HIS24 Myelodysplatic Syndrome (MDS) And Myeloproliferative Neoplasm (MPN): Principles Of Diagnosis And Management Flashcards
Classification of Myeloid neoplasms and Acute leukaemia
- ***MPN
- ***MDS
- ***MDS/MPN
- ***AML and related precursor neoplasms
- Mastocytosis
- Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1, PCM1-JAK2
- Myeloid neoplasm with germline predisposition
Myelodysplastic syndrome (MDS)
Clonal (neoplastic, from 1 cell) haematological disorder associated with ineffective haematopoiesis, cytopenia (NOT proliferative), propensity of clonal progression to AML
Ineffective haematopoiesis: 記住: ***Hypercellular BM but Cytopenia
Key features:
- Cytopenia >= 1 lineage (Erythroid, Myeloid, Megakaryocytes)
- Hypercellular BM —> but abnormal/dysplastic cells undergo premature apoptosis —> Cytopenia
- Morphologic dysplasia >= 1 lineage
- +/- Increase in blasts of myeloid lineage (<20%) —> immature cells / blasts may increase —> ***progress to AML
Male preponderance (2:1) with incidence increasing after 5th decade of life (median age at presentation ~75 yo)
MDS typical presentation
- Incidental finding of cytopenia >=1 lineage
- Symptoms / Complications in relation to cytopenia >=1 lineage
- In symptomatic patients, ~90% have significant Macrocytosis (>100 fl) at presentation
Classification of MDS
Low-grade MDS (Dysplasia without excess blasts)
- ***blast <5% (BM, PB)
- ***no high risk karyotype / cytogenetics
- indolent in presentation
- main problem is cytopenia
- lower risk of progression to AML (usually <10%)
- survival variable depending on subtype
High-grade MDS (Dysplasia with excess blasts and/or high risk cytogenetics)
- ***blast 5-19% (BM, PB)
- ***high risk karyotype / cytogenetics
- more symptomatic (more severe cytopenia)
- high risk progression to AML within 2 years (>50%) —> Pre-leukaemia
- poor long term survival
Aims of investigations for MDS
- Exclude alternative and reversible causes (of cytopenia)
- Confirm diagnosis - demonstrate ineffective haematopoiesis + dysplasia +/- increase in blasts + ***confirm clonality (genetics / molecular)
- Prognosis
- Fitness to treatment, esp. for high risk patients
***Investigations for suspected MDS
- CBC with blood film review + D/C
- look for dysplasia, cytopenia - Reticulocyte count
- often low - Serum active vit B12, folate (serum + red cell)
- excluded B12, folate deficiency - LFT, RFT, LDH
- Other investigations: depending on clinical context guided by history, physical examinations depending on preliminary CBC and other findings
- e.g. exclude end-stage liver disease
Diagnostic investigations (after excluding obvious alternative causes): 1. BM aspiration, Trephine biopsy
- BM aspiration for cytogenetic, molecular studies —> to prove clonality
Prognostic factors for MDS
- ***Cytopenia severity
- ***BM blast %
- ***Cytogenetics (Karyotype + Gene mutations)
- Performance status
- Timely treatment and good supportive care
***Principles of treatment of MDS
Low-grade MDS / R-IPSS very low to intermediate risk MDS
1. Supportive (e.g. transfusion)
2. Erythropoietin-stimulating factors (ESA)
3. G-CSF (for Granulopoiesis)
—> main aim to stimulate erythropoiesis
(- Lenalidomide for 5q deletion syndrome (rare)
- TGFβ targeting (Luspatercept))
High-grade MDS / R-IPSS intermediate to very high risk MDS
1. **Hypomethylating agents (Azacitidine, Decitabine)
—> only prolong survival and delay progression to AML
2. **Allogeneic HSCT in young and transplant-eligible patients
—> only modality proven to have long term cure
Hypomethylating / Demethylating agents MOA
Pathogenesis:
Abnormal DNA methylation
—> Inactivation of tumour suppressor genes / genes responsible for transcription
