Myelodysplastic Syndrome (MDS) (BSH 2021(1) and BSH 2021(2))

Intro

Definition: A group of clonal bone marrow neoplasms characterise by ineffective hematopoiesis, morphological dysplasia, peripheral cytopenias and a variable risk of developing AML

4 per 100,000 per year (>30/100,000/year of >70 y.o.)

Median age at diagnosis: 75 y.o.

2:1 Male:Female

All patients should be offered a review at a regional expert centre given rarity of disease.  

diagnostics

definitions

WHO thresholds for cytopenias:

• Hb <100, Neut <1.8, Plt <100 but higher values do not exclude MDS

WHO-defined diagnosis of MDS:

• Needs to be in context of persistent, unexplained cytopenia

• Either morphological dysplasia in >10% of cells of a single lineage

• Or myeloblasts >5 - <20%

• Or clonality with a typical MDS-associated cytohgenetic abnormality

CHIP (Clonal Haematopoeisis of Indeterminate potential) or ARCH (Age-related clonal haematopoeisis)

• MDS-associated mutations occurring in the absence of any other clinicopathological features of MDS

• Found in >10% of people >70 y.o.

• <1% per year risk of transformation to haem malignancy. ??FBC monitoring

ICUS (Idiopathic Cytopenia of Undetermined Significance)

• Cytopenia(s) lasting >6 months with <10% marrow dysplasia, lacking a clonal abnormality and with no other discernible cause

• 9% at 10 years risk of transformation to myeloid malignancy. ??How to monitor

CCUS (Clonal Cytopenia of Undetermined Significance)

• Cytopenia(s) lasting >6 months with <10% marrow dysplasia, a detectable clonal abnormality which is not considered a presumptive MDS abnormality, and with no other discernible cause

• High risk of eventual transformation to haem malignancy

WHO-HAEM5 Classification

MDS with defining genetic abnormalities

• MDS with low blasts and isolated 5q deletion (MDS-5q). <5% BM, <2% PB blasts. 5q deletion alone, or with one other abnormality that is not monosomy 7 or 7q deletion.

• MDS with low blasts and SF3B1 mutation (MDS-SF3B1). >15% ring sideroblasts can substitute for SF3B1 mutation. <5% BM and <2% PB blasts. Absence of 5q deletion, monosomy 7 or complex karyotype.

• MDS with biallelic TP53 inactivation (MDS-biTP53). <20% BM or PB blasts. 2+ TP53 mutations or one mutation with TP53 copy number loss.

MDS, morphologically defined

• MDS with low blasts (MDS-LB). <5% BM and <2% PB blasts

• MDS, hypoplastic (MDS-h). <5% BM and <2% PB blasts. <25% BM cellularity (adjusted for age)

• MDS with increased blasts

  • MDS-IB1: 5-9% BM or 2-4% PB

  • MDS-IB2: 10-19% BM or 5-19% PB or Auer rods

  • MDS with fibrosis (MDS-f): 5-19% BM or 2-19% PB blasts

Figure 2 on Page 8 of the BSH guideline has an excellent diagnostic flow chart for the previous (very similar) WHO 2016 MDS subtypes.

 Diagnosis

History

• Recurrent infection

• Alcohol intake

• Prior chemo/radiotherapy exposure

• FHx of MDS/AML or pulmonary/liver fibrosis

• Social/Occupat./Environmental deficiencies or exposures to benzenes, copper, zinc, selenium, lead, B6

Examination

• Dysmorphic features

• Splenomegaly, bruising, bleeding, infections, skin lesions

Bloods

• FBC, Film, Reticulocytes, LDH, B12, Folate, Ferritin, DCT, U&E, LFT

• Hep B/C, HIV

Marrow Morphology/Histology

• MGG stain with assessment of 500 cells inc. 30 megakaryocytes – dysplasia should be present in at least 10% of cells of relevant lineage

• Blast %

• Iron stain (Prussian Blue / Perls) - >15% ring sideroblasts for MDS-RS (or >5% if SF3B1 mut. present)

• Trephine - Cellularity, Fibrosis (reticulin stain)

• Haematology 2018 Review Article - illustrated review of the specificity of various dysplastic marrow features for the morphological diagnosis of MDS.

