Anaplastic Large Cell Lymphoma

CD30+ T-cell NHL — ALK+ vs ALK− biology, brentuximab vedotin–CHP frontline standard, and divergent outcomes by ALK status

Key Points

• ALCL is a CD30-positive T-cell lymphoma that comprises ALK-positive (ALK+) and ALK-negative (ALK−) systemic subtypes, plus primary cutaneous ALCL — each with distinct biology, prognosis, and treatment.
• ALK+ ALCL, typically driven by the t(2;5)(p23;q35) NPM1–ALK fusion, predominantly affects younger patients and carries a favorable prognosis with 5-year OS of ~70–80%.
• ALK− ALCL more often affects older adults, lacks ALK rearrangement, and has a worse prognosis (5-year OS ~40–50%), similar to other PTCL subtypes.
• The ECHELON-2 trial established brentuximab vedotin (BV) + CHP (cyclophosphamide, doxorubicin, prednisone) as the standard first-line regimen for CD30+ PTCL including ALCL, demonstrating superior PFS and OS over CHOP.
• DUSP22 rearrangement in ALK− ALCL confers a prognosis similar to ALK+ disease; TP63 rearrangement predicts very poor outcomes.
• Primary cutaneous ALCL is a distinct, indolent entity managed with skin-directed therapy and has an excellent prognosis; systemic therapy is rarely needed.

Classification and Molecular Biology

ALCL is defined by large pleomorphic cells with abundant cytoplasm, horseshoe- or kidney-shaped nuclei ("hallmark cells"), and uniform strong CD30 expression. It is divided into three main entities: **Systemic ALK+ ALCL:** Driven in ~80% of cases by the t(2;5)(p23;q35) translocation creating the NPM1–ALK fusion protein, which constitutively activates JAK/STAT3, PI3K/AKT, and RAS/ERK signaling. Other less common ALK rearrangement partners include TPM3, TFG, ATIC, and CLTC. ALK+ ALCL predominantly affects children and young adults and has an excellent prognosis. **Systemic ALK− ALCL:** Lacks…

Clinical Features and Diagnosis

Systemic ALCL typically presents with peripheral and/or abdominal lymphadenopathy, B symptoms (fever, night sweats, weight loss), and elevated LDH. Extranodal involvement (skin, soft tissue, bone, lung) occurs in approximately 40–60% of systemic ALCL cases; primary bone ALCL is a recognized variant with good prognosis. Bone marrow involvement is present in ~10–30% of cases. ALK+ ALCL affects a younger median age (~30 years), whereas ALK− ALCL predominantly affects adults over 55. Children and adolescents with ALCL are almost exclusively ALK+. Diagnosis is established by biopsy with…

Staging and Risk Stratification

ALCL is staged by the Lugano classification (modified Ann Arbor). Advanced stage (III–IV) is present in the majority of systemic ALCL cases at diagnosis. The IPI (International Prognostic Index) and PIT score are used for risk stratification. In ALK+ ALCL, the IPI performs well: low-risk patients have 5-year OS exceeding 90%; high-risk patients have 5-year OS of ~40–60%. Molecular subgrouping is the most powerful prognosticator in ALK− ALCL: - ALK+ ALCL: 5-year OS ~70–80% - ALK− ALCL with DUSP22 rearrangement: 5-year OS ~90% - ALK− ALCL, triple-negative: 5-year OS ~40–50% - ALK− ALCL with…

Treatment

**First-Line Therapy** The ECHELON-2 trial (N=452) was a landmark phase III study demonstrating that brentuximab vedotin (BV) + CHP (cyclophosphamide, doxorubicin, prednisone) is superior to CHOP for CD30+ PTCL, with a significant portion of patients having ALCL. Updated 5-year follow-up confirmed superior OS with BV+CHP (overall HR 0.68). BV+CHP is now the standard frontline regimen for systemic ALCL (both ALK+ and ALK−). For patients achieving CR/PR after frontline therapy, consolidation with auto-SCT is generally recommended for ALK− ALCL and high-risk ALK+ ALCL, based on retrospective…

Prognosis and Special Considerations

Prognosis in ALCL is largely determined by ALK status and molecular subgrouping. ALK+ ALCL in children and young adults is one of the most curable aggressive lymphomas, with long-term remission rates >75%. In contrast, ALK− ALCL without DUSP22 rearrangement carries prognosis comparable to other aggressive PTCL subtypes. ALK+ ALCL in pediatric patients is treated with ALCL99 or Berlin-Frankfurt-Münster (BFM) protocols, which incorporate vinblastine and differ from adult regimens. Pediatric outcomes are excellent with chemotherapy alone, and the role of transplant consolidation is debated in…