—> Leukaemogenic / Stopped transcription
MOA: Decitabine/Azacitidine Incorporate into DNA/RNA respectively 1. ***Inhibit DNA methyltransferase —> Induce DNA ***hypomethylation —> ***Reactivation of silenced genes (esp. tumour suppressor genes)
- Block protein, DNA synthesis
—> ***Cytotoxicity - Block DNA synthesis
—> ***Inhibit cellular proliferation
Case 1:
- 80 yo
- retired teacher, non-smoker, non-drinker
- hypertension, hyperlipidaemia well controlled
- fresh per-rectal bleeding, anaemic symptoms for 4 weeks
- Hb: 5.1
- WBC: 1.8
- Platelet count: 56
- MCV: 115
- last blood test in 2016 showed normal blood counts
- pallor
- LN, liver, spleen not palpable
- external haemorrhoids on per-rectal exam
- Hb: 5.1 —> Low
- WBC: 1.8 —> Low
- Platelet count: 56 —> Low
- MCV: 115 —> High (Macrocytosis)
- 2016 normal —> Acquired condition
- Over a month —> Insidious
- LN, liver, spleen not palpable —> ***Consistent with MDS
Differential diagnosis of Pancytopenia with significant Macrocytosis (MCV>110):
- ***MDS
- ***Pernicious anaemia (a type of Megaloblastic anaemia, organ-specific autoimmune disease —> Ab against intrinsic factor for B12 absorption in terminal ileum —> B12 deficiency)
- Acute leukaemia (occasionally) (esp. elderly AML / AML with MDS-related changes)
Investigations:
1. PB blood film
- RBC:
—> Macrocytosis
—> Absent Polychromasia (i.e. Recticulocytopenia —> production problem)
- WBC:
—> Leukopenia
—> Hypolobated neutrophils, No hypersegmented neutrophils (***Hypersegmented —> B12 folate deficiency)
—> Hypogranular neutrophils
—> Pseudo Pelger-Huet anomaly
—> Abnormally lobulated neutrophil
—> Circulating blasts (2%) with no Auer rod
- Platelets:
—> Thrombocytopenia with no platelet clumps
- Conclusion: Pancytopenia + Dysplastic features + Occasional circulating blasts
3. LRFT, LDH —> Normal
4. Clotting profile —> Normal
5. Serum active B12, Serum and Red cell folate —> Normal
Diagnostic investigation:
1. BM aspirate
- Markedly hypercellular BM
- Erythroid:
—> Erythropoiesis increased
—> Marked N:C asynchrony (usually synchronised development)
—> Ring sideroblasts on Fe stain (abnormal incorporation of Fe / abnormal Fe complex)
—> Bilobed Erythroid cells (usually 1 single nuclei)
- Myeloid:
—> Hypolobated / Abnormally lobated myeloid series (4%)
- Megakaryocytes:
—> Micromegakaryocytes
—> Separate nuclei + Hypolobated (usually hyperlobated)
- Conclusion: Hypercellular BM, Trilineage dysplasia, Leukaemic blasts
Diagnosis:
- MDS (∵ Cytopenia + Hypercellular BM) with multilineage dysplasia and ring sideroblasts
Further investigation:
- Cytogenetics —> Complex karyotype with del(5)(q13q33), del(9)(q22q32), -7, -13, -14
—> very poor risk by R-IPSS
Treatment:
- Started on Azacitidine in view of good performance status
Differential diagnosis of Pancytopenia with significant Macrocytosis (MCV>110)
- ***MDS
- ***Pernicious anaemia (a type of megaloblastic anaemia, organ-specific autoimmune disease —> Ab against intrinsic factor for B12 absorption in terminal ileum —> B12 deficiency)
- Acute leukaemia (occasionally) (esp. elderly AML / AML with MDS-related changes)
Myeloproliferative neoplasm (MPN)
Clonal HSC disorder characterised by **proliferation of >=1 haematopoietic lineages in BM/PB
—> **NO premature apoptosis (vs MDS)
—> ***NO cytopenia
Key features:
- Increased circulating cells
- Hypercellular BM
- Absence of myelodysplastic features
Cause:
- Driver mutation / Gene fusion activate ***Tyrosine kinases (e.g. JAK kinase) + Cytokines signalling
Classification of MPN
Philadelphia chromosome +ve:
**1. Chronic myeloid leukaemia
- defined by **BCR-ABL1-positive (t(9;22)(q34.1;q11.2): ***Philadelphia chromosome +ve) (BCR-ABL-1-negative does not exist!!!)
