17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/3ykn5ops9bft5.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T68eb,## Summary Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are blood-predominant and tissue-predominant manifestations of the same mature B-cell neoplasm. CLL is diagnosed when the peripheral blood contains **≥5 × 10^9/L clonal B cells for at least 3 months** with a compatible immunophenotype. SLL has tissue disease with **<5 × 10^9/L circulating clonal B cells** and no cytopenia attributable to marrow infiltration. A smaller circulating clone without CLL/SLL manifestations is monoclonal B-cell lymphocytosis (MBL).[1] The decisive management principle is that **CLL is treated for active disease, not for the diagnosis or lymphocyte count alone**. Treatment indications include progressive marrow failure, massive/progressive/symptomatic lymphadenopathy or splenomegaly, rapid lymphocyte progression, poorly controlled autoimmune cytopenia, symptomatic extranodal disease, or defined disease-related constitutional symptoms.[1] Before first systemic therapy—and again before each subsequent line when relevant—test for **del(17p) by FISH and TP53 mutation**. Determine **IGHV mutation status once**. TP53 disruption strongly influences drug selection and argues against chemoimmunotherapy. Modern therapy is dominated by targeted agents, particularly covalent BTK inhibitors and venetoclax-based regimens.[2,3] Venetoclax requires tumor-lysis risk stratification, hydration, antihyperuricemic prophylaxis, review of drug interactions, and scheduled chemistry monitoring during dose escalation. The standard CLL ramp is **20 mg daily for 7 days, then 50 mg, 100 mg, 200 mg, and 400 mg at weekly steps**.[4] A major recent change is the **February 19, 2026 U.S. FDA approval of fixed-duration acalabrutinib plus venetoclax** for adults with CLL/SLL. In the approved regimen, acalabrutinib 100 mg approximately every 12 hours is given for up to 14 28-day cycles; venetoclax starts in cycle 3 with the standard 5-week ramp and continues at 400 mg daily through cycle 14.[5] For relapsed disease after a covalent BTK inhibitor, pirtobrutinib has a distinct noncovalent mechanism and received traditional U.S. approval in December 2025.[6] Longitudinal care includes infection prevention, vaccination, skin-cancer surveillance, management of autoimmune cytopenias and hypogammaglobulinemia, cardiovascular and bleeding risk review during BTK-inhibitor therapy, and vigilance for **Richter transformation**.[1-3] ## Disease spectrum | Entity | Peripheral-blood clonal B cells | Tissue disease / disease effects | Clinical implication | |---|---:|---|---| | CLL | ≥5 × 10^9/L for ≥3 months | May be present or absent | Leukemic presentation of CLL/SLL | | SLL | <5 × 10^9/L | Nodal/tissue disease; no cytopenia attributable to marrow infiltration for the SLL definition | Tissue-predominant presentation | | MBL | <5 × 10^9/L | No lymphadenopathy, organomegaly, cytopenia, or disease symptoms attributable to the clone | Precursor state; observation rather than CLL therapy | The threshold uses the **clonal B-cell count**, not the total lymphocyte count.[1] ## Biology and clinically relevant molecular features CLL cells are mature B lymphocytes whose survival depends on intrinsic genomic lesions and signals from the lymph-node and marrow microenvironment. B-cell receptor signaling and BCL-2–mediated resistance to apoptosis are particularly important therapeutic targets. BTK inhibition disrupts survival and tissue trafficking; BCL-2 inhibition with venetoclax restores apoptotic susceptibility.[2,3] ### TP53 disruption TP53 dysfunction may arise from **del(17p)**, a **TP53 mutation**, or both. It predicts inferior disease control with conventional chemoimmunotherapy and remains one of the most treatment-relevant high-risk features. Because resistant subclones can emerge, repeat TP53 sequencing and del(17p) assessment before a new treatment line when the result could alter therapy.[2,3] ### IGHV mutation status IGHV mutation status is biologically stable and ordinarily needs to be measured only once. Unmutated IGHV is associated with a more aggressive natural history than mutated IGHV. In the targeted-therapy era, IGHV retains prognostic value but should not be used alone to decide whether treatment is needed.