Aplastic Anaemia (bsh 2024)

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 <60 (by an 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

Organomegaly/Lymphadenopathy usually absent

 

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

 

work-up of aplastic anaemia

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

Inherited BM Failure Syndromes

Mycobacterial Infection

 

Inherited BM Failure Syndromes (IBMFS)

 

Fanconi Anaemia (FA)

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

  • 90% pts have BM failure (AA)

  • Increased risk of malignancy

  • DEB Test for chromosomal breakage analysis

 

Dyskeratosis Congenita (DC)

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

  • 80% pts have BM failure (AA)

  • Increased risk of malignancy

  • Telomere length by FISH / PCR

Schwachman-Diamond Syndrome (SDS)

  • SBDS gene mutations

  • Pancreatic insufficiency with cytopenias and recurrent infection

  • ~20% have BM failure (AA)

  • Increased risk of malignancy

Diamond-Blackfan Anaemia (DBA)

  • RSP19 gene mutation (Autosomal dominant)

  • Red cell aplasia in the neonate/infant

  • Associated features: Craniofacial, Skeletal, Cardiac, Urogenital tract

  • Increased risk of malignancy

  • Mx: Steroids, Transfusion, Chelation, BM Transplant

Congenital Dyserythropoietic Anaemia (CDA)

  • Dyserythropoiesis

  • Extra-haematopoietic features are rare

Congenital Amegakaryocytic Thrombocytopenia and Syndromic Thrombocytopenia (CAMT)

  • MPL gene mutations

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

  • Increased risk of malignancy

Severe Congenital Neutropenia (SCN)

  • Neutropenia

  • Extra-haematopoietic features are rare

  • Increased risk of malignancy

GATA2 Deficiency Syndromes

  • GATA2 mutation with lymphedema, immunodeficiency, sensorineural deafness, lung disease

  • Emberger Syndrome = GATA2 mutation with lymphoedema

  • MonoMAC = GATA2 mutation with monocytopenia +/- mycobacterial infection

 

TAR (Thrombocytopenia with Absent Radii)

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

 

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 – Small platelets, macrocytosis, anisopoikilocytosis, neut toxic granulation, may exclude other causes

HbF% - Prognostic indicator in children. May be elevated in IBMFS

B12/Folate

LFT - to detect hepatitis

Viral Serology – Hep A/B/C/E, EBV, CMV, Parvovirus B19, HIV. Note even in posthepatitis AA, virology for known viruses is often negative.

Autoantibodies – ANA, Anti-dsDNA

PNH Screen - Flow for GPI-anchored proteins

Chromosomal breakage analysis - Diepoxybutane (DEB) test. Performed on peripheral blood, consider screening all transplant candidates and siblings of FA patients.

Leucocyte Telomere length - performed on peripheral blood. Classic finding in DC but can be seen in other rare cases

CXR - screen for infection

Skeletal XR’s - for suspected IBMFS

HRCT Chest - to assess for lung fibrosis in suspected IBMFS

Abdo USS – splenomegaly, displaced kidneys (Fanconi)

Echo

HLA Tissue Typing – pre-transplant

Genetic Tests - e.g. NGS panels to help distinguish AA from hypocellular MDS. Note however that somatic mutations present in 20-30% of AA patients.

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/SNP array

  • Cytogenetic abnormalities present in up to 12% of cases

  • (del)13q, Trisomy 8, Monosomy 7

 

management of aplastic anaemia

Supportive Care

 

Red Cell Transfusion

  • Rh and Kell-matched products preferred

  • Irradiated if ATG, Campath or HSCT

  • No specific transfusion threshold, individual plans should be made

  • Alloimmunisation and Iron overload significant problems

 

Platelet Transfusions

  • Irradiated if ATG, Campath or HSCT

  • Not indicated for asymptomatic patients with chronic thrombocytopenia

  • Keep >10 if stable and currently on active therapy

  • 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 (Exjade) are licensed

  • Venesect after successful recovery of counts

  • See also iron chelator details

 

Infection Prevention in Severe Neutropenia

  • Nurse in isolation

  • Quinolone (eg Ciprofloxacin) prophylaxis

  • Itraconazole / posaconazole prophylaxis

  • Aciclovir prophylaxis if on immunosuppression

  • Epo & GCSF are ineffective. GCSF does not improve longterm outcomes

Vaccination

  • Case reports of vaccination triggering primary episodes and relapses of AA

  • Benefit likely to outweigh risk so discuss with patient

  • Wait 6 months after ATG before vaccination due to reduced responses

Psychological Support

 