—> translocation of gene from chromosome 22 to 9
(100% of CML with BCR-ABL1-positive)
Philadelphia chromosome -ve MPNs:
- **2. Polycythaemia Vera (JAK2 V617F)
- **3. Primary myelofibrosis (JAK2, CALR, MPL)
- **4. Essential thromobocythaemia (JAK2, CALR, MPL)
5. Chronic neutrophilic leukaemia
6. Chronic eosinophilia leukaemia, NOS
7. MPN, unclassifiable
(***ALL can progress to AML!!!)
CML, BCR-ABL1+
***Triphasic disease (defined by blast % in BM/PB):
1. Chronic phase (CP) (<10%)
2. Accelerated phase (AP) (10-19%)
3. Blast phase (BP) (>20%)
—> AP, BP rarely seen in modern era due to Tyrosine kinase inhibitors
CP:
- 50% asymptomatic at presentation
- Fatigue, weight loss, fever
- ***Splenomegaly
- CBC findings:
—> Leukocytosis (very high)
—> Left shift with entire myeloid series on PB + **Bimodal prominence of **Neutrophils and **Myelocytes
—> **Absolute Basophilia
—> **Anaemia (intense proliferation of myeloid / megakaryocytes lineage —> suppressed erythropoiesis)
—> **Thrombocytosis
—> Blasts not increased (<2%) - BM findings:
—> Hypercellular with increased Myeloid:Erythroid ratio
—> Blasts <10%
—> Entire myeloid series with ***Bimodal prominence
—> Increased small + hypolobated megakaryocytes
Diagnostic investigations for CML
- BM, PB morphology
- Cytogenetic, FISH (for t(9;22): ABL: chromosome 9, BCR: chromosome 22)
- Quantitative real-time PCR (to detect BCR-ABL1 for diagnosis and disease monitoring)
***Treatment of CML
- Tyrosine kinase inhibitors (x rmb):
- 1st generation: ***Imatinib
- 2nd generation: Nilotinib, Dasatinib
- 3rd generation: Ponatinib (only for T315l kinase domain mutation)
MOA:
Inhibitor of BCR-ABL1
—> binds to kinase domain (ATP binding domain) of ABL1
—> ATP cannot bind
—> cannot donate phosphate group for subsequent effector function, proliferation
- Allo-HSCT
- only indicated in AP, BP of CML
Polycythaemia Vera
- Slight male preponderance
- Median age 55-60
***記: Leukocytosis + Polycythaemia + Thrombocytosis
CBC (***Panmyelosis: ↑ ALL 3 lineages):
- ↑ Hb, Haematocrit, RBC
- ↑ WBC
- ↑ Platelet
Cytogenetics: JAK2 V617F
Presentations:
1. Fatigue, Aquagenic pruritis (∵ cytokines ↑)
- Mild - moderate splenomegaly (70%) + hepatomegaly (40-50%)
- Secondary to vascular disturbances and ↑ red cell mass (e.g. numbness of hands, feet due to microvascular obstruction, arterial thrombosis, stroke, AMI, VTE, embolisms)
- Gout (high uricaemia due to high cell turnover, uric acid release from cells)
—> May progress into secondary Myelofibrosis (Post-PV MF)
Essential thrombocythaemia
- Another peak in women at 30
- Median age 50-60
- 30-50% asymptomatic, present with incidental finding of abnormal blood counts
***記: 齋Thrombocytosis
CBC:
- Marked isolated ***Thrombocytosis + Platelet anisocytosis
- Hb normal
- WBC usually normal / mildly ↑
Cytogenetics: JAK2, CALR, MPL
- Symptoms:
1. Vascular disturbances
- **Thrombotic / haemorrhagic episodes (↑ platelet dysfunction, abnormal platelet adhesion, **consumption of von Willebrand factor —> ***aVWD)
- Mild splenomegaly occur in 15-20%
—> May progress into secondary Myelofibrosis (Post-ET MF)
Primary myelofibrosis
- Both genders affected
- Median age: 65-70
- Insidious onset
- Symptoms depend on phase of disease