[2,3] ### Common cytogenetic findings | Finding | General implication | Practical use | |---|---|---| | del(17p) | TP53 loss; high-risk biology | Strongly influences systemic treatment choice | | del(11q) | Historically associated with nodal burden | Mainly prognostic/contextual with current targeted therapy | | Trisomy 12 | Distinct biologic subgroup | Prognostic/contextual | | Isolated del(13q) | Often more favorable when sole lesion | Prognostic; does not override clinical treatment criteria | ## Clinical presentation Many patients are identified after an incidental CBC shows persistent lymphocytosis. Others present with painless lymphadenopathy, splenomegaly, fatigue, infection, anemia, thrombocytopenia, or constitutional symptoms. Common manifestations include: - persistent absolute lymphocytosis; - cervical, axillary, or inguinal lymphadenopathy; - splenomegaly with early satiety or left-upper-quadrant discomfort; - anemia or thrombocytopenia from marrow infiltration, hypersplenism, bleeding, nutritional causes, kidney disease, or autoimmune destruction; - recurrent bacterial or viral infection; - autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP); - unintentional weight loss, fever, drenching night sweats, or function-limiting fatigue in active disease. ### Features requiring urgent evaluation - sepsis or severe infection; - symptomatic severe anemia or clinically important bleeding; - rapidly falling hemoglobin or platelet count; - brisk hemolysis; - rapidly enlarging focal lymph node, major LDH rise, new hypercalcemia, severe focal pain, or abrupt constitutional symptoms suggesting Richter transformation; - symptomatic bulky disease causing airway, vascular, ureteric, gastrointestinal, or other organ compromise; - suspected venetoclax-associated tumor lysis syndrome (TLS); - major hemorrhage, clinically important arrhythmia, or severe hypertension during BTK-inhibitor therapy. A very high lymphocyte count by itself is rarely an emergency in CLL; leukostasis is uncommon compared with acute leukemia.[1] ## Diagnosis ### Peripheral blood and flow cytometry CLL generally requires **≥5 × 10^9/L clonal B lymphocytes in peripheral blood for at least 3 months**.[1] The typical immunophenotype includes: - CD19 positive; - CD5 positive; - CD23 positive; - relatively dim CD20; - weak surface immunoglobulin; - light-chain restriction. A blood film often shows small mature lymphocytes with condensed chromatin. Smudge cells are common but are neither specific nor sufficient for diagnosis. ### Important mimic: mantle cell lymphoma Mantle cell lymphoma can also express CD5. An atypical phenotype, strong B-cell antigen expression, absent CD23 in a suspicious context, cyclin D1 positivity, or a **CCND1 rearrangement/t(11;14)** should prompt a lymphoma-directed diagnostic pathway rather than assuming CLL. ### Bone marrow and lymph-node biopsy Bone marrow biopsy is **not routinely required to establish typical CLL** when peripheral blood findings are diagnostic. It is useful when unexplained cytopenias need clarification or another marrow disorder is suspected.[1] Lymph-node biopsy is appropriate when SLL needs tissue confirmation, another lymphoma is plausible, or Richter transformation is suspected. ## Baseline evaluation For a newly diagnosed patient, document: - CBC with differential and blood film; - renal and liver function; - lymph-node and spleen burden; - symptoms and functional status; - medication list and major comorbidities; - infection history and vaccination status; - immunoglobulin level when recurrent infection or treatment planning makes it useful; - hemolysis studies when anemia may be immune-mediated: reticulocyte count, bilirubin, LDH, haptoglobin, and direct antiglobulin testing. Routine CT surveillance is not required for a stable asymptomatic patient. Cross-sectional imaging is useful when symptoms, bulky disease, treatment planning, or suspected transformation justify it.[1,2] ## Staging ### Rai staging | Stage | Findings | |---|---| | 0 | Lymphocytosis only | | I | Lymphocytosis plus lymphadenopathy | | II | Lymphocytosis plus splenomegaly and/or hepatomegaly, with or without lymphadenopathy | | III | Lymphocytosis plus anemia, classically hemoglobin <11 g/dL | | IV | Lymphocytosis plus thrombocytopenia, classically platelets <100 × 10^9/L | ### Binet staging | Stage | Criteria | |---|---| | A | Fewer than 3 involved lymphoid areas; no anemia or thrombocytopenia | | B | 3 or more involved lymphoid areas; no anemia or thrombocytopenia | | C | Anemia and/or thrombocytopenia regardless of involved areas | Staging describes burden and prognosis; **stage alone is not a treatment trigger**. Establish why a cytopenia is present before attributing it to CLL.[1] ## When to start treatment Treatment is indicated for **active disease**. The 2018 iwCLL criteria remain foundational and are incorporated into current consensus pathways.