Myelodysplastic/Myeloproliferative Neoplasm (MDS/MPN) in Transformation to Acute Myeloid Leukemia (AML)

1. Definition

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) are a group of clonal hematopoietic stem cell disorders that demonstrate both dysplastic (ineffective hematopoiesis) and proliferative (myeloid hyperplasia) features. Transformation to Acute Myeloid Leukemia (AML) is defined by the presence of ≥20% blasts in the bone marrow or peripheral blood.

2. Causes

Acquired somatic mutations in hematopoietic progenitor cells
Chromosomal abnormalities (e.g. monosomy 7, trisomy 8)
Environmental exposure (benzene, radiation)
Prior chemotherapy or radiotherapy (therapy-related MDS/MPN)

3. Risk Factors

Risk Factor	Details
Age > 60 years	Most patients present in older age
Cytogenetic abnormalities	Poor-risk karyotypes (monosomy 7, complex)
Prior MDS, MPN, or other clonal hematologic disease	Especially CMML, atypical CML
Cytopenias or rising blast count	Indicates disease progression
Exposure to genotoxic drugs	Alkylators, topoisomerase II inhibitors

4. Types / Classifications

WHO 5th Edition (2022) — MDS/MPN Subtypes

Subtype	Distinct Features
CMML (Chronic Myelomonocytic Leukemia)	Persistent monocytosis >1×10⁹/L
aCML (Atypical Chronic Myeloid Leukemia)	Neutrophilic leukocytosis without BCR-ABL1
MDS/MPN with SF3B1 mutation	Thrombocytosis + ring sideroblasts
MDS/MPN-U (Unclassifiable)	Overlap features not meeting above criteria

Transformation to AML: Defined as ≥20% myeloblasts in blood or bone marrow (NICE AML guideline 2021).

5. Pathogenesis

Initial mutations (e.g., TET2, SRSF2, ASXL1) impair hematopoietic differentiation.
Progressive accumulation of mutations (e.g., TP53, RUNX1, FLT3) leads to clonal evolution.
Dysregulated proliferation and impaired apoptosis drive increased marrow cellularity, cytopenias, and transformation.
Leukemic transformation occurs when blast burden reaches ≥20%.

6. Clinical Presentation

Symptoms:

Fatigue, weight loss, night sweats
Frequent infections (neutropenia)
Easy bruising or bleeding (thrombocytopenia)
Abdominal fullness (splenomegaly in CMML)
Bone pain (rare)

Signs:

Pallor, petechiae
Splenomegaly or hepatomegaly
Sternal tenderness
Fever (infection or transformation)

7. Organ & System Complications

System	Complication
Hematologic	Pancytopenia, hemorrhage, leukostasis in AML phase
Immune	Neutropenia-related infections
Hepatosplenic	Splenomegaly, portal hypertension
Neurological	CNS involvement in advanced AML (rare)
Metabolic	Tumor lysis syndrome (during transformation or treatment)

8. Diagnostic Investigations

Test	Purpose
CBC	Pancytopenia, leukocytosis, rising blasts
Peripheral smear	Dysplasia, blasts, monocytosis
Bone marrow aspirate/biopsy	Gold standard for diagnosis and classification
Flow cytometry	Immunophenotyping of blasts
Cytogenetics (karyotype)	Risk stratification (e.g., monosomy 7, complex)
Molecular testing	FLT3, NPM1, ASXL1, RUNX1, TP53 mutations

9. Other Relevant Investigations

LFTs, renal panel — baseline before chemotherapy
LDH, uric acid — assess for high cell turnover
Coagulation profile — risk of DIC or bleeding
HLA typing — for transplant consideration
Infectious screen — Hep B/C, HIV, CMV before immunosuppressive therapy

10. Treatment

Curative/Definitive:

Allogeneic hematopoietic stem cell transplant (HSCT) in eligible patients with remission

Empirical:

Empiric antibiotics in febrile neutropenia
Blood and platelet transfusions as needed

Supportive:

Hypomethylating agents (azacitidine, decitabine) for patients unfit for induction
Growth factors (G-CSF) in select cytopenic cases
Transfusions for anemia and thrombocytopenia
Antimicrobials, antifungals, antivirals during neutropenia

AML-Specific Therapy (post-transformation):

Regimen	Indication
"7+3" chemotherapy (cytarabine + anthracycline)	Fit patients <65–70 years
Azacitidine + Venetoclax	Elderly or unfit patients
FLT3/IDH inhibitors	If mutations are present (targeted therapy)

Palliative:

Supportive care only in frail, elderly, or refractory patients
Symptom control, transfusion support, and goals-of-care discussion

11. Long-Term Effects / Complications of Treatment

Monitoring & Complications Table

Treatment Type	Complication	Monitoring
Chemotherapy	Myelosuppression, infection	CBC, cultures, febrile neutropenia workup
Hypomethylating agents	Cytopenias, GI side effects	CBC every 1–2 weeks, LFTs
Targeted therapies	QT prolongation, cytopenia, hepatotoxicity	ECG, electrolytes, LFTs
HSCT	GVHD, infections, relapse	Chimerism, viral loads, organ function tests

12. Surveillance for the Disease

Surveillance Measure	Frequency
CBC and differential	Every 1–2 weeks during active treatment
Bone marrow biopsy	At diagnosis, post-treatment, or relapse
MRD testing (if available)	After induction and during remission follow-up
Cytogenetics / mutation tracking	Periodically or if relapse suspected
Infection monitoring	Throughout neutropenia and post-HSCT
Post-transplant GVHD screening	Monthly to quarterly depending on course

References

NHS/NICE Guidelines:
- NICE NG217: Acute myeloid leukaemia in adults: diagnosis and management
- British Society of Haematology (BSH) guideline on AML (2022)
Malaysia Clinical Practice Guidelines:
- Ministry of Health Malaysia. Management of Acute Myeloid Leukaemia, 2nd Edition, 2019. Available from: https://www.moh.gov.my/
UpToDate:
- “Chronic myelomonocytic leukemia: Clinical features, diagnosis, and prognosis”
- “Overview of myelodysplastic/myeloproliferative neoplasms”
- “Treatment of acute myeloid leukemia in older adults who are not candidates for intensive induction chemotherapy”