Aplastic Anaemia (BSH 2015 + 2017)

Pancytopenia with a hypocellular marrow & no abnormal infiltrate or fibrosis

Camitta Criteria requires 2 or more of: Hb <100, Plt <50, Neut <1.5

 

Intro

 

2-3 cases per million per year in Europe (higher incidence in East Asia)

70-80% Idiopathic

Two peaks at 10-25 yo and >60 yo

 

Assessing Severity: Modified Camitta Criteria

 

Severe Aplastic Anaemia (SAA)

  • <25% BM cellularity (or 25-50% with <30% haematopoeitic cells)

  • 2 or more of:

    • Neut <0.5

    • Plt <20

    • Reticulocytes <20 (or <60 by automated count)

 

Very Severe Aplastic Anaemia (VSAA)

  • As for SAA but Neutrophils <0.2

 

Non-Severe Aplastic Anaemia (NSAA)

  • Not meeting criteria for SAA or VSAA

 

Clinical Presentation

 

Anaemia and thrombocytopenia symptoms more common than infections at the start

 

Precipitants:

  • Preceding history of jaundice --> ?Post-Hepatic AA – rare. Occurs 2-3 months after illness

  • SLE – pancytopenia in SLE may be due to AI, fibrosis or more rarely AA

  • Drugs – Chloramphenicol, Carbamazepine, Phenytoin, Quinine

  • Occupation History – Benzenes, Radiation

  • Family History – see later for congenital syndromes

 

Differential Dx of pancytopenia with a hypocellular marrow

 

Aplastic Anaemia

PNH

Hypoplastic MDS

Hypoplastic AML

Lymphoma – e.g. Hairy Cell

Myelofibrosis

Anorexia / Starvation

Drug Induced

Congenital BM Failure Syndromes

Mycobacterial Infection

 

Congenital BM Failure Syndromes

 

Fanconi Anaemia

  • Short stature, skin hypo/hyperpigmentation, Skeletal abnormalities (e.g. thumb)

  • DEB Test for chromosomal breakage analysis

 

Dyskeratosis Congenita

  • Triad: Nail dystrophy + Oral Leukoplakia + Skin reticular pigmentation

  • Telomere length by FISH / PCR

 

Emberger Syndrome

  • GATA2 mutation with lymphedema

 

TAR (Thrombocytopenia with Absent Radii)

  • Other bones of forearm also affected. Asscoiated with cow’s milk intolerance

 

MonoMAC

  • Moncytopenia with mycobacterial infection

  • Overlap with Emberger

  • GATA2 mutation.

 

Schwachman-Diamond

  • Pancreatic insufficiency with cytopenias and recurrent infection

 

Diamond-Blackfan Anaemia

  • Red cell aplasia in the neonate/infant

  • RSP19 gene mutation

 

Congenital Amegakaryocytic Thrombocytopenia

  • Isolated severe thrombocytopenia from birth, BM failure later in childhood

  • MPL gene mutation

 

Investigations

 

AA is a diagnosis of exclusion, tests listed aimed at ruling out other causes.

 

FBC – Lymphocyte count often normal. If monocytopenia, think Hairy Cell / GATA2

Reticulocyte count

Film – macrocytosis, anisopoikilocytosis, may exclude other causes

HbF% - prognostic indicator in children

B12/Folate

LFT

Viral Serology – Hep A/B/C, EBV, CMV, Parvovirus B19, HIV

Autoantibodies – ANA, Anti-dsDNA

PNH Flow

Chromosomal breakage analysis / Telomere length / Lymphocyte subsets

CXR

Skeletal XR’s

HRCT Chest

Abdo USS – splenomegaly, displaced kidneys (Fanconi)

Echo

HLA Tissue Typing – pre-transplant

Next Generation Sequencing (NGS) – to find cryptic mutations. Takes 2-4 months.

