Chronic lymphocytic leukemia (CLL/SLL)

Diagnosis & Prognostication

• Diagnostic criteria: ≥5 × 10⁹/L clonal B cells in PB w/ characteristic phenotype: CD5+, CD19+, CD20 dim, CD23+, surface Ig dim, FMC7-, CD79b-. SLL = same disease w/ <5k circulating, nodal/splenic.
• Smudge cells: fragile lymphocytes on smear — classic.
• Monoclonal B-cell lymphocytosis (MBL): clonal B cells <5k w/o lymphadenopathy/cytopenias — pre-cursor to CLL; high-count MBL (clonal B ≥0.5 to <5 × 10⁹/L) progresses ~1 to 2%/yr, low-count MBL far less.
• Workup: CBC w/ smear, flow (CLL-typical), TP53 mutation/del 17p (FISH + sequencing), IGHV mutation status (mutated = better; unmutated = worse), other FISH (del 13q — best, +12, del 11q — ATM, del 17p — TP53 worst), B2M.
• CLL-IPI: age >65, advanced stage (Rai/Binet), ↑ B2M, IGHV unmutated, del(17p)/TP53 — 4 risk groups.
• Rai staging: 0=lymphocytosis only, I=LAD, II=splenomegaly/hepatomegaly, III=anemia (Hb <11), IV=thrombocytopenia (plt <100k).

When to Treat

• Watch & wait until iwCLL criteria: progressive marrow failure (Hb <10 or plt <100k from CLL), massive/progressive splenomegaly (≥6 cm BCM) or LAD (≥10 cm), AIHA/ITP poorly responsive to corticosteroids, B sx, lymphocyte doubling time <6 mo.
• No survival benefit to early treatment: observation in asymptomatic. Surveillance q3-6 mo.

Treatment — Frontline

• BTKi (continuous, covalent): Acalabrutinib (Calquence) — preferred 2nd-gen; ELEVATE-RR (Byrd JCO 2021) — non-inferior PFS, less afib/HTN vs ibrutinib in high-risk R/R; FDA Nov 2019 (R/R), Nov 2019 (newly dx). Zanubrutinib (Brukinsa) — FDA Jan 2023 for CLL/SLL based on ALPINE (Brown JR NEJM 2023 — superior PFS vs ibrutinib in R/R) and SEQUOIA (Tam Lancet Oncol 2022, newly dx). Ibrutinib (Imbruvica) — older 1st-gen; afib/HTN/bleeding/arthralgia. Frontline acalabrutinib often combined w/ obinutuzumab (ELEVATE-TN — Sharman Lancet 2020 — A+O and A alone both superior PFS vs chlor+obi; A+O numerically longer PFS than A alone (not powered for this comparison)).
• Venetoclax + obinutuzumab (V+O): time-limited 12 mo (CLL14, Fischer NEJM 2019, in comorbid/unfit pts; CLL13 supports use in fit pts). Good option for pts wanting finite therapy.
• Acalabrutinib + venetoclax (A+V), fixed-duration, all-oral; adding obinutuzumab (IV) makes the triplet partly intravenous: FDA approved Feb 19, 2026 (A+V only; A+V+O not FDA-approved) for previously untreated CLL/SLL based on AMPLIFY (Brown JR et al, NEJM 2025; enrolled only pts w/o 17p/TP53). 36-mo PFS 76.5% (A+V) and 83.1% (A+V+O) vs 66.5% chemoimmunotherapy. First all-oral fixed-duration regimen approved for frontline CLL. AMPLIFY excluded del(17p)/TP53, so A+V has no randomized data in that subgroup; continuous BTKi is preferred there (a trial/data gap, not necessarily an FDA label restriction).
• Ibrutinib + venetoclax (I+V) fixed-duration: GLOW (Kater AP et al, NEJM Evidence 2022), CAPTIVATE (Tam C et al, Blood 2022; phase 2, no comparator arm). PFS benefit vs chlor+obi in GLOW. EU and Canada approved frontline; not FDA-approved as combo for frontline CLL. FLAIR (Munir T et al, NEJM 2024) — I+V superior to FCR in fit pts.
• TP53/del 17p: avoid chemo (FCR/BR ineffective); BTKi or V+O preferred.
• FCR (fludarabine + cyclophosphamide + rituximab): historical; only IGHV-mutated young fit pts may have curative-like long PFS plateau (CLL8). Risk of t-MDS/AML, infections; largely supplanted by targeted.

R/R CLL

• Pirtobrutinib (Jaypirca): non-covalent reversible BTKi. FDA Jan 2023 for R/R MCL ≥2 LOT incl covalent BTKi; Dec 1, 2023 for R/R CLL/SLL after ≥2 LOT incl BTKi + BCL2 inhibitor (accelerated; BRUIN, Mato AR et al, NEJM 2023 (389:33); ORR 73.3%, mPFS 19.6 mo in 247 covalent-BTKi-pretreated pts (100 also BCL2i-exposed), broader than the 108-pt double-exposed cohort of the accelerated approval); Dec 3, 2025 traditional approval expanded to R/R CLL/SLL after any prior covalent BTKi (BRUIN CLL-321 vs idelalisib-R or BR: mPFS 11.2 vs 8.7 mo, HR 0.58). Active vs C481S/R (covalent binding-site) mutations; acquired resistance to pirtobrutinib arises via non-C481 BTK mutations (T474 gatekeeper, L528W kinase-dead, V416L, A428D) or PLCG2. BRUIN CLL-314 (vs ibrutinib, BTKi-naïve) showed noninferior ORR.
• Lisocabtagene maraleucel (Breyanzi) for CLL/SLL: FDA Mar 14, 2024 for R/R CLL/SLL after ≥2 LOT incl covalent BTKi and BCL2 inhibitor (TRANSCEND CLL 004, Siddiqi T et al, Lancet 2023; FDA efficacy set n=65: CR 20%, ORR 45%, durable; Lancet primary set, BTKi progression plus venetoclax failure, n=49: CR/CRi 18%). First CAR-T approved for CLL. Class AEs: CRS, ICANS, prolonged cytopenias.
• Sequencing options: BTKi → V+O → pirtobrutinib → CAR-T → allo-HSCT.
• Allo-HSCT: for fit pts w/ failure of multiple targeted lines; less common in BTKi era.

Complications

• Richter's transformation: transformation to aggressive lymphoma (usually DLBCL ~80%; rarely Hodgkin). Suspect w/ rapid clinical decline, ↑ LDH, asymmetric large LAD — PET-guided biopsy. Clonally related = poor prognosis (median OS ~12 mo); clonally unrelated = better. Treat as DLBCL ± allo-HSCT consolidation.
• Autoimmune cytopenias: AIHA (~10%), ITP, PRCA — treat w/ steroids ± rituximab; rarely splenectomy.
• Infections: hypogammaglobulinemia → IVIG for recurrent serious infections; PJP/HSV/VZV ppx during fludarabine or post-allo; pneumococcal/influenza/COVID vaccines.
• Second malignancies: skin cancers (esp Merkel cell — counsel re: skin checks), lung, melanoma — all increased.