Essay answer on CML 10 marks question blood and bone marrow findings in CML from Harrison with proper flowcharts and diagrams??

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CML chronic myeloid leukemia blood smear peripheral blood bone marrow

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CML peripheral blood smear left shift myelocytes metamyelocytes basophilia leukocytosis

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Blood and Bone Marrow Findings in Chronic Myeloid Leukemia (CML)

[Harrison's Principles of Internal Medicine, 22nd Ed., Chapter 110 — p. 878–882]

1. Introduction

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative neoplasm of the pluripotent hematopoietic stem cell, defined by the presence of the BCR::ABL1 fusion gene resulting from the reciprocal translocation t(9;22)(q34.1;q11.2) — the Philadelphia (Ph) chromosome. The disease has a characteristic triphasic natural history: chronic phase → accelerated phase → blast crisis. Peripheral blood and bone marrow findings are central to diagnosis, prognostication, and monitoring.

2. The Philadelphia Chromosome & Pathophysiology

Philadelphia chromosome t(9;22) translocation and BCR-ABL1 fusion oncoproteins — Harrison's Fig 110-1

Harrison's Fig. 110-1: A. The Philadelphia chromosome cytogenetic abnormality. B. Breakpoints in chromosome 9 (ABL1) and chromosome 22 (BCR) generate three BCR::ABL1 oncoproteins — p210 (most common in CML), p190 (Ph+ ALL), and p230 (rare, indolent).

The t(9;22)(q34.1;q11.2) is present in >90% of classical CML cases. The hybrid BCR::ABL1 oncogene encodes p210^BCR::ABL1 (major breakpoint), a constitutively active tyrosine kinase that drives:

↑ Proliferation (via RAS, MAPK, STAT, PI3K, MYC)
↓ Apoptosis
↑ Genetic instability → disease progression

3. Peripheral Blood Findings (Chronic Phase)

╔══════════════════════════════════════════════════════════════════╗
║           PERIPHERAL BLOOD FINDINGS IN CML (CHRONIC PHASE)       ║
╠══════════════════════════════════════════════════════════════════╣
║  PARAMETER             │  FINDING                                 ║
╠════════════════════════╪═════════════════════════════════════════╣
║  WBC Count             │  10–500 × 10⁹/L  (leukocytosis)        ║
║  Differential          │  Left-shifted granulopoiesis            ║
║                        │  Neutrophils predominate                 ║
║                        │  Bands, Myelocytes, Metamyelocytes       ║
║                        │  Promyelocytes, Blasts (usually ≤5%)    ║
║  Basophils             │  INCREASED (≥7% in 10% of patients)     ║
║  Eosinophils           │  Frequently increased                    ║
║  Blasts (PB)           │  ≥3% in 8–10% of patients               ║
║  Platelets             │  Thrombocytosis (common)                 ║
║                        │  >450 × 10⁶/L in 30–35%                ║
║                        │  Thrombocytopenia (rare, poor prognosis) ║
║  Hemoglobin            │  Anemia in ~1/3 patients                 ║
║                        │  Hgb <10 g/dL in 10–15%                 ║
║  Count oscillations    │  Cyclic in 10–20% without treatment      ║
╚════════════════════════╧═════════════════════════════════════════╝

Key biochemical abnormalities (peripheral blood):

Parameter	Finding
Leukocyte Alkaline Phosphatase (LAP) score	LOW (distinguishes CML from leukemoid reaction)
Vitamin B₁₂	HIGH (due to ↑ transcobalamin from granulocytes)
Uric acid	HIGH (hyperuricemia — ↑ cell turnover)
Lactic dehydrogenase (LDH)	HIGH
Lysozyme	HIGH

4. The "Left Shift" — Flowchart of CML Peripheral Blood Differential

                    PERIPHERAL BLOOD DIFFERENTIAL IN CML
                    ══════════════════════════════════════

  NORMAL GRANULOCYTE SERIES:
  Myeloblast → Promyelocyte → Myelocyte → Metamyelocyte → Band → Neutrophil
  (marrow)    (marrow)       (marrow)     (marrow)         (blood) (blood)

