What determines the prognosis of anaplastic large cell lymphoma (ALCL)?

Prognostic Determinants in Anaplastic Large Cell Lymphoma

The most critical prognostic determinant in ALCL is ALK (anaplastic lymphoma kinase) protein expression status, which independently predicts survival and defines distinct disease entities with dramatically different outcomes. 1

Primary Prognostic Factor: ALK Expression Status

ALK-positive ALCL has significantly superior outcomes compared to ALK-negative disease, with 5-year overall survival rates of 70% versus 49% respectively, and 5-year failure-free survival rates of 60% versus 36% 1. This survival advantage is maintained even when controlling for other clinical variables 2.

Key characteristics by ALK status:

• ALK-positive patients present at a younger median age (approximately 30 years) compared to ALK-negative patients (median 52-61 years) 1, 2, 3
• ALK positivity results from chromosomal translocation t(2;5) in 40-60% of cases, producing the NPM-ALK fusion protein 1
• ALK expression is an independent predictor of survival even after adjusting for age, International Prognostic Index (IPI), and other clinical factors 2, 4

Secondary Prognostic Factors

Clinical Risk Stratification

The following factors significantly impact prognosis 1, 2:

• Age: Patients ≥40 years have worse outcomes; the favorable prognosis of ALK positivity is diminished with older age 1, 4
• Disease stage: Early stage (I-II) disease is the only significant pretreatment prognostic factor in multivariate analysis 1
• Serum LDH: Normal LDH independently predicts improved overall survival (P<0.00001) 2
• IPI score: Score ≤3 independently predicts better outcomes (P<0.0005) 2
• Performance status: ECOG <2 correlates with improved survival 2
• Extranodal sites: ≤1 extranodal site predicts better outcomes 2
• β2-microglobulin: Levels ≥3 mg/L independently predict worse survival (P<0.001) 4

Molecular Prognostic Markers in ALK-Negative Disease

For ALK-negative ALCL specifically, molecular subtypes provide additional prognostic stratification 1:

• DUSP22 rearrangement (present in 30% of ALK-negative cases): Associated with intermediate prognosis, with 5-year progression-free survival and overall survival rates of approximately 40%, though significantly better than other ALK-negative subtypes 1
• TP63 rearrangement (present in ~8% of cases): Associated with very poor prognosis, with 5-year overall survival of only 17% 1
• Triple-negative ALCL (lacking ALK, DUSP22, and TP63 rearrangements): Poor prognosis with 5-year progression-free survival and overall survival rates of 19% and 28% respectively 1

Clinical Presentation Patterns

Most patients present with advanced disease 1:

• 65% of ALK-positive and 58% of ALK-negative patients present with stage III or IV disease 1
• 70% have B symptoms (fever, night sweats, weight loss) at presentation 1
• Extranodal involvement occurs in approximately 95% of cases, with common sites including liver, bone marrow, gastrointestinal tract, and skin 1

Treatment Response as Prognostic Indicator

Complete response to first-line anthracycline-based chemotherapy differs significantly by ALK status 4:

• ALK-positive: 86% complete response rate 4
• ALK-negative: 68% complete response rate 4

Ki-67 expression ≥80% independently predicts lower complete response rates (P=0.04) 5

Risk Stratification Algorithm

A practical four-tier risk stratification can be constructed using age and β2-microglobulin 4:

1. Lowest risk: Age <40 years + β2-microglobulin <3 mg/L (8-year OS: 84%)
2. Intermediate-low risk: One adverse factor present
3. Intermediate-high risk: Both adverse factors present
4. Highest risk: Age ≥40 years + β2-microglobulin ≥3 mg/L (8-year OS: 22%)

Critical Clinical Caveat

The prognostic advantage of ALK positivity is age-dependent and diminishes in older patients 1, 4. In multivariate analysis including age as a continuous variable, ALK status may lose independent significance, suggesting that the survival benefit is most pronounced in younger patients 1, 4.