[1-3] At least one of the following supports treatment: 1. **Progressive marrow failure**, typically worsening anemia and/or thrombocytopenia attributable to CLL. Hemoglobin <10 g/dL or platelets <100 × 10^9/L are commonly used thresholds, but a stable platelet count below 100 does not automatically mandate therapy.[1] 2. **Massive, progressive, or symptomatic splenomegaly**, classically ≥6 cm below the left costal margin when massive.[1] 3. **Massive, progressive, or symptomatic lymphadenopathy**, classically ≥10 cm in longest diameter when massive.[1] 4. **Progressive lymphocytosis**, such as ≥50% increase over 2 months, or lymphocyte-doubling time <6 months after excluding other causes of lymphocytosis.[1] 5. **Autoimmune anemia or thrombocytopenia poorly responsive to corticosteroids** or otherwise requiring CLL-directed therapy.[1] 6. **Symptomatic or functionally important extranodal involvement**.[1] 7. **Disease-related symptoms**, including one or more of: ≥10% unintentional weight loss in 6 months, substantial fatigue limiting usual function, fever ≥38.0°C for at least 2 weeks without infection, or night sweats for at least 1 month without infection.[1] Do not start CLL therapy for hypogammaglobulinemia alone, a rising lymphocyte count that does not meet progression criteria, or a high absolute lymphocyte count without another treatment indication.[1] > **Clinical pearl:** Early targeted treatment of asymptomatic patients outside a specific evidence-based indication has not replaced observation as standard care. “Watch and wait” is active surveillance, not therapeutic neglect.[1-3] ## Pretreatment workup Before systemic therapy, obtain or update: - FISH including del(17p); - TP53 mutation testing; - IGHV mutation status if never measured; - CBC, renal and liver function; - hepatitis B screening before anti-CD20 therapy; - pregnancy assessment when relevant; - vaccination and infection-risk review; - cardiovascular history, blood pressure, arrhythmia history, bleeding history, anticoagulant/antiplatelet use when a BTK inhibitor is being considered; - tumor burden and renal function when venetoclax will be used. Treatment selection should also consider prior therapies, reason for discontinuation, drug interactions, frailty, kidney function, preference for continuous versus fixed-duration therapy, access, and local regulatory indications.[2,3] ## First-line systemic therapy Contemporary treatment is usually built around a **BTK inhibitor** or a **venetoclax-containing fixed-duration regimen**. Exact selection varies by jurisdiction and by the patient's biology and comorbidities.[2,3] ### Covalent BTK inhibitors Acalabrutinib and zanubrutinib are widely used second-generation covalent BTK inhibitors. They are generally favored over first-generation ibrutinib when a covalent BTK strategy is chosen because comparative data show favorable efficacy and/or tolerability profiles in relevant settings.[2,3,7] Important class toxicities include: - bleeding; - atrial arrhythmia and other cardiovascular events; - hypertension; - infection; - cytopenia; - peri-procedural bleeding risk; - drug interactions, particularly CYP3A interactions. Assess blood pressure and cardiac symptoms longitudinally. Peri-procedural interruption depends on bleeding risk and the specific product label. ### Venetoclax-based fixed-duration therapy Venetoclax is a potent BCL-2 inhibitor capable of deep remissions, but TLS prevention is essential.[4] For CLL/SLL, the standard dose ramp is: | Week | Venetoclax dose | |---|---:| | 1 | 20 mg once daily | | 2 | 50 mg once daily | | 3 | 100 mg once daily | | 4 | 200 mg once daily | | 5 and thereafter | 400 mg once daily when this is the regimen target | Before initiation: - measure lymph-node size and absolute lymphocyte count; - assess kidney function; - correct clinically important electrolyte abnormalities; - provide hydration and antihyperuricemic prophylaxis according to TLS risk; - review CYP3A/P-gp interactions; - plan chemistry monitoring at the label-specified intervals; - use inpatient monitoring for patients whose TLS risk and renal function warrant it.[4] > **Caution:** Venetoclax should not be started at the full treatment dose. The ramp, prophylaxis, and laboratory schedule are safety-critical components of therapy.[4] ### Acalabrutinib plus venetoclax On **February 19, 2026**, the U.S. FDA approved acalabrutinib plus venetoclax for adults with CLL/SLL.[5] In the approved fixed-duration schedule: - acalabrutinib: **100 mg approximately every 12 hours**, for up to 14 28-day cycles; - venetoclax: begins in cycle 3 with the standard 5-week escalation, then **400 mg once daily through cycle 14**.[5] The pivotal AMPLIFY population excluded del(17p) and TP53-mutated disease, so treatment decisions in TP53-disrupted CLL require careful use of evidence specific to that high-risk group.