  IN CML (LEFT SHIFT — all stages seen in peripheral blood):
  ┌─────────────┐
  │ Myeloblast  │  ≤5% (chronic phase)
  └──────┬──────┘
         │
  ┌──────▼──────┐
  │Promyelocyte │  Present
  └──────┬──────┘
         │
  ┌──────▼──────┐
  │  Myelocyte  │  Predominant (more than metamyelocytes — KEY FEATURE)
  └──────┬──────┘
         │
  ┌──────▼──────────┐
  │ Metamyelocyte   │  Present
  └──────┬──────────┘
         │
  ┌──────▼──────┐
  │    Band     │  Present
  └──────┬──────┘
         │
  ┌──────▼──────┐
  │  Neutrophil │  Present (majority of WBC)
  └─────────────┘
         +
  ┌─────────────┐     ┌─────────────┐
  │  Basophilia │  +  │  Eosinophilia│  (Characteristic findings)
  └─────────────┘     └─────────────┘

  KEY DISTINCTION from Leukemoid Reaction:
  CML: Myelocytes > Metamyelocytes + LOW LAP score
  Leukemoid: Metamyelocytes > Myelocytes + HIGH LAP score

5. Bone Marrow Findings (Chronic Phase)

╔══════════════════════════════════════════════════════════════════╗
║              BONE MARROW FINDINGS IN CML (CHRONIC PHASE)          ║
╠══════════════════════════════════════════════════════════════════╣
║  PARAMETER              │  FINDING                                ║
╠═════════════════════════╪════════════════════════════════════════╣
║  Cellularity            │  HYPERCELLULAR (90–100%)               ║
║  Myeloid series         │  MARKED MYELOID HYPERPLASIA            ║
║  M:E Ratio              │  15–20:1 (markedly elevated)           ║
║  Blasts (marrow)        │  ≤5% (chronic phase)                   ║
║                         │  ≥5% in 5% of patients at presentation ║
║  Basophils (marrow)     │  ≥5% in 10–15% of patients            ║
║  Megakaryocytes         │  Increased, small/dwarf megakaryocytes  ║
║  Erythropoiesis         │  Relatively suppressed                  ║
║  Reticulin fibrosis     │  Grade 3–4 in 30–40% of patients       ║
║  Collagen fibrosis      │  RARE at diagnosis                      ║
║  "Spent phase"          │  Myelophthisis/burnt-out marrow (rare   ║
║  (myelofibrosis)        │  now in TKI era)                       ║
╚═════════════════════════╧════════════════════════════════════════╝

Important: In 10% of patients, the percentage of marrow blasts and basophils can be significantly higher than in the peripheral blood, conferring worse prognosis or even representing disease transformation.

6. Diagnostic Flowchart for CML

               SUSPECTED CML — DIAGNOSTIC ALGORITHM
               ═══════════════════════════════════════════

  Unexplained sustained leukocytosis ± splenomegaly
                         │
                         ▼
            ┌────────────────────────┐
            │  Peripheral Blood CBC  │
            │  + Differential        │
            └───────────┬────────────┘
                        │
              ┌─────────▼──────────────────────────┐
              │ Left-shifted leukocytosis            │
              │ + basophilia + low LAP score         │
              └─────────┬──────────────────────────--┘
                        │
                        ▼
            ┌────────────────────────┐
            │  Bone Marrow Aspiration│
            │  + Trephine Biopsy     │
            └───────────┬────────────┘
                        │
              ┌─────────▼──────────────────────────┐
              │ Hypercellular; myeloid hyperplasia   │
              │ M:E ratio 15–20:1; blasts ≤5%       │
              └─────────┬──────────────────────────--┘
                        │
                        ▼
            ┌────────────────────────┐
            │ Cytogenetics (G-banding)│
            │ t(9;22)(q34.1;q11.2)   │
            │ Philadelphia chromosome │
            └───────────┬────────────┘
                        │
              ┌─────────┴─────────┐
              │                   │
           Ph+ (90%)         Ph- (~10%)
              │                   │
              ▼                   ▼
         CML Confirmed      FISH / RT-PCR
                           for BCR::ABL1
                               │
                    ┌──────────┴──────────┐
                    │                     │
              BCR::ABL1 +           BCR::ABL1 –
              (Ph- CML)         Consider atypical CML,
              TKI therapy        CMML, MDS/MPN

