47  CLL / Small Lymphocytic Lymphoma

Key Points
  • CLL vs SLL: Same disease; CLL = ≥5K B-lymphocytes/μL PB; SLL = lymph node/spleen involvement
  • Phenotype: CD5+, CD19+, CD23+, weak sIg; clonal κ or λ restriction
  • Epi: ~5–7 per 100K/yr; age 70; male 2:1; ~5% familial
  • Prognosticstics: TP53 mut/del(17p) worst; NOTCH1, SF3B1 intermediate; unmutated IGHV aggressive; del(13q) best
  • BTK inhibitors: Ibrutinib, acalabrutinib, zanubrutinib 1st-line; continuous ± fixed-duration
  • Venetoclax: BCL2 inhibitor; fixed-duration 12 mo a/w obinutuzumab or rituximab
  • Refractory: Pirtobrutinib (BTK mut), CAR-T (tisagenlecleucel), allo-SCT
  • Complications: Infection, AIHA, ITP, Richter (CLL→DLBCL), TLS

47.1 Definition & Epidemiology

  • CLL/SLL identical disease
    • CLL: ≥5K clonal B-cells/μL PB × ≥3 mo
    • SLL: lymph node/tissue, minimal PB involvement
  • Incidence: 5–7 per 100K/yr; western countries most common leukemia
  • Demographics: age 70 median; M:F 2:1; 5% familial
  • Pathogenesis: clonal B-cell expansion w/ accumulated mutations; microenvironment-driven

47.2 Diagnosis

  • Diagnostic criteria: ≥5K clonal B-cells/μL PB × ≥3 mo
  • Flow cytometry phenotype
    • CD5+ (aberrant), CD19+, CD23+, weak sIg, weak CD20
    • CD10−, FMC7−
    • Clonality: κ or λ restriction
  • Labs: CBC, CMP, LDH, uric acid, β2-microglobulin
  • Prognostic markers: See table below
    • IGHV ≥98% homology = unmutated (worse)
    • IGHV <98% = mutated (better)
  • Biopsy: Not needed if dx confirmed; obtain if SLL or morphologic concern
Prognostic Markers in CLL
Marker Prognostic Impact Testing
TP53 mutation/del(17p) Worst prognosis; rapid progression; treatment resistance TP53 sequencing, FISH del(17p)
NOTCH1 mutation Intermediate risk; higher failure rates w/ chemotherapy Targeted sequencing
SF3B1 mutation Intermediate risk; del(11q)-like outcomes Targeted sequencing
Unmutated IGHV Aggressive course; shorter time to treatment IGHV sequencing (98% threshold)
del(11q) Intermediate risk; ATM loss FISH
del(13q) Favorable; longest overall survival FISH
Trisomy 12 Intermediate FISH
Beta-2 microglobulin ↑ level = adverse; surrogate for tumor burden & prognosis Serum quantification
TP53 wild-type, mutated IGHV Best prognosis Combined markers

47.3 Presentation & Staging

  • Asymptomatic: ~50%; incidental elevated WBC; “watch & wait” appropriate
  • Symptomatic: B-sx, lymphadenopathy, hepatosplenomegaly, fatigue, infections
  • Rai staging (USA)
    • Stage 0: lymphocytosis only
    • Stage I: + lymphadenopathy
    • Stage II: + hepatosplenomegaly
    • Stage III: + anemia (Hb <11)
    • Stage IV: + thrombocytopenia (<100K)
  • Binet staging (Europe): A (<3 areas) → B (≥3 areas) → C (cytopenia)
  • MRD status (≤10^-4 clonal cells): predicts remission durability

47.4 Early-Stage CLL (Rai 0–I, Binet A)

  • Watch & wait standard; no survival benefit from immediate tx
    • ~10% progress/yr to require treatment
  • Intervene if: doubling time <6 mo, ↑ LDH/β2-microglobulin, cytopenias, B-sx, bulky dz

47.5 Newly Diagnosed Advanced CLL (Rai II–IV, Binet B–C)

  • BTK inhibitors: Standard 1st-line
    • Ibrutinib: Continuous; OR ~70%, median PFS ~20 mo
    • Acalabrutinib, zanubrutinib: Comparable; lower tox than ibrutinib
  • Venetoclax-based: 12-mo fixed-duration
    • Venetoclax + obinutuzumab (CLL14) or + rituximab
    • Deeper remissions; MRD-negative in majority
    • Better tolerability than FCR (fludarabine/cyclophosphamide/rituximab)
  • High-risk (TP53 mut/del(17p), unmutated IGHV)
    • BTK inhibitors or venetoclax preferred
    • Avoid chemotherapy (FCR poor)
    • Consider allo-SCT if early relapse