***記: Leukocytosis + Anaemia + Thrombocytosis
CBC:
- Leukocytosis (**Myeloid)
- **Anaemia
- Thrombocytosis (Megakaryocytes) (late stage MF: Thrombocytopenia)
- **Leukoerythroblastic blood picture (∵ Fibrotic BM —> Proliferation of myeloid cells —> push immature WBC + RBC into PB)
—> **Tear-drop poikilocytes (RBC pass through abnormal BM sinusoids / splenic sinusoids —> squeeze out)
- Late stage: Pancytopenia
Cytogenetics: JAK2, CALR, MPL
Features:
- Clonal proliferation —> Splenomegaly, Anaemia
- ***Bone marrow stromal changes (∵ stimulation of marrow fibrosis) —> Coarsening of reticulin fibres + Collagen fibrosis + Thickened trabecular bone
- Secondary inflammatory state (∵ ***Hypercytokinemia) —> Constitutional symptoms, cachexia
Presentation:
- ***↑ BM fibrosis —> suppress erythropoiesis
- ***Constitutional symptoms, Anaemic symptoms, Massive splenomegaly (∵ Hypercytokinemia)
- ***Hypercytokinemia —> suppress erythropoiesis
- ***Markedly ↑ LDH (∵ cellular proliferation)
Aims of investigations for PV, ET, MF
- Morphologic diagnosis by PB and BM
- Proof of clonality (by cytogenetic, molecular studies)
- Exclusion of CML BCR-ABL1+ (some CML have isolated thrombocytosis)
- Exclusion of reactive causes (esp. for ET/MF without somatic mutations)
- Prognostic assessment (***risk of thrombosis in PV, ET, survivals for MF)
***Investigations for MPN
General investigations
- History, P/E (spleen, liver size, assessment of thrombotic/haemorrhagic events, CV risk factors, medical history)
- CBC with D/C + Blood film review
- LRFT, LDH, urate
- EPO level (suppressed in PV)
- Clotting profile + Exclusion of aVWD (esp. extreme thrombocytosis with bleeding tendency)
- Hep B, C serology (for treatment)
- CXR
- Investigations to exclude reactive causes
Diagnostic investigations
- BM exam, Trephine biopsy
- Cytogenetic analysis
- Molecular studies (JAK2, CALR, MPL, BCR-ABL1 to exclude CML)
Risk factors for thrombosis in PV and ET
High risk of thrombosis in PV:
- Age >60
- History of thrombosis
- CVS risk factors
High risk of thrombosis in ET:
- Age >60
- History of thrombosis
- CVS risk factors
- JAK2V617F
PMF risk assessment
Genetically-inspired IPSS (GIPSS)
Other systems:
MIPSS70
MPN disease burden and treatment
- Vascular complications (i.e. risk of thromboembolism)
- Antiplatelet for managing risk
- Cytoreduction for maintaining normal Hct, platelet etc. - Organomegaly + Symptoms
- JAK/STAT inhibition (Ruxolitinib) (esp. PMF ∵ most symptomatic)
- Cytoreduction (Hydroxyurea and IFN) - Disease progression and survival
- JAK/STAT inhibition (Ruxolitinib)
- Cytoreduction (Hydroxyurea and IFN)
- Allo-HSCT (***PV, ET does NOT require HSCT unless progress to MF)
MOA of Ruxolitinib in MF
JAK2 inhibitor —> inhibit Clonal proliferation + Cytokine proliferation 1. Control constitutional symptoms 2. Control organomegaly 3. Stabilising marrow fibrosis
Treatment of Low-risk and High-risk PV
Low-risk PV:
- Low-dose aspirin
- Phlebotomy (Venesection) to maintain Hct <45%
- Manage CVS risk factors
- Monitor for new thrombosis / bleeding
- Evaluate indications for cytoreductive therapy
- Monitor signs/symptoms of disease progression
High risk PV:
- Low-dose aspirin
- Phlebotomy to maintain Hct <45%
- Manage CVS risk factors
