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PA18.1-2 | Benign Leukocytosis & Leukemias — Case Study

CLINICAL SCENARIO

A 38-year-old man presents with six months of progressive fatigue, dragging left-sided abdominal discomfort, and unintentional weight loss of 8 kg. Examination reveals massive splenomegaly (18 cm below the costal margin) and mild hepatomegaly. His full blood count shows WBC 120 × 10⁹/L with a differential showing a complete granulocyte spectrum (blasts 2 %, promyelocytes 5 %, myelocytes 18 %, metamyelocytes 12 %, band forms 14 %, segmented neutrophils 40 %, eosinophils 5 %, basophils 4 %), Hb 9.6 g/dL (normochromic normocytic), platelets 680 × 10⁹/L. Leukocyte alkaline phosphatase (LAP) score = 8 (low). No fever, no recent infection, no corticosteroid use. Bone marrow biopsy: hypercellular with myeloid hyperplasia and < 10 % blasts. Cytogenetics: t(9;22)(q34;q11.2) detected in 20/20 metaphases.

Instructions

Work through this case systematically using the three SDLs from Cluster H7: SDL 1 (reactive leukocytosis and leukaemoid reaction), SDL 2 (acute leukaemias), and SDL 3 (chronic leukaemias). Your written analysis must flow logically from the initial differential diagnosis through the confirmatory workup to the final diagnosis and its implications. Write in continuous, referenced prose — avoid bare bullet lists. Each section has a word target; stay within 20 % of it. Submit your completed assignment and then provide a structured peer review of one classmate's submission using the peer-review rubric provided.

Length: Section 1: 200–250 words. Section 2: 180–220 words. Section 3: 200–250 words. Section 4: 220–270 words. Section 5: 180–220 words. Section 6: 200–250 words. Total: 1,180–1,460 words.

What to Submit

Section 1 — First-Pass Differential: Reactive vs Leukaemoid vs Leukaemia

Using the clinical history and blood count, construct a prioritised differential diagnosis for a WBC of 120 × 10⁹/L. Explain which features argue for a reactive/leukaemoid reaction and which features make true leukaemia more likely. Specifically address: (a) the basophilia and eosinophilia, (b) the absence of fever or identifiable precipitant, (c) the thrombocytosis, and (d) the splenomegaly.

Guidance: SDL 1 covers the causes of reactive neutrophilia (infection, inflammation, steroids, tissue necrosis) and the hallmarks of a leukaemoid reaction (WBC > 50 × 10⁹/L, toxic granulation, Döhle bodies, elevated LAP). Use this framework explicitly — your answer should cite specific SDL 1 criteria and explain why this patient does or does not meet them.

Section 2 — Is This Acute or Chronic Leukaemia?

The blood film shows blasts at only 2 % with a complete granulocyte maturation spectrum. Explain how the blast percentage and the maturation pattern help distinguish acute from chronic leukaemia. What is the WHO blast threshold for diagnosing acute leukaemia, and is it met here? Describe what you would expect to see if this were AML (including Auer rods and relevant cytochemical stains).

Guidance: SDL 2 (Acute Leukaemias) covers the WHO ≥ 20 % blast threshold, morphological features of AML (Auer rods, Sudan Black B positivity, MPO positivity) vs ALL (TdT, CD10, lymphoblast morphology). Your answer must directly compare acute leukaemia criteria to this patient's findings to justify why AML/ALL is excluded.

Section 3 — Identifying the Specific Chronic Leukaemia Entity

Given that chronic leukaemia is now the leading diagnosis, explain the role of each investigation in reaching the specific diagnosis: (a) leukocyte alkaline phosphatase score, (b) peripheral blood film morphology, (c) bone marrow biopsy blast percentage, (d) conventional cytogenetics. State the final specific diagnosis with full justification.

Guidance: SDL 3 (Chronic Leukaemias) covers CML, CLL, and the chronic myeloproliferative disorders. Key CML criteria: WBC > 100 × 10⁹/L with full myeloid spectrum, basophilia, low LAP, t(9;22)/BCR-ABL1, < 10 % blasts = chronic phase. Contrast the low LAP in CML with the elevated LAP in leukaemoid reactions and polycythaemia vera. Name the cytogenetic finding precisely (Philadelphia chromosome).

Section 4 — Pathophysiology: From t(9;22) to Massive Leucocytosis

Describe how the BCR-ABL1 fusion oncogene drives the pathophysiology of CML. Cover: (a) the mechanism of unregulated tyrosine kinase activity, (b) the effect on apoptosis and myeloid progenitor expansion, (c) why the LAP score is low in CML despite massive granulocyte output, and (d) the pathogenesis of splenomegaly in CML.

Guidance: Integrate cell biology (constitutive kinase → RAS/MAPK and PI3K/AKT signalling → reduced apoptosis → clonal expansion) with the haematological picture. The low LAP is a classic teaching point: CML neutrophils are mature in morphology but functionally abnormal — down-regulation of LAP gene expression. Splenomegaly reflects extramedullary haemopoiesis plus splenic sequestration.