[5] ### TP53-disrupted disease For del(17p) and/or TP53-mutated CLL, avoid relying on chemoimmunotherapy. Continuous BTK-inhibitor strategies and other targeted approaches are preferred, with selection tailored to prior exposure, comorbidities, and local approvals.[2,3] ## Relapsed or refractory CLL/SLL Management depends on what the disease has already seen, whether prior therapy failed from resistance or intolerance, duration of prior response, TP53 status, and patient-specific toxicities.[2,3] ### Progression during a covalent BTK inhibitor Resistance to one covalent BTK inhibitor is generally not managed by simply switching to another covalent BTK inhibitor. Options may include venetoclax-based therapy, a noncovalent BTK inhibitor, cellular therapy, or a clinical-trial strategy depending on prior exposure and jurisdiction.[2,3,6] ### Intolerance to a covalent BTK inhibitor If the prior drug was stopped for intolerance rather than disease resistance, switching to another better-tolerated covalent BTK inhibitor may be reasonable in selected patients.[2,3] ### Pirtobrutinib Pirtobrutinib is a noncovalent BTK inhibitor. On **December 3, 2025**, the U.S. FDA granted traditional approval for adults with relapsed/refractory CLL/SLL previously treated with a covalent BTK inhibitor. The recommended dose is **200 mg orally once daily**.[6] ### Cellular therapy Lisocabtagene maraleucel is a CD19-directed CAR-T therapy with a U.S. indication for selected adults with relapsed/refractory CLL/SLL after at least two prior lines that included a BTK inhibitor and a BCL-2 inhibitor; the indication was granted under accelerated approval based on response and durability data.[8] Referral to a center experienced in cellular therapy is appropriate when the patient approaches this treatment space, because candidacy, bridging therapy, infection risk, cytokine-release syndrome, neurologic toxicity, and prolonged cytopenia require specialist planning. ## Autoimmune cytopenias ### Autoimmune hemolytic anemia Consider AIHA when anemia is accompanied by reticulocytosis, indirect hyperbilirubinemia, low haptoglobin, elevated LDH, and a compatible direct antiglobulin test. Exclude bleeding, marrow failure, renal disease, and nutritional deficiency. Initial therapy is usually directed at the autoimmune process. CLL-directed therapy is appropriate when autoimmune cytopenia is poorly controlled, recurrent, or accompanied by another active-disease indication.[1-3] ### Immune thrombocytopenia ITP should be distinguished from marrow-infiltration thrombocytopenia, hypersplenism, infection, drug effect, thrombotic microangiopathy, and other causes. A disproportionate platelet decline with relatively preserved other cell lines may support the diagnosis. Treatment is individualized according to bleeding risk, platelet count, response, and concurrent CLL activity. ## Infection prevention and supportive care CLL itself and its therapies impair humoral and cellular immunity. ### Vaccination Use age- and risk-appropriate **non-live vaccines**, ideally before highly immunosuppressive therapy when feasible. Influenza, COVID-19, pneumococcal, and recombinant zoster vaccination are commonly relevant. Vaccine responses may be blunted, but vaccination remains worthwhile.[2,3] Avoid live vaccines in significantly immunocompromised patients unless a specialist has established that the product is safe in the specific circumstance. ### Hypogammaglobulinemia Low immunoglobulin concentration alone is not an indication for immunoglobulin replacement. Consider replacement in selected patients with recurrent or severe bacterial infections plus clinically important hypogammaglobulinemia despite appropriate preventive measures.[2,3] ### Anti-CD20 therapy and hepatitis B Screen for hepatitis B before anti-CD20 monoclonal antibody therapy. Patients with evidence of current or prior infection may require antiviral prophylaxis or close virologic monitoring according to hepatology/infectious-disease guidance. ### Secondary malignancy and skin cancer CLL is associated with increased risk of secondary malignancy, particularly nonmelanoma skin cancer. Continue standard cancer screening and encourage regular skin surveillance and sun protection.[2,3] ## Richter transformation Richter transformation most commonly represents transformation to an aggressive large B-cell lymphoma. Suspect it when there is: - rapid growth of one or a few lymph-node regions; - new or rapidly worsening constitutional symptoms; - disproportionate LDH elevation; - hypercalcemia; - new extranodal disease; - abrupt clinical deterioration despite otherwise indolent CLL. PET/CT can help identify the most metabolically active site, but diagnosis requires tissue biopsy. Excisional or core biopsy of the most suspicious accessible lesion is preferred over assuming that CLL progression explains the presentation.