- Monitor for new thrombosis / bleeding
- Hydroxyurea / Peg-IFNα 2A (suppress proliferation, immunomodulation, promote apoptosis) (based on age and patient-specific variables)
- Monitor for response and signs/symptoms of disease progression
- Adequate response —> continue treatment
- Inadequate / loss of response —> change of cytoreductive therapy
Treatment of very low, low, intermediate, high-risk ET
Very low, Low, Intermediate risk ET:
- Aspirin
- Manage CVS risk factors
- Monitor for new thrombosis, disease-related major bleeding
- Monitor for acquired vWD
- Monitor signs/symptoms of progression
- Evaluate indications of cytoreductive therapy
- Asymptomatic —> continue Aspirin
- Symptomatic with indications of cytoreduction —> start cytoreductive agents
High-risk ET:
- Aspirin
- Manage CVS risk factors
- Monitor for new thrombosis, disease-related major bleeding
- Monitor for acquired vWD
- Monitor signs/symptoms of progression
- Hydroxyurea / Peg-IFNα 2A +/- Anagrelide (inhibit megakaryocytes maturation) (based on age and patient-specific variables, disease factors)
- Adequate response —> continue treatment
- Inadequate / loss of response —> change of cytoreductive therapy
Proposed algorithm for PMF treatment
MF with prognosis assessed (by clinical, molecular studies)
- Predicted long term survival, Low risk AML
- Ruxolitinib (based on symptoms, organomegaly)
- Cytoreduction
- Anaemia, Cytopenia management - Predicted short median survival, High risk AML
- Allo-HSCT if transplant eligible
- Ruxolitinib (based on symptoms, organomegaly)
- Cytoreduction
- Anaemia, Cytopenia management
Case 2:
- 80 yo man
- ex-smoker, 40 pack-years, non-drinker
- hypertension well controlled with 1 antihypertensive
- dizziness and headache for 2 weeks
- generalised pruritis, worse after taking bath (Aquagenic pruritis)
- Hb 19.2
- MCV 80
- WBC 19
- platelet 725
- CBC + D/C + PB film
—> packed
—> Leukocytosis with left-shift, occasional myelocytes
—> Thrombocytosis with platelet anisocytosis - Biochemistry
- LRFT normal
- LDH ↑ at 800
- Urate ↑
- EPO markedly suppressed - BM aspirate, Trephine biopsy
- Marked trilineage hyperplasia (Panmyelosis)
- Pleomorphic megakaryocytes
- Absent marrow fibrosis - Suggestion: PV
- Molecular study, Cytogenetics
- JAK V617F mutation
- Cytogenetics: Normal - Treatment
- Aspirin
- Venesection (放血)
- Hydroxyurea
Differential diagnoses of genuine erythrocytosis
Primary (endogenous EPO level suppressed by -ve feedback):
- PV (MPN)
Secondary (EPO level ↑ / NOT suppressed):
- Chronic hypoxaemic states (e.g. chronic lung diseases, OSA, cyanotic congenital heart disease)
- Renal conditions with increased EPO production (e.g. polycystic kidney disease, renal cell carcinoma)
- Rare paraneoplastic states (e.g. RCC, HCC)
- Others (e.g. smoking)
Case 3:
- 28 yo female
- good past health
- heavy menses
- pain and numbless over hands
- Hb 12.9
- MCV 90
- WBC 9.12
- platelet 1126
- Afebrile
- No palpable LN
- liver, spleen not palpable
- other systems unremarkable
- CBC + D/C + PB film
- Marked isolated thrombocytosis
- Platelet anisocytosis (many giant platelets)
- No Leukocytosis
- No Basophilia
- No blasts in circulation
- No tear-drop poikilocytes