Section 5 — Prognostic Stratification and Disease-Phase Classification

Classify this patient's disease phase (chronic, accelerated, or blast crisis) using WHO 2022 criteria. Calculate the Sokal score components conceptually (explain what each variable contributes, rather than plugging in numbers you haven't been given). Identify two clinical or haematological features that would indicate transformation to accelerated phase or blast crisis.

Guidance: WHO chronic phase: < 10 % blasts, < 20 % basophils, no blast crisis features. Accelerated phase triggers include blasts 10–19 %, basophils ≥ 20 %, new cytogenetic evolution, platelet refractory to therapy. Blast crisis: ≥ 20 % blasts or extramedullary blast proliferation. The Sokal score uses age, spleen size, platelet count, and blast %; higher score = worse prognosis in the TKI era.

Section 6 — Management Principles and Monitoring

Outline the first-line treatment for CML in chronic phase and the rationale for the chosen drug class. Explain the three levels of treatment response (haematological, cytogenetic, molecular) and the standard time-points at which they are assessed. What is the significance of a major molecular response (BCR-ABL1 IS ≤ 0.1 %) and what is treatment-free remission (TFR)?

Guidance: First-line: imatinib (TKI) targets BCR-ABL1 kinase. Haematological response by 3 months, complete cytogenetic response by 12 months, deep molecular response (MR4 or MR4.5) for TFR eligibility. Mention resistance mechanisms briefly (ABL kinase domain mutations, e.g. T315I) to show awareness of second-generation TKIs (dasatinib, nilotinib). TFR is only attempted after sustained deep molecular response for ≥ 2 years.

Grading Rubric — H7 Case Study Rubric — Leukaemoid Reaction vs CML

Criterion	Points	Full-marks descriptor
Differential Diagnosis Construction (Section 1) — Quality of reactive vs leukaemia reasoning using SDL 1 criteria	5 pts	Clearly distinguishes reactive/leukaemoid from leukaemia using all four specified features (basophilia, absence of precipitant, thrombocytosis, splenomegaly); explicitly references LAP and leukaemoid criteria from SDL 1; prioritised differential is logical.
Acute vs Chronic Leukaemia Discrimination (Section 2) — Correct use of WHO blast threshold and morphological criteria	5 pts	Correctly states WHO ≥ 20 % blast threshold; explains why this patient's 2 % blast count excludes acute leukaemia; accurately describes AML morphology (Auer rods, MPO/Sudan Black) and explains why it is absent here; clear link to SDL 2.
Diagnosis Identification with Investigative Justification (Section 3) — Correct diagnosis reached with explicit use of LAP, morphology, BM, and cytogenetics	6 pts	Diagnoses CML in chronic phase; explains all four investigations (low LAP contrasted with leukaemoid reaction/PV, full myeloid spectrum on film, < 10 % BM blasts, t(9;22) named as Philadelphia chromosome with BCR-ABL1); SDL 3 criteria used explicitly.
Pathophysiology of BCR-ABL1 and CML (Section 4) — Mechanistic chain from translocation to clinical picture	6 pts	Explains constitutive tyrosine kinase activity; links to downstream RAS/MAPK and/or PI3K/AKT signalling; demonstrates reduced apoptosis → clonal myeloid expansion; explains low LAP as functional neutrophil abnormality (down-regulated LAP gene); explains splenic pathogenesis (extramedullary haemopoiesis + sequestration).
Disease-Phase Classification and Prognostication (Section 5) — Correct WHO phase classification and Sokal score conceptual understanding	4 pts	Correctly classifies chronic phase using WHO 2022 criteria (blasts < 10 %, basophils < 20 %, no blast crisis features); explains all four Sokal score variables conceptually; identifies two valid accelerated/blast crisis triggers.
Management and Monitoring (Section 6) — TKI rationale, response milestones, and TFR	4 pts	Names imatinib as first-line TKI with mechanism (BCR-ABL1 kinase inhibition); correctly describes all three response levels with standard timepoints; defines MMR (BCR-ABL1 IS ≤ 0.1 %); explains TFR eligibility (sustained deep molecular response ≥ 2 years); mentions resistance and second-generation TKIs.

PEER REVIEW

You will be assigned one classmate's submission after the primary deadline. Read their complete response before beginning your review. Use the rubric above to score each of the six sections. For every criterion, provide: (1) the score you are awarding with a one-sentence justification, (2) one specific strength — cite a sentence or finding from their text, and (3) one specific, actionable suggestion for improvement. Your tone must be collegial and constructive. Your review must be 400–550 words. Unsupported scores (score without justification) will not be accepted. Peer review is graded separately for quality; reviewers who simply award maximum marks without comment will receive zero review credit.