[2,3] ## Monitoring during observation For patients without a treatment indication, follow-up frequency depends on disease trajectory and clinical risk. At each visit, assess: - CBC trend; - lymph-node and spleen burden; - constitutional symptoms; - recurrent infection; - autoimmune cytopenia features; - medication and vaccination status; - skin and other malignancy risk. Do not use routine serial CT solely to follow stable asymptomatic CLL.[1-3] ## Monitoring during treatment Monitoring depends on regimen but commonly includes: | Therapy | Key monitoring | |---|---| | BTK inhibitor | CBC, bleeding, blood pressure, atrial arrhythmia/cardiac symptoms, infection, interactions, peri-procedural plan | | Venetoclax | TLS risk before start, scheduled electrolytes/creatinine during escalation, CBC, infection, interactions | | Anti-CD20 monoclonal antibody | Infusion reactions, CBC, infection, hepatitis B reactivation risk | | Cellular therapy | Cytopenia, infection, cytokine-release syndrome, neurologic toxicity, prolonged immune suppression | Persistent cytopenia on treatment should not automatically be attributed to drug toxicity; assess disease progression, infection, autoimmune causes, marrow disease, and nutritional factors as appropriate. ## Response and progression Clinical response integrates blood counts, lymph-node/spleen burden, symptoms, and, in selected settings, marrow assessment. Minimal residual disease testing can provide prognostic information and is incorporated into some fixed-duration strategies and trials, but it should be used only where the result has a defined clinical role.[2,3] A transient rise in peripheral lymphocytes can occur after starting a BTK inhibitor because malignant cells redistribute from lymphoid tissue into blood. Isolated early redistribution lymphocytosis with improving nodes and symptoms is not necessarily disease progression.[2] ## Special populations ### Older adults and frailty Chronologic age alone should not determine treatment. Account for frailty, falls, cognition, polypharmacy, renal function, cardiac disease, anticoagulation, infection history, and the burden of frequent monitoring. Fixed-duration and continuous therapies have different practical tradeoffs.[2,3] ### Kidney impairment Reduced kidney function materially increases venetoclax TLS risk and may alter monitoring intensity. Renally cleared concomitant drugs and contrast exposure also require review. ### Cardiovascular disease Atrial fibrillation, ventricular arrhythmia history, uncontrolled hypertension, heart failure, and antithrombotic therapy influence BTK-inhibitor selection. Coordinate anticoagulation and bleeding-risk management rather than stopping indicated stroke prevention without a plan. ### Pregnancy CLL during pregnancy is uncommon. Treatment decisions require maternal-fetal medicine and hematology input because teratogenicity, fetal exposure, treatment timing, and maternal disease urgency differ among agents. Avoid extrapolating routine nonpregnant regimens without specialist review. ## Disposition and referral Most newly diagnosed asymptomatic CLL is managed as an outpatient. Urgent hospital-based care is appropriate for: - severe infection or sepsis; - hemodynamically important anemia or bleeding; - severe autoimmune hemolysis; - symptomatic bulky organ compromise; - suspected TLS; - serious treatment toxicity; - suspected Richter transformation with rapid clinical decline. Hematology referral is appropriate for all newly diagnosed CLL/SLL when diagnosis, prognostic testing, surveillance intensity, or treatment planning is not already being managed by a hematology service. ## Decision pathway **CLL/SLL confirmed** → **Is there an iwCLL active-disease indication?** → **No:** observation, infection prevention, vaccination, CBC and symptom/organ-burden follow-up. → **Yes:** update del(17p)/TP53; obtain IGHV if never done; assess kidney, cardiac, bleeding, infection, drug-interaction, and TLS risks. → **Select targeted strategy** based on biology, comorbidity, prior therapy, patient preference, local approvals, and access. → **Venetoclax planned?** Perform formal TLS risk stratification and label-specified escalation/monitoring. → **Relapse after covalent BTK inhibitor?** Distinguish resistance from intolerance; consider a different mechanism rather than automatic within-class substitution for resistance. → **Abrupt focal progression or disproportionate systemic deterioration?