47.6 Relapsed/Refractory CLL

  • Prior BTK inhibitor
    • Venetoclax approved
    • Pirtobrutinib (non-covalent BTK) for BTK-mut; 80% response
    • Acalabrutinib/zanubrutinib alternatives
  • Prior venetoclax
    • BTK inhibitor (ibrutinib preferred if naive)
    • Idelalisib + rituximab (PI3K inhibitor); OR ~60% but GI tox, PCP risk
  • CAR-T cell: Tisagenlecleucel (CD19-targeted)
    • OR 50–60%, CR ~40%
    • CRS/neurotoxicity manageable
  • Allo-SCT: RIC preferred; high-risk, early relapse, refractory
  • Chemotherapy: FCR obsolete; bendamustine + rituximab if no TP53 mut

47.7 Complications

Infections - Bacterial: S. pneumoniae, H. influenzae; vaccinate pre-BTK/venetoclax - Viral: CMV, HSV, VZV; prophylaxis high-risk - Opportunistic: PCP w/ idelalisib (TMP-SMX prophylaxis) - Fungal: Cryptococcal, atypical mycobacteria rare

AIHA (10% of CLL) - Direct Coombs+ in 35%, hemolysis in fewer - Rx: corticosteroids, IVIG, splenectomy if steroid-refractory

ITP (2–10%) - Rituximab, splenectomy for refractory

Richter transformation (2–10%) - CLL → aggressive DLBCL - Sudden deterioration, ↑ LDH - Median survival ~5 mo untreated - Rx: salvage chemo ± CAR-T, allo-SCT

Second malignancies - 5–10× ↑ skin cancer; baseline & surveillance exams

Tumor lysis syndrome - Risk: high burden + initiate therapy - Monitor: UA, K+, PO4, Cr - Rx: allopurinol/febuxostat, hydration, rasburicase ± allopurinol

Clinical Pearls
  • Early-stage asymptomatic: Watch & wait standard; no survival benefit from immediate tx
  • BTK inhibitors 1st-line: Standard for most; excellent PFS even high-risk
  • Venetoclax-based: Deeper remissions; fixed-duration feasible; MRD-negative improves outcome
  • TP53 mut/del(17p): Avoid chemotherapy; use BTK inhibitor or venetoclax
  • Prophylaxis: Vaccinate before BTK/venetoclax; monitor infections, AIHA, ITP

47.8 Prognosis & Follow-Up

Early-stage asymptomatic: >15 yr median OS; no benefit from immediate tx

Advanced favorable (del(13q), mutated IGHV): 10+ yr median OS w/ targeted agents

High-risk (del(17p), TP53 mut, unmutated IGHV): 5–8 yr median OS w/ BTK/venetoclax

Monitoring: Baseline labs, imaging (CT CAP if significant adenopathy) - Surveillance: CBC, LDH, β2-microglobulin q3–6mo; imaging PRN - On therapy: labs q1–3mo; hold BTK if infection/tox - TLS labs if initiating; infection prophylaxis; HBV/CMV screening

47.9 Bibliography

Baliakas P, Iskas M, Gardiner A, et al. Adverse prognostic significance of TP53 mutations in CLL is independent of del(17p): implications for risk stratification and treatment selection. Blood. 2018;131(18):2028-2038.

Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. NEJM. 2014;371(3):213-223.

Fischer K, Bahlo J, Fink AM, et al. Long-term remission after bendamustine therapy in chronic lymphocytic leukemia. J Clin Oncol. 2016;34(2):151-159.

Furman RR, Sharman JP, Coutre SE, et al. Idelalisib & rituximab in relapsed chronic lymphocytic leukemia. NEJM. 2014;370(11):997-1007.

Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients w/ CLL & comorbidities. NEJM. 2014;370(12):1101-1110.

Moreno C, Hodson DJ, Ferrer G, et al. Autoimmune cytopenias in chronic lymphocytic leukemia: Prevalence, clinical correlations & prognosis. Blood. 2010;116(23):4771-4776.

Roberts KG, Sekhri V, Gu Z, et al. Comprehensive assessment of genes for genetic risk of pediatric acute lymphoblastic leukemia. Blood. 2015;125(1):133-141.

Scarfò L, Chatzikonstantinou T, Rigolin GM, et al. TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical and therapeutic implications. Leukemia. 2019;33(12):2814-2824.

Thompson PA, Wierda WG. Venetoclax-based therapy for chronic lymphocytic leukemia. Blood Adv. 2018;2(21):3112-3121.

Wang L, Frequency of BCL2 inhibitor venetoclax-induced myelosuppression in chronic lymphocytic leukemia. Leuk Res. 2020;97:106397.

Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in first-line treatment of chronic lymphocytic leukemia. J Clin Oncol. 2018;36(23):2371-2379.