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GERICLINICS

GeriQBank · Paper III · Q6

Alkylating Agents · Intramedullary vs Extramedullary Haemolysis · What is Dysplasia

Low Yield
Topic
Haematology, Oncology & Screening
Chapter
Haematology
Years asked
Not recorded in the source
Frequency
Not set in Papers III–IV, 2009–2025

Detailed answer

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Attempt it firstOutline your answer before revealing it — definition, causes, evaluation, management and the geriatric angle.Reveal answer

Part A — Alkylating Agents

1.

Alkylating agents attach an alkyl group directly to DNA (usually N7 of guanine), causing intra- and inter-strand cross-linking that blocks replication/transcription → apoptosis.

2.

Cell-cycle non-specific — kill dividing and resting cells; hence toxic to normal stem cells and a classic cause of secondary MDS/AML.

Class Drugs

Nitrogen mustards Cyclophosphamide, ifosfamide, chlorambucil, melphalan, bendamustine Nitrosoureas Carmustine, lomustine (cross blood-brain barrier)

Alkyl sulfonates Busulfan

Triazenes Dacarbazine, temozolomide, procarbazine Platinum compounds Cisplatin, carboplatin, oxaliplatin — NOT true alkylators, correctly called "platinating agents" Toxicities: myelosuppression, alopecia, infertility (class-wide); cyclophosphamide/ifosfamide → haemorrhagic cystitis (prevent with mesna); busulfan/carmustine → pulmonary fibrosis; cisplatin → nephro/ototoxicity. Alkylators vs Topoisomerase II Inhibitors — Therapy-Related Neoplasms Feature Alkylating agents/radiation Topoisomerase II inhibitors Latency 5–10 years 1–3 years MDS prodrome Yes No — direct AML Cytogenetics Unbalanced losses: −5/del5q, −7/del7q Balanced translocations: 11q23, 21q22 Part B — Intramedullary vs Extramedullary Haemolysis Intramedullary = precursor dies inside the marrow before reaching blood = ineffective erythropoiesis (Pathy's: "dyserythropoiesis with intramedullary abortion"). Extramedullary = mature red cell dies after entering circulation (extravascular in spleen/liver, or intravascular in vessels).

The single best discriminator: reticulocyte count. True (extramedullary) haemolysis → HIGH reticulocytes. Intramedullary haemolysis → LOW/inappropriately normal reticulocytes, despite raised LDH, raised indirect bilirubin, low haptoglobin.

Feature Intramedullary Extravascular Intravascular Site Inside bone marrow Spleen/liver macrophages Within blood vessels Reticulocytes LOW HIGH HIGH Haptoglobin Low Low Absent Free plasma Hb Absent Absent Present Haemoglobinuria Absent Absent Present Film Dysplastic cells Spherocytes Schistocytes Examples MDS, B12/folate deficiency, thalassaemia AIHA, hereditary spherocytosis PNH, MAHA, prosthetic valve Bedside rule: "Haemolysis picture + LOW reticulocytes = the problem is INSIDE the marrow."

Part C — What is Dysplasia

1.

Dysplasia = disordered growth/maturation of cells within a tissue — abnormal size/shape/arrangement, NO invasion, potentially reversible.

2.

Distinguish: Hyperplasia (↑number) / Hypertrophy (↑size) / Metaplasia (mature→mature type change) / Dysplasia (disordered maturation) / Anaplasia (loss of differentiation, malignant).

3.

Pathy's definition: "A lineage is dysplastic when qualitative cytological abnormalities are observed on >10% of the cells of the lineage." MD Geriatrics – Haematology Compendium Page 13 of 34 Lineage Dysplastic features Dyserythropoiesis Megaloblastoid change, nuclear budding, internuclear bridging, ring sideroblasts Dysgranulopoiesis Hypogranular neutrophils, pseudo-Pelger-Huët cells, Auer rods (if excess blasts) Dysmegakaryopoiesis Micromegakaryocytes, hypolobated nuclei Critical caveat: Pathy's states dysplasia alone is NOT sufficient for MDS diagnosis — must exclude reactive causes: B12/folate deficiency, hypothyroidism, copper deficiency, EBV/HIV, alcohol, chemotherapy, benzene, certain antibiotics.

Latest Updates (2023–Present)

WHO-HAEM5 replaced "therapy-related myeloid neoplasm" with "myeloid neoplasm post cytotoxic therapy (MN-pCT)", now including PARP inhibitors, excluding methotrexate. Modern understanding: alkylators/radiation mostly select pre-existing clonal haematopoiesis (TP53/PPM1D-mutant clones resistant to DNA damage) rather than creating new mutations — TP53 mutations found in up to 40% of MN-pCT. Morphological dysplasia has poor inter-observer reproducibility; WHO 2022/ICC 2022 have moved toward genetic definition of subtypes (MDS-SF3B1 by mutation, not RS%; MDS-biTP53, MDS-5q by genetics).

MD Geriatrics – Haematology Compendium Page 14 of 34

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