Flow Cytometry

• Optional - may assist in assessing myeloblast %

Cytogenetics

• Abnormalities detected in approx. 50% of MDS cases

• Karyotyping should be attempted on all cases, and on at least 20 metaphases if no abnormality detected

• FISH can assess for selected common abnormalities - e.g. -7, del(5q), +8

• Single Nucleotide Polymorphism (SNP) analysis is a further alternative

• MDS-defining abnormalities in a cytopenic patient = -5, del(5q), -7, del(7q), i(17q)

• (Full list of other, less common, MDS-defining abnormalities can be found in Fig 1. the guideline)

Molecular Genetics

• Genetic mutations identified in 90% of cases, some with prognostic significance

• Next Generation Sequencing (NGS) using targeted panels now widely available and should be considered for all patients

• Patients should be consented for testing due to possibility of detecting germline mutations

• Detection of mutations alone is not diagnostic of MDS as can occur in otherwise healthy individuals

• Some specific uses

  • SF3B1 mutation - >95% of MDS-RS cases, favourable prognosis

  • TP53 mutation occuring in isolated del(5q) predicts poorer prognosis

  • Future trial criteria, e.g. for targeted therapies

Further Investigations to consider (i.e. exclusion of other causes)

• Epo level

• PNH screen

• Fanconi anaemia screen

• Mutational analysis if constitutional cause suspected

• HLA typing of patient and siblings if transplant considered

• Virology - HIV, Hep B/C/E, Parvo, CMV

• Red cell extended phenotyping if chronic transfusion expected

• JAK2 if MPN/MDS overlap suspected

• Copper levels

Prognostics

IPSS-R

IPSS-R designed for use at diagnosis & the recommended scoring system for prognosis

(but there are pragmatic considerations - the NICE approval for azacitidine is based on IPSS)

The WHO WPSS can be used at any time during the course of the disease

 IPSS

Assesses outcomes for untreated, primary MDS in adults

Therapy sometimes guided by IPSS (based on blast % / karyotype / No. of cytopenias) , not IPSS-R

Low risk patients = IPSS Low / Intermediate 1 (INT-1)

High risk patients = IPPS INT-2 / High

IPSS-M

Score developed to factor in molecular results (NEJM 2022)

Online calculator (also calculates IPSS and IPSS-R)

management

Supportive Care

Transfusion

• Transfusion-dependence predicts poorer prognosis and lower Quality of Life (QoL) scores

• Irradiated products after ATG or transplant

• Transfuse to correct symptomatic anaemia and improve QoL, individualised decisions to transfuse

• Consider extended phenotyping for those on chronic transfusion programme

Neutropenia + Infection

• GCSF in low risk disease with recurrent infections, or to support therapy (e.g. azacitidine)

• Antifungal prophylaxis if receiving active treatment

Thrombocytopenia + Active bleeding

• Routine prophylactic transfusion may be appropriate in recurrent bleeding

• But not required in stable non-bleeding patients regardless of absolute count

• TXA, esp for mucous membrane bleeding

• ?TPO Agonists. Current trial ongoing of eltrombopag for low/Int-1 with plt count <30

Spiritual and Emotional health needs

• Rare disease, difficult to understand, many treatments, poor outlook

• Involve specialist nurses, re-discuss diagnosis regularly with patient

• Offer patient support groups

Low Risk MDS (IPSS Low/int-1, IPSS-R 3.5 or below)

General Approach

Discuss potentially eligible patients w/ allogeneic transplant team early after diagnosis, as early HSCT preferred

Non-transplant options include:

• Supportive Care

• ATG + Ciclosporin - consider in patients <60 y.o. with normal karyotype or trisomy 8

• Lenalidomide - consider in 5q- and 1 or fewer other karyotypic abnormalities

• Erythropoietin - add GSCF in siderolblastic variants. Stop after 16 weeks if no response