7. CML Phases — Evolving Blood & Marrow Findings

╔══════════════════════════════════════════════════════════════════════════╗
║         CML PHASES: BLOOD AND BONE MARROW PROGRESSION                    ║
╠══════════════════════════════╦══════════════════╦════════════════════════╣
║  PARAMETER                   ║ CHRONIC PHASE    ║ ACCELERATED/BLAST      ║
╠══════════════════════════════╬══════════════════╬════════════════════════╣
║  WBC (×10⁹/L)                ║  10–500          ║  Rising, uncontrolled   ║
║  Blasts – Peripheral Blood   ║  <5%             ║  ≥10% (AP) / ≥20% (BP) ║
║  Blasts – Bone Marrow        ║  ≤5%             ║  ≥15% (AP) / ≥20% (BP) ║
║  Basophils – Blood           ║  ↑ (mild)        ║  ≥20% (AP criterion)   ║
║  Platelets                   ║  Often ↑         ║  Persistent ↓ (<100×10⁹)║
║  Basophils – Marrow          ║  ≤5–15%          ║  ≥20% (AP criterion)   ║
║  Marrow cellularity          ║  Hypercellular   ║  Hypercellular/fibrotic ║
║  M:E ratio                   ║  15–20:1         ║  Distorted further      ║
║  Reticulin fibrosis          ║  30–40% grade 3–4║  ↑↑ (common)           ║
║  Additional cytogenetics     ║  Ph only (95%)   ║  Double Ph, +8, i(17q) ║
╚══════════════════════════════╩══════════════════╩════════════════════════╝

    AP = Accelerated Phase; BP = Blast Phase/Blast Crisis

8. Presenting Signs — Summary Table (Harrison's Table 110-1)

Parameter	Percentage at Presentation
Age ≥60 years	40–50% (median 55–65 years)
Splenomegaly	30%
Hepatomegaly	5–10%
Lymphadenopathy	5%
Hgb <10 g/dL	10–15%
Platelets >450 × 10⁶/L	30–35%
Platelets <100 × 10⁶/L	3–5%
WBC ≥50 × 10⁹/L	35–40%
Marrow blasts ≥5%	5%
Marrow basophils ≥5%	10–15%
PB blasts ≥3%	8–10%
PB basophils ≥7%	10%
Additional chromosomal abnormalities	4–5%

9. Cytogenetic and Molecular Findings

            CYTOGENETICS & MOLECULAR DIAGNOSIS IN CML
            ═══════════════════════════════════════════════

  G-banding (Karyotype)
        ↓
  t(9;22)(q34.1;q11.2) detected in 90% of cases
        ↓
  Philadelphia (Ph) chromosome = der(22)

  ┌──────────────────────────────────────────────────────┐
  │  Additional chromosome analysis findings in CML:     │
  │  • Trisomy 8           → adverse prognosis in AP/BP  │
  │  • Double Ph           → disease acceleration        │
  │  • Isochromosome 17q   → poor prognosis              │
  │  • 17p deletion        → TP53 loss                   │
  │  • 20q-                → progression signal          │
  │  • Additional CAs in 4–5% at diagnosis               │
  └──────────────────────────────────────────────────────┘

  FLUORESCENCE IN SITU HYBRIDIZATION (FISH)
  BCR::ABL1 dual-color dual-fusion probe
  → Detects Ph+ cells in blood OR marrow
  → More sensitive than G-banding

  RT-PCR (Quantitative)
  → Detects BCR::ABL1 transcripts:
     e13a2 (b2a2) → p210 (most common CML)
     e14a2 (b3a2) → p210 (equally common)
     e1a2         → p190 (Ph+ ALL, rare CML, worse prognosis)
     e19a2        → p230 (rare, indolent CML)
  → Used for monitoring response to TKI therapy
  → International Scale (IS): reported as %BCR::ABL1

10. CML vs. Leukemoid Reaction — Key Differential

Feature	CML	Leukemoid Reaction
WBC	Very high (>50,000)	Elevated (<50,000 usually)
Left shift	Myelocytes > Metamyelocytes	Metamyelocytes > Myelocytes
Basophilia	Present	Absent
LAP score	LOW (<20)	HIGH (>100)
Philadelphia chromosome	Present	Absent
BCR::ABL1	Positive	Negative
Splenomegaly	Common	Related to cause
Cause	Clonal neoplasm	Reactive (infection, etc.)