- No hypochromic, microcytic RBC —> NOT Fe deficiency - Biochemistry
- LRFT, LDH, urate normal
- Fe profile —> normal —> NOT Fe deficiency
- PT 12.4s (10.9-13.6), APTT 36s (25.1-33.9) - BM aspirate, Trephine biopsy
- Marked megakaryocytic hyperplasia with large and hyperlobated megakaryocytes
- No evidence of marrow fibrosis
- Erythroid, Myeloid series unremarkable - Suggestions: ET
- Molecular studies, Cytogenetics
- CALR exon 9 mutation —> proving clonality
- Cytogenetics —> normal
- RT-PCR for BCR-ABL1 —> negative - Treatment
- Peg-IFNα 2A for cytoreduction
- Aspirin for prevention of thromboembolism
- not consider hydroxyurea because teratogenic and young age, possibility of secondary malignancy
Differential diagnoses of isolated thrombocytosis
Primary
- ET (MPN)
- CML BCR-ABL1+ (rare) (MPN)
Secondary (reactive) (Thrombocytosis rarely extreme)
- Bleeding / Fe deficiency (most common)
- Paraneoplastic phenomena
- Inflammation (sub-acute/chronic infections, autoimmune diseases) (rare)
Case 4:
- 58 yo female
- reduced exercise tolerance, weight loss, loss of appetite, abdominal discomfort for 6 months
- pallor
- palpable liver 5cm below right costal margin
- enlarged spleen to umbilicus
- Hb 7.6
- WBC 43.37
- Platelet 550
- CBC + D/C + PB film
- marked RBC anisopoikilocytosis
- prominent tear-drop poikilocytes
- Leukocytosis with left-shift
- thrombocytosis with many giant platelets
- occasional nucleated RBC, myelocytes, blasts (all immature cells) —> Leuko-erythroblastic blood picture - Biochemistry
- LRFT normal
- LDH ↑ at 1100
- urate ↑ - BM aspirate, Trephine biopsy
- BM aspirate —> dry tap
- Trephine biopsy
—> streaming artefacts
—> ↓ erythropoiesis
—> ↑ granulopoiesis
—> megakaryopoiesis
—> megakaryocytes showed nuclear atypia, clustering, abnormal topographic distributed
—> Reticulin staining showed marked coarsening of reticulin fibres with many intersections and focal collagen fibrosis (i.e. severe BM fibrosis)
—> thickened trabecular bone - Suggestion: PMF
- Cytogenetics, molecular studies
- Cytogenetics: Normal
- Molecular studies: JAK2 V617F
- Next-generation sequencing showed high risk mutations (ASXL1, EZH2, SRSF2 mutations) - Treatment
- Ruxolitinib for symptom and splenomegaly control
- Allogeneic HSCT from sibling donor in view of very high risk disease
MDS/MPN
Clonal haematological disorders characterised by
- proliferation in 1 lineage (typically leukocytosis) —> ↑ Circulating cell + Hypercellular marrow
- cytopenia in >=1 other lineage(s) (typically anemia / thrombocytopenia)
- dysplasia in >=1 lineage
Presentation very similar to MDS apart from proliferative element
Example: Chronic myelomonocytic leukaemia (CMML)
- **CMML typically present in elderly with
- Leukocytosis
- Monocytosis
- +/- Anaemia (Dysplastic change in Erythroid lineage)
- +/- Thrombocytopenia (Dysplastic change in Megakaryocyte lineage)
Investigations, Therapy similar to MDS
Case 5:
- 79 yo man
- anaemic symptoms
- easy bruising
- pallor
- hepatosplenomegaly
- Hb 6
- WBC 35
- platelet 45
- CBC + D/C + PB film
- Monocytosis
- Occasional promonocytes
- Dysplastic neutrophils (hypogranular with abnormal lobulation) - BM exam
- Markedly ↑ Myeloid series, Monocytosis
- Dysplastic Myeloid series + Megakaryocytes - Diagnosis: CMML
