrezenmeier H, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells

than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired

aplastic ane- mia. Blood. 2007;110(4):1397-1400.

Fanconi’s anemiaMC inherited causeGenes – FANCA, B, C, D99% AR, except FANCB – XLRFaulty DNA damaged response &

genomic instability

Hematopoeitic failure & cancer predisposition

Median age – 7yrsUsual sequence – thrombocytopenia

granulocytopenia

Macrocytic anemiaFrequently terminates into MDS / AMLDiagnosis- chromosome breakage analysisBM – hypocellular & fatty replacement

with degree of peripheral pancytopenia

Congenital anomaliesHyperpigmentation of skinCafe au lait spotsShort statureSkeletal abnormalitiesMale hypogonadismAbnormalities of eyes n earsDevelopmental delayRenal n cardiac anomalies

complicationsRisk of hematological malignancies – 33%

Risk of non-hematological malignancies – 28%

Limb n skeletal abnormalities – 70%

ManagementMild to moderate cytopenia – monitor

counts every 3-4mths n BMA yearlyModerate to severe cytopenia Androgen therapy – oral

oxymetholone, 2-5mg/kg/day, slowly tapered

Response seen in 50% within 1-2mths

Prednisolone 1mg/kg added from day2

G-CSF daily/ every 2days with erythropoeitin given sc or iv 3times/week

Increase ANC, platelets & Hb levels

Allogenic HSCT – only curative treatment

in children < 10yrs, survival rate > 80%

Gene therapy – experimental

THANK YOU