 

BM Features of AA

 

Aspirate

  • Hypocellular trails with prominent fat spaces

  • Dysplastic red cells are common and can be marked

  • Megakaryocytes and Granulocytes reduced, but not dysplastic

  • Haemophagocytosis & increased macrophage numbers seen in early disease

  • Eosinophilic background staining

Trephine

  • Hypocellular

  • Focal hyperplasia of erythroid or granulocytic cells all at same stage of maturation

Cytogenetics/FISH

  • Cytogenetic abnormalities present in up to 12% of cases

  • (del)13q, Trisomy 8, Monosomy 7

 

Supportive Care

 

Transfusion

 

Rh and Kell-matched products

Irradiated if ATG, Campath or HSCT

 

Red Cells

  • No specific threshold

  • Alloimmunisation and Iron overload significant problems

 

Platelets

  • Not indicated if stable, off treatment

  • Keep >10 if stable, on treatment

  • Keep >20 during ATG treatment

  • Keep >20 in sepsis

  • HLA alloimunisation —> platelet refractoriness and increased graft rejection post HSCT

 

Iron Chelation

  • Patient-by-patient decision

  • Desferrioxamine and Deferasirox are licensed

  • Venesect after successful recovery of counts

 

Infection Prophylaxis

  • Mouthwash

  • Neutropenic diet

  • Ciprofloxacin

  • Itraconazole / posaconazole

  • (Septrin not routinely required)

 

Immunosuppression Therapy (IST)

 

Horse ATG + Ciclosporin

 

Indications

  • 1st line for NSAA who are transfusion dependent, bleeding, infections or for lifestyle

  • 1st line for SAA/VSAA if no HLA-matched sibling, or patient is older than 35-50 years.

  • No upper age limit but mortality increases in >60 yo’s

 

Horse ATG

  • 40mg/kg/day for four days

  • Must be given into a central vein

  • Give test dose due to risk of anaphylaxis

    • Methylprednisolone + Piriton prior to each dose

  • Keep platelets >20 prior to each dose

 

Protocol

  • Give ATG for four days

  • 4 weeks prednisolone to prevent serum sickness

  • Start Ciclosporin with target level 100-200 ug/l and continue to minimum 12 months

  • GCSF not required

  • Future care: Avoid vaccination (known trigger for relapse)

 

Serum Sickness

  • Most common 7-14 days after ATG

  • Treat with QDS hydrocortisone

 

Assessing Response (SAA)

  • None – still meets severe disease category

  • Partial – transfusion independent, no longer in severe category

  • Complete – normal Hb, Neut >1.5, Plt >150

 

Outcomes

  • 6 months response rate approx. 70%

  • 5 year OS

    • <20 yo: 100%

    • >60 yo: 56%

  • 35% relapse, 15% MDS/AML, 10% haemorrhagic PNH

  • Factors predicting a good outcome

    • Young age, less severe disease

    • Retic >25, Lymph >1.0

    • Trisomy 8 or del(13q)

    • Presence of PNH clone

 

Eltrombopag

 

Small molecule, oral thrombopoeitin receptor agonist

Small trials have shown a 40% response rate

Concern about long term risk of clonal evolution

 

Stem Cell Transplant (HSCT)

 

Indications

  • 1st line for SAA <50 yo, with an HLA-matched sibling donor

  • 2nd line if no response to IST, with a matched, unrelated donor

  • Syngeneic donor – consider at any age as long term OS is >90%

 

Pre-transplant work-up

  • Repeat BM biopsy and PNH flow

  • Assess co-morbidities

  • Conditioning regimen

  • Stem cell dose – minimum 3x10e6 CD34+ cells per Kilogram

  • Address fertility issues

 

Outcomes

  • OS 70-80% in ages 30-50

 

Specific Scenarios

 

Elderly

 

Outcomes worse, tolerability of treatment is poor

Consider QoL issues and patients wishes

ATG + Ciclosporin if fit

Alternatives: Ciclosporin alone, Danazol, Alemtuzumab

 

Pregnancy

 

1st presentation may occur in pregnancy, and may spon. Remit post delivery

Relapse post-IST is common in pregnancy

50% of pregnancies in patients post-IST involve a maternal complication

Ciclosporin is safe in pregnancy

Focus is on supportive care

 

PNH in AA

 

Small clones occur in 50% of AA patients, and may vary over time. Uncertain significance.

Test by flow cytometry at diagnosis

  • If negative, test 6 monthly for 2 years then annually

  • If positive, test 3 monthly for 2 years and reduce frequency only if stable leve

  • Register with national PNH service

 

Children (2017 amendment)

 

Investigate and workup as for adults

1st line treatment for SAA

  • 1st choice – matched, sibling HSCT

  • 2nd choice – 10/10 unrelated HSCT or Immunosuppressive Therapy (IST)

  • 3rd choice – 9/10 unrelated HSCT

  • 4th choice (any order) – 2nd course of IST, Androgens, Alemtuzumab, Eltrombopag, other HSCT sources (haploidentical, cord blood)