** Biopsy for suspected Richter transformation. ## Recent guideline and regulatory developments > **Current practice:** Contemporary consensus emphasizes targeted therapy, repeat TP53/del(17p) assessment before each treatment line when relevant, and selection based on prior drug class exposure rather than a fixed chemotherapy sequence.[2,3] > **Current practice:** U.S. FDA approval of fixed-duration acalabrutinib plus venetoclax on February 19, 2026 expanded first-line all-oral treatment options. The pivotal untreated population excluded del(17p)/TP53-mutated disease, which matters when applying the evidence.[5] > **Evidence note:** Pirtobrutinib received traditional U.S. approval on December 3, 2025 for relapsed/refractory CLL/SLL previously treated with a covalent BTK inhibitor, providing a noncovalent BTK option after that class.[6] ## References 1. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. *Blood.* 2018;131(25):2745-2760. PMID: 29540348. DOI: 10.1182/blood-2017-09-806398. https://ashpublications.org/blood/article/131/25/2745/37141/iwCLL-guidelines-for-diagnosis-indications-for 2. National Cancer Institute. **Chronic Lymphocytic Leukemia Treatment (PDQ®)–Health Professional Version.** Continuously updated. https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq 3. Lymphoma Research Foundation Workshop Panel. Consensus recommendations from the 2024 Lymphoma Research Foundation workshop on treatment selection and sequencing in CLL/SLL. *Blood Adv.* 2025. DOI: 10.1182/bloodadvances.2024014474. https://ashpublications.org/bloodadvances/article/9/2/349/518050/Consensus-recommendations-from-the-2024-Lymphoma 4. U.S. Food and Drug Administration. **VENCLEXTA (venetoclax) tablets, prescribing information.** Revised May 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/208573s032lbl.pdf 5. U.S. Food and Drug Administration. FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. February 19, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-venetoclax-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma 6. U.S. Food and Drug Administration. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. December 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic 7. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. *N Engl J Med.* 2023;388(4):319-332. PMID: 36511784. DOI: 10.1056/NEJMoa2211582. https://pubmed.ncbi.nlm.nih.gov/36511784/ 8. U.S. Food and Drug Administration. FDA grants accelerated approval to lisocabtagene maraleucel for chronic lymphocytic leukemia and small lymphocytic lymphoma. March 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-chronic-lymphocytic-leukemia-and-small19:T690b,## Summary Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are blood-predominant and tissue-predominant manifestations of the same mature B-cell neoplasm. CLL is diagnosed when the peripheral blood contains **≥5 × 10^9/L clonal B cells for at least 3 months** with a compatible immunophenotype. SLL has tissue disease with **<5 × 10^9/L circulating clonal B cells** and no cytopenia attributable to marrow infiltration. A smaller circulating clone without CLL/SLL manifestations is monoclonal B-cell lymphocytosis (MBL).[1] The decisive management principle is that **CLL is treated for active disease, not for the diagnosis or lymphocyte count alone**. Treatment indications include progressive marrow failure, massive/progressive/symptomatic lymphadenopathy or splenomegaly, rapid lymphocyte progression, poorly controlled autoimmune cytopenia, symptomatic extranodal disease, or defined disease-related constitutional symptoms.[1] Before first systemic therapy—and again before each subsequent line when relevant—test for **del(17p) by FISH and TP53 mutation**. Determine **IGHV mutation status once**. TP53 disruption strongly influences drug selection and argues against chemoimmunotherapy. Modern therapy is dominated by targeted agents, particularly covalent BTK inhibitors and venetoclax-based regimens.[2,3] Venetoclax requires tumor-lysis risk stratification, hydration, antihyperuricemic prophylaxis, review of drug interactions, and scheduled chemistry monitoring during dose escalation. The standard CLL ramp is **20 mg daily for 7 days, then 50 mg, 100 mg, 200 mg, and 400 mg at weekly steps**.[4] A major recent change is the **February 19, 2026 U.S. FDA approval of fixed-duration acalabrutinib plus venetoclax** for adults with CLL/SLL. In the approved regimen, acalabrutinib 100 mg approximately every 12 hours is given for up to 14 28-day cycles; venetoclax starts in cycle 3 with the standard 5-week ramp and continues at 400 mg daily through cycle 14.