Aplastic Anaemia (BCSH 2015 + 2017 amendment)

Pancytopenia with a hypocellular marrow & no abnormal infiltrate or fibrosis

Camitta Criteria requires >2 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

 

Assess Severity: Modified Camitta Criteria

 

Severe Aplastic Anaemia (SAA)

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

-       >2 or more of:

o   Neut <0.5

o   Plt <20

o   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 infectious 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 Diagnosis 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.

 

Schwann-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 à 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

o   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

o   <20 yo: 100%

o   >60 yo: 56%

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

-       Factors predicting a good outcome

o   Young age, less severe disease

o   Retic >25, Lymph >1.0

o   Trisomy 8 or del(13q)

o   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 not 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 3x106 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

-       3rd choice – 9/10 unrelated HSCT

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