What are the current National Comprehensive Cancer Network (NCCN) guidelines for Chronic Lymphocytic Leukemia (CLL) treatment?

Current NCCN Guidelines for CLL Treatment

The NCCN recommends targeted therapies with BTK inhibitors or venetoclax-based regimens as the preferred first-line treatment for all patients with CLL, with treatment selection based on del(17p)/TP53 mutation status, IGHV mutation status, patient fitness, and comorbidities. 1

Key Diagnostic Criteria

• CLL diagnosis requires ≥5,000 clonal B lymphocytes/μL in peripheral blood sustained for at least 3 months, confirmed by flow cytometry showing characteristic phenotype (CD19+, CD5+, CD20 dim, CD23+, with kappa or lambda restriction) 1, 2
• Mandatory testing includes FISH with 4 probes to detect del(17p), del(11q), trisomy 12, and del(13q) 2
• IGHV mutation status should be determined before first treatment 1, 2
• TP53 mutation testing is required before first treatment and at each relapse 2

Treatment Initiation Criteria

Treatment should only be initiated in symptomatic patients meeting iwCLL criteria for active disease 1, 2. Observation ("watch and wait") is appropriate for asymptomatic early-stage patients 1.

First-Line Treatment Algorithm

For Patients with del(17p) or TP53 Mutation:

• Second-generation covalent BTK inhibitors (acalabrutinib or zanubrutoclax) administered continuously are the preferred option 2
• These agents overcome the poor prognosis historically associated with del(17p)/TP53 mutations 1

For Patients WITHOUT del(17p) or TP53 Mutation:

Mutated IGHV:

• Time-limited venetoclax-based combination therapy (venetoclax + obinutuzumab) is the preferred first option 2
• FCR (fludarabine, cyclophosphamide, rituximab) remains preferred for patients <65 years with mutated IGHV who are fit enough for chemoimmunotherapy 1

Unmutated IGHV:

• Both continuous BTK inhibitor therapy and finite venetoclax-based combination therapy are valid options 2
• Selection should consider potential toxicities, drug interactions, patient preference, and logistical aspects 2

For Frail Patients with Significant Comorbidities:

• Consider supportive care or less intensive regimens 1
• Avoid purine analog-based therapies in this population 1

Relapsed/Refractory Disease Management

Treatment selection depends on: 2

• Prior treatment received
• Biological risk features (del(17p), TP53 mutation, IGHV status)
• Duration of response to prior finite therapy
• Reason for discontinuing prior BTK inhibitor (if applicable)

Effective options include: 1

• Ibrutinib
• Acalabrutinib
• Idelalisib + rituximab
• Duvelisib
• Venetoclax ± rituximab

Supportive Care Considerations

Infection Prophylaxis:

• Universal antimicrobial prophylaxis is NOT routinely recommended for BTK or BCL-2 inhibitor monotherapy 1
• Consider PCP prophylaxis only in patients with additional risk factors (prior alemtuzumab, purine analog therapy, or prolonged high-dose corticosteroids) 1
• Herpes virus prophylaxis with acyclovir or valacyclovir is recommended during venetoclax therapy 1

HBV Reactivation Prevention:

• All patients should be screened for HBsAg and HBcAb before treatment 1
• HBsAg-positive patients require antiviral prophylaxis with high-barrier agents (entecavir or tenofovir) starting at treatment initiation and continuing ≥12 months after therapy completion 1

Immunoglobulin Replacement:

• Consider IVIG replacement for patients with hypogammaglobulinemia and recurrent/severe infections 3
• Target IgG trough levels of 600-800 mg/dL 3

Tumor Lysis Syndrome:

• Prophylaxis should be considered based on tumor burden, particularly when initiating venetoclax 1

Allogeneic Stem Cell Transplant

Allogeneic HCT is NOT considered a reasonable option after initial purine analog-based therapy failure, given the efficacy of targeted therapies 1. It may be considered only for: 1

• CLL/SLL refractory to small-molecule inhibitor therapy in patients without significant comorbidities
• Patients with del(17p)/TP53 mutation in remission with complex karyotype (≥3 abnormalities)

Important Caveats

• Clinical trial participation is strongly encouraged and considered the best management approach 1
• Most NCCN recommendations are Category 2A (uniform consensus based on lower-level evidence) unless otherwise specified 1
• Absolute lymphocyte count alone is NOT an indication for treatment 1
• Growth factor support should be considered for neutropenic patients 1
• The complete and most current NCCN Guidelines are freely available at NCCN.org 1