PNH Clones in Aplastic Anaemia

See also: PNH Page

Principles

  • PNH clone present in 50-60% of AA cases

  • Presence of a large PNH clone makes a diagnosis of IBMFS unlikely

  • Presence of a PNH clone does not directly influence treatment of the AA but additional anti-complement therapy may be required if thrombosis or haemolysis develops

  • All UK pts should be referred to national PNH centre

Monitoring

  • If positive, test every 3 months for one year, then annually if clone stable

  • If negative, test in 6 months and then annually

First line treatment of Severe / Very Severe AA

Age <40:

  • HLA-identical sibling allograft

  • If no sibling donor, consider matched unrelated allograft for children (or for case-by-case adults requiring urgent correction of neutropenia)

  • Alternative, ATG + Ciclosporin +/- Eltrombopag

Age >40:

  • ATG + Ciclosporin +/- Eltrombopag

  • If no response, matched unrelated allograft vs non-transplant options

Age >60:

  • Requires careful assessment of fitness to proceed with ATG

  • Higher rates of dysrhythmias, MI and heart failure

Immunosuppression Therapy (IST)

  

Horse Anti-Thymocyte Globulin (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 (consider increment studies prior to treatment)

  • SE: Fever, rash, rigors, hypo/hypertension, oedema, ARDS, anaphylaxis, serum sickness

  • Long-term SE: 8-25% MDS/AML at 10 years

  • Prospective and meta-analysis data found superiority over rabbit ATG

Ciclosporin

  • 5mg/kg/day, aiming for trough levels of 150-200 ug/l

  • Continue for minimum 12 months and then consider slow weaning

  • Interaction with posaconazole requires pre-emptive dose adjustments

Protocol

  • Give ATG for four days

  • Start Ciclosporin on Day 1

  • 4 weeks prednisolone to prevent serum sickness

  • Infection prevention as per section above

  • GCSF not required

 

Serum Sickness

  • Most common 7-14 days after ATG

  • Arthralgia, myalgia, rash, fever

  • 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

  • Response is delayed - at least 3-4 months on average

  • SAA 6 months response rate 50-70%, VSAA 23%

  • Late events occur in 50% of pts - 35% relapse, 8-25% MDS/AML, 10% haemorrhagic PNH

  • 5 year OS

    • <20 yo: 100%

    • >60 yo: 56%

  • 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

150mg daily from Day 14 until 6 months (or 3 months if achieve a CR)

Improves outcomes when added to ATG + Ciclosporin

Not currently approved in UK for first line use (as of early 2024)

Concern about long term risk of clonal evolution - avoid in pts with monosomy 7, consider BM surveillance.

RACE Trial 2022

  • 1st line ATG + Ciclosporin with or without Eltrombopag

  • 6 mo overall response benefit (68% vs 41%)

  • No difference in 2 yr overall survival

 

Alternative IST to ATG+Ciclo?

Alemtuzumab?

  • Seek expert advice

  • Response rate 35-55% in R/R patients

Do NOT use:

  • Mycophenolate, Sirolimus, Corticosteroids and Cyclophosphamide

Stem Cell Transplant (HSCT)

 

Indications

  • 1st line for SAA <40 yo, with an HLA-matched sibling donor (40-50yo = grey zone)

  • 2nd line if no response to IST, with an HLA-matched, unrelated donor

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

Pre-transplant work-up

  • Repeat BM biopsy and PNH flow

  • Assess co-morbidities

  • Select donor, conditioning regimen and stem cell dose

  • Address fertility issues

  • Offer psychological support

Conditioning Regimens

  • Beyond scope of Haembase. See guideline

Outcomes

  • OS 70-90% in ages 30-50

 

Specific Scenarios

 

Non-Severe AA

  • Poorly defined treatment recommendations

  • Many patients do not require any treatment

  • Consider if: transfusion dependent, progress to severe AA, lifestyle factors

  • If treating, prefer ATG + Ciclosporin (Eltrombopag is not approved)

Elderly (>60 yo)

  • Outcomes worse, tolerability of treatment is poor

  • Consider QoL issues and patients wishes

  • ATG + Ciclosporin if fit

  • Alternatives: Ciclosporin alone, Danazol, Alemtuzumab

  • (NB Danazol has been discontinued in the UK)

 

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

  • Keep platelets >20

  • Focus is on supportive care