What is the management of anaplastic large cell lymphoma (ALCL)?

Management of Anaplastic Large Cell Lymphoma (ALCL)

For newly diagnosed systemic ALCL, brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, prednisone) is the preferred first-line regimen based on Category 1 evidence from the ECHELON-2 trial, which demonstrated superior progression-free survival and overall survival compared to standard CHOP. 1, 2

Initial Treatment Strategy by Disease Stage and ALK Status

ALK-Positive ALCL (Better Prognosis)

Stage I-II Disease:

• Multiagent chemotherapy for 6 cycles with or without involved-site radiation therapy (ISRT), OR 3-4 cycles with ISRT 1
• Brentuximab vedotin + CHP is the preferred regimen (Category 1) 1, 2
• Alternative regimens include CHOP, CHOEP (CHOP plus etoposide), or dose-adjusted EPOCH 1

Stage III-IV Disease:

• Multiagent chemotherapy for 6 cycles without radiation 1
• Same preferred and alternative regimens as stage I-II 1
• ALK-positive ALCL has favorable outcomes with anthracycline-based regimens, with better prognosis than ALK-negative disease 1

ALK-Negative ALCL

All Stages:

• Clinical trial participation is preferred for all stages 1
• If no clinical trial available: multiagent chemotherapy (6 cycles) with or without ISRT for stage I-IV disease 1
• Brentuximab vedotin + CHP remains preferred (Category 2A) 1
• Important exception: ALK-negative ALCL with DUSP22 rearrangement has prognosis similar to ALK-positive disease and may be treated according to ALK-positive algorithm 1

Primary Cutaneous ALCL (pcALCL)

Localized Disease:

• Surgical excision or radiation therapy (24-30 Gy) as first-line treatment, achieving complete remission in ≥95% of cases 1
• Spontaneous regression occurs in up to 44% of patients, particularly with solitary lesions 1
• Relapses occur in approximately 40% after surgery or radiation but do not worsen prognosis 1

Multifocal Disease:

• Low-dose methotrexate is reasonable despite limited evidence 1
• Brentuximab vedotin (1.8 mg/kg up to 180 mg every 3 weeks for maximum 16 cycles) for patients who received prior systemic therapy 2
• Multiagent chemotherapy (particularly CHOP) is NOT recommended as first-line for skin-limited disease due to high relapse rates (71%) 1
• Reserve multiagent chemotherapy only for extracutaneous spread 1

First-Line Consolidation

Consider high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) for patients achieving good response to induction therapy. 1

• Multiple retrospective studies show improved outcomes with first-line consolidation HDT/ASCR 1
• ALCL patients showed nonsignificant trend toward improved event-free survival (67%) with HDT/ASCR compared to other PTCL subtypes 1
• Initiate consolidation within 4-6 weeks post-auto-HSCT or upon recovery 2

Relapsed/Refractory Disease

Second-Line Therapy (Transplant-Eligible Patients)

Clinical trial participation is preferred. 1

Preferred Single Agents:

• Brentuximab vedotin (1.8 mg/kg up to 180 mg every 3 weeks) 1, 2
• Belinostat 1
• Pralatrexate 1
• Romidepsin 1

Preferred Combination Regimens:

• DHAP (dexamethasone, cisplatin, cytarabine) 1
• ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) 1
• GDP (gemcitabine, dexamethasone, cisplatin) 1
• GemOx (gemcitabine, oxaliplatin) 1
• ICE (ifosfamide, carboplatin, etoposide) 1

Proceed to HDT/ASCR or allogeneic stem cell transplant based on patient eligibility and chemosensitivity. 1

Transplant-Ineligible Patients

• Use same preferred single agents or combination regimens as above 1
• Consider maintenance strategies upon response 1

Emerging Targeted Therapies

ALK Inhibitors (for ALK-positive ALCL):

• Crizotinib, alectinib, and ceritinib are being used in clinical settings for relapsed/refractory disease 3
• These agents target the NPM-ALK fusion protein characteristic of ALK-positive ALCL 3

Brentuximab Vedotin Mechanism:

• Anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E (antitubulin agent) 1, 2
• CD30 is uniformly and strongly expressed on ALCL cells 4, 3
• FDA-approved for multiple ALCL indications with demonstrated efficacy 2

Key Prognostic Factors

Favorable:

• ALK-positive status (better outcomes than ALK-negative) 1, 3
• DUSP22 rearrangement in ALK-negative disease 1
• Younger age 1
• Lower International Prognostic Index scores 3, 5

Unfavorable:

• ALK-negative status 1
• Age >60 years 5
• Ann Arbor stage III-IV 5
• High serum LDH 5
• Performance status >2 5
• CD56 positivity 5

Critical Pitfalls to Avoid

• Do not use CHOP as first-line for multifocal primary cutaneous ALCL limited to skin due to 71% relapse rate; reserve for extracutaneous spread 1
• Do not assume all ALK-negative ALCL has poor prognosis; check for DUSP22 rearrangement which confers better outcomes 1
• Do not delay brentuximab vedotin + CHP in favor of standard CHOP for newly diagnosed systemic ALCL, as ECHELON-2 demonstrated superior survival 1, 2
• Do not overlook spontaneous regression potential in primary cutaneous ALCL; observation may be appropriate for some patients 1
• Avoid ADCETRIS in severe renal impairment (CrCL <30 mL/min) 2