What is the role of an Anaplastic Lymphoma Kinase (ALK) inhibitor, such as crizotinib (crizotinib) or ceritinib (ceritinib), in the treatment of a patient with ALK-positive (ALK+) Large B-cell Lymphoma (LBCL)?

ALK Inhibitors Are Effective Targeted Therapy for ALK+ LBCL

ALK inhibitors, particularly alectinib, should be used in patients with relapsed or refractory ALK-positive large B-cell lymphoma (ALK+ LBCL), as they demonstrate superior and more durable responses compared to crizotinib, with recent multi-institutional data showing meaningful clinical activity in this rare, chemotherapy-resistant disease. 1, 2

Evidence for ALK Inhibitor Use in ALK+ LBCL

Alectinib as the Preferred ALK Inhibitor

• Alectinib demonstrates an 80% objective response rate in relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL), with 60% achieving complete responses in a phase II trial of 10 patients. 2

• The 1-year progression-free survival with alectinib was 58.3%, and overall survival was 70.0% in patients who had progressed on standard chemotherapy. 2

• Alectinib is better tolerated than crizotinib, with the most common grade 3+ adverse event being neutropenia in only 20% of patients, and no unexpected toxicities. 2

• In the recent multi-institutional study of 39 ALK+ LBCL patients, alectinib showed more durable responses than crizotinib among the 12 patients who received ALK inhibitors. 1

• Alectinib has superior CNS penetration compared to crizotinib, which is critical given the aggressive nature of ALK+ LBCL. 3

Crizotinib as an Alternative Option

• Crizotinib is FDA-approved for pediatric and young adult patients with relapsed or refractory ALK-positive ALCL and has demonstrated an 83% objective response rate (58% complete response) in a phase II study. 3

• The estimated 2-year progression-free survival and overall survival rates with crizotinib were 65% and 66%, respectively, in ALK-positive ALCL. 3

• However, crizotinib lacks CNS penetration, making it less suitable for patients with CNS involvement. 3

• Case reports of crizotinib in ALK+ LBCL specifically show limited durability, with rapid progression despite initial partial responses. 4

Clinical Context: Why ALK Inhibitors Matter

Poor Outcomes with Standard Chemotherapy

• Standard anthracycline-based chemotherapy produces dismal outcomes in ALK+ LBCL, with median event-free survival of only 0.6 years and median overall survival of 1.5 years despite 92% of patients receiving frontline anthracycline-based regimens. 1

• Even intensified chemotherapy regimens (used in 43% of patients) and upfront autologous stem cell transplantation (15% of patients) failed to improve outcomes substantially. 1

• The 5-year overall survival rate remains only 42% with conventional approaches, highlighting the urgent need for biologically targeted therapies. 1

• Historical data show a 5-year survival rate of only 28% for ALK+ LBCL treated with standard regimens. 5

ALK+ LBCL Is Biologically Distinct

• ALK+ LBCL is uniformly CD20-negative, rendering rituximab ineffective and eliminating a key component of standard DLBCL therapy. 5, 4

• The disease is driven by ALK rearrangements activating STAT3/STAT5, PI3K/AKT, PLCG2, and ERK pathways, making it an ideal target for ALK inhibition. 5

• ALK+ LBCL predominantly affects males and can occur at any age, with aggressive clinical behavior and frequent advanced-stage presentation. 5

Treatment Algorithm for ALK+ LBCL

Frontline Treatment

• Initiate anthracycline-based chemotherapy (CHOP or dose-adjusted EPOCH) as initial therapy, recognizing its limitations. 1
• Consider early integration of ALK inhibitors in the frontline setting based on emerging data, though this remains investigational. 1

Relapsed/Refractory Disease

• Prioritize alectinib over crizotinib for relapsed or refractory ALK+ LBCL based on superior durability and CNS activity. 1, 2
• Dose alectinib at 300 mg orally twice daily (reduce to 150 mg twice daily for patients <35 kg). 2
• If alectinib is unavailable, use crizotinib at 250 mg twice daily, but monitor closely for rapid progression. 3, 4

Additional Therapeutic Options

• Lenalidomide demonstrates activity in ALK+ LBCL, including durable complete responses in some patients. 1
• Immune checkpoint inhibitors have shown activity and should be considered in the relapsed setting. 1
• Allogeneic stem cell transplantation achieved sustained remission in 3 of 5 patients and should be considered for eligible patients with chemosensitive disease. 1

Critical Pitfalls to Avoid

• Do not rely solely on chemotherapy intensification or upfront autologous transplantation, as these strategies have not improved outcomes in ALK+ LBCL. 1

• Do not use rituximab, as ALK+ LBCL is CD20-negative and will not respond to anti-CD20 therapy. 5, 4

• Do not choose crizotinib for patients with CNS involvement, as it lacks CNS penetration; alectinib is the preferred option. 3

• Monitor for pneumonitis with crizotinib, which can be life-threatening and requires immediate discontinuation. 3

• Recognize that responses to ALK inhibitors may not be as durable in LBCL as in NSCLC, necessitating close monitoring and consideration of consolidative allogeneic transplantation. 1