Consider iron chelation in some low risk patients with a very good prognosis – Desferrioxamine preferred due to experience of use

Eyrthopoietin Stimulating Agents (ESA)

• Offer to patients with IPSS Low/Int-1 + symptomatic anaemia or Hb <100 and Nordic score is 0 or 1

• Start soon after diagnosis and before established transfusion dependence

• Maximum 24 week trial - 8 wks initial dose, 8 wks higher dose, 8 wks with GCSF added

• EPO-alpha 30,000 units/week, rising to 60,000/week

• Darbepoetin 150ug/week, rising to 300ug/week

• Continue if complete or partial response achieved

• Complete response: Hb >115 and transfusion independent

• Partial response: Hb rise by >20 and transfusion independent but remains <115

• Nordic Score: 1 point each for 2+ units RBC/month and serum EPO >500u/l

Luspatercept

• Erythroid maturation agent. SC injection every 3 weeks. MEDALIST trial.

• No market authorisation in UK at present (2021)

Iron Chelation

• 2o end organ damage from iron accumulation is the main non-leukaemic cause of death in MDS

• Consider chelation for low/Int-1 risk patients after 20 units RBC or ferritin >1000 or prior to allograft

• See the Iron Overview page for information on chelation drugs

MDS-5q

(Diagnostic note: One additional cytogenetic abnormality is allowed except for chromosome 7 abnormalities, which carry a very poor prognosis. Also, MDS-IB trumps 5q- diagnosis)

Typically presents as refractory anaemia in older women with macrocytosis, thrombocytosis and non-lobulated megakaryocytes (micromegakaryocytes).

Relatively indolent natural history. Median OS 6 years in IPSS score 0 patients.

Low dose lenalidomide (5-10mg) induces a durable transfusion independency in ~60% patients within 6-8 weeks (MDS004 Study). May induce a complete cytogenetic response (CCyR).

Even during CCyR during lenalidomide therapy, morphology demonstrates persistence of non-lobated micomegakaryocytes. These patients can have a treatment holiday, and re-starting lenalidomide at relapse then still effective.

Rare presentation: Granulocytic sarcomas with 5q-. Responds well to low dose SC Ara-C.

Other Good Prognosis Cytogenetic Subtypes

SF3B1 mutation in MDS with Ring Sideroblasts (MDS-RS) and MDS/MPN with ring sideroblasts and thrombocytopenia (MDS/MPN-RS-T)

High Risk MDS (IPSS int-2/high, IPSS-r >3.5/high/very high)

General Approach

High risk patient group with median OS 0.8-1.6 years

Transplant eligible patients

• Early HSCT - Consider precede by induction chemotherapy if >10% blasts or hypercellular bone marrow

Transplant ineligible patients

• Offer trial where available

• Intensive chemotherapy - consider if good PS, minimal co-morbidities, no high risk karytopic abnormalities. Remission rates 40-60%, lasting a median of 10-12 months.

• Azacitidine - 45% transfusion independence, improve QoL and 2yr OS benefit (AZA001 study)

Other Poor Prognosis Cytogenetic Subtypes

SRSF2 mutation in MDS with Ring Sideroblasts

TP52 mutation adds poor prognosis in all MDS subtypes.

SYNDROMES ASSOcIATED WITH MDS

N.B. Not a comprehensive list and beyond the scope of FRCPath exams. But interesting!

VEXAS Syndrome (NIH website & Blood 2021)

Acquired mutation in UBA1 gene (often included in myeloid NGS panels), on the X chromosome, which codes for E1 ubiquitin activating enzyme. Normal function of the enzyme is in regulation of proteins involved in cell division, immune responses and much more.

Causes bone marrow failure and autoinflammation (Skin, cartilage, lungs, joints, vascular)

VEXAS

• Vacuolated myeloid and erythroid precursors on BM morphology

• E1 ubiquitin activating enzyme (coded for by UBA1)

• X chromosome

• Autoinflammation

• Somatic mutation