11. Summary Flowchart — CML Blood & Bone Marrow at a Glance

                    CML — BLOOD & BONE MARROW AT A GLANCE
                    ══════════════════════════════════════

  BCR::ABL1 (p210) — constitutive tyrosine kinase activity
                         │
                         ▼
     Clonal expansion of pluripotent hematopoietic stem cell
                         │
          ┌──────────────┼──────────────┐
          │              │              │
    ┌─────▼──────┐ ┌────▼──────┐ ┌────▼──────────┐
    │  Peripheral │ │  Bone     │ │  Spleen /     │
    │    Blood    │ │  Marrow   │ │  Extramedullary│
    └─────┬───────┘ └────┬──────┘ └───────────────┘
          │              │
    ┌─────▼──────────────▼──────────────────────────────┐
    │ PERIPHERAL BLOOD            BONE MARROW            │
    │ • Leukocytosis 10–500×10⁹  • Hypercellular 90–100%│
    │ • Full myeloid left shift   • Myeloid hyperplasia  │
    │ • Basophilia + Eosinophilia • M:E ratio 15–20:1    │
    │ • Blasts ≤5%                • Blasts ≤5%           │
    │ • Thrombocytosis (common)   • Dwarf megakaryocytes │
    │ • Anemia (1/3)              • ↑ Reticulin fibrosis │
    │ • LOW LAP score             • Ph chromosome+       │
    │ • ↑ B12, LDH, uric acid                           │
    └──────────────────────────────────────────────────--┘
                         │
           ┌─────────────┼─────────────┐
           │             │             │
    ┌──────▼──────┐ ┌───▼───────┐ ┌───▼──────────┐
    │  CHRONIC    │ │ACCELERATED│ │  BLAST CRISIS │
    │   PHASE     │ │  PHASE    │ │               │
    │  Blasts <5% │ │Blasts     │ │Blasts ≥20%    │
    │             │ │15–19%     │ │(Myeloid 70% / │
    │             │ │Basophils  │ │Lymphoid 30%)  │
    │             │ │≥20%       │ │               │
    └─────────────┘ └───────────┘ └───────────────┘

12. Key Points to Remember (10-Mark Essay)

CML = BCR::ABL1 fusion gene from t(9;22)(q34.1;q11.2) → Philadelphia chromosome
Peripheral blood: massive leukocytosis (10–500×10⁹/L), full spectrum of myeloid cells ("left shift"), basophilia, eosinophilia, thrombocytosis, anemia in 1/3; blasts usually <5%
Hallmark of blood smear: myelocytes predominate over metamyelocytes (reverse of leukemoid reaction)
LAP score is LOW — critical diagnostic distinction from leukemoid reaction
Bone marrow: markedly hypercellular, myeloid hyperplasia, M:E ratio 15–20:1, blasts ≤5%, dwarf megakaryocytes, reticulin fibrosis (30–40%)
Diagnosis confirmed by cytogenetics (G-banding), FISH, and RT-PCR for BCR::ABL1
Biochemistry: ↑ B₁₂, ↑ LDH, ↑ uric acid, ↑ lysozyme, LOW LAP
Disease progression is marked by ↑ blasts, ↑ basophils, additional cytogenetic abnormalities (trisomy 8, double Ph, i(17q)), worsening cytopenias
Bone marrow blasts can be higher than peripheral blood in 10% of patients — marrow biopsy is essential
With TKI therapy (imatinib era), reticulin fibrosis resolves and the "spent phase" of myelofibrosis is now extremely rare

Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter 110: Chronic Phase Chronic Myeloid Leukemia, pp. 878–882.

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