[5] For relapsed disease after a covalent BTK inhibitor, pirtobrutinib has a distinct noncovalent mechanism and received traditional U.S. approval in December 2025.[6] Longitudinal care includes infection prevention, vaccination, skin-cancer surveillance, management of autoimmune cytopenias and hypogammaglobulinemia, cardiovascular and bleeding risk review during BTK-inhibitor therapy, and vigilance for **Richter transformation**.[1-3] ## Disease spectrum | Entity | Peripheral-blood clonal B cells | Tissue disease / disease effects | Clinical implication | |---|---:|---|---| | CLL | ≥5 × 10^9/L for ≥3 months | May be present or absent | Leukemic presentation of CLL/SLL | | SLL | <5 × 10^9/L | Nodal/tissue disease; no cytopenia attributable to marrow infiltration for the SLL definition | Tissue-predominant presentation | | MBL | <5 × 10^9/L | No lymphadenopathy, organomegaly, cytopenia, or disease symptoms attributable to the clone | Precursor state; observation rather than CLL therapy | The threshold uses the **clonal B-cell count**, not the total lymphocyte count.[1] ## Biology and clinically relevant molecular features CLL cells are mature B lymphocytes whose survival depends on intrinsic genomic lesions and signals from the lymph-node and marrow microenvironment. B-cell receptor signaling and BCL-2–mediated resistance to apoptosis are particularly important therapeutic targets. BTK inhibition disrupts survival and tissue trafficking; BCL-2 inhibition with venetoclax restores apoptotic susceptibility.[2,3] ### TP53 disruption TP53 dysfunction may arise from **del(17p)**, a **TP53 mutation**, or both. It predicts inferior disease control with conventional chemoimmunotherapy and remains one of the most treatment-relevant high-risk features. Because resistant subclones can emerge, repeat TP53 sequencing and del(17p) assessment before a new treatment line when the result could alter therapy.[2,3] ### IGHV mutation status IGHV mutation status is biologically stable and ordinarily needs to be measured only once. Unmutated IGHV is associated with a more aggressive natural history than mutated IGHV. In the targeted-therapy era, IGHV retains prognostic value but should not be used alone to decide whether treatment is needed.[2,3] ### Common cytogenetic findings | Finding | General implication | Practical use | |---|---|---| | del(17p) | TP53 loss; high-risk biology | Strongly influences systemic treatment choice | | del(11q) | Historically associated with nodal burden | Mainly prognostic/contextual with current targeted therapy | | Trisomy 12 | Distinct biologic subgroup | Prognostic/contextual | | Isolated del(13q) | Often more favorable when sole lesion | Prognostic; does not override clinical treatment criteria | ## Clinical presentation Many patients are identified after an incidental CBC shows persistent lymphocytosis. Others present with painless lymphadenopathy, splenomegaly, fatigue, infection, anemia, thrombocytopenia, or constitutional symptoms. Common manifestations include: - persistent absolute lymphocytosis; - cervical, axillary, or inguinal lymphadenopathy; - splenomegaly with early satiety or left-upper-quadrant discomfort; - anemia or thrombocytopenia from marrow infiltration, hypersplenism, bleeding, nutritional causes, kidney disease, or autoimmune destruction; - recurrent bacterial or viral infection; - autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP); - unintentional weight loss, fever, drenching night sweats, or function-limiting fatigue in active disease. ### Features requiring urgent evaluation - sepsis or severe infection; - symptomatic severe anemia or clinically important bleeding; - rapidly falling hemoglobin or platelet count; - brisk hemolysis; - rapidly enlarging focal lymph node, major LDH rise, new hypercalcemia, severe focal pain, or abrupt constitutional symptoms suggesting Richter transformation; - symptomatic bulky disease causing airway, vascular, ureteric, gastrointestinal, or other organ compromise; - suspected venetoclax-associated tumor lysis syndrome (TLS); - major hemorrhage, clinically important arrhythmia, or severe hypertension during BTK-inhibitor therapy. A very high lymphocyte count by itself is rarely an emergency in CLL; leukostasis is uncommon compared with acute leukemia.[1] ## Diagnosis ### Peripheral blood and flow cytometry CLL generally requires **≥5 × 10^9/L clonal B lymphocytes in peripheral blood for at least 3 months**.[1] The typical immunophenotype includes: - CD19 positive; - CD5 positive; - CD23 positive; - relatively dim CD20; - weak surface immunoglobulin; - light-chain restriction. A blood film often shows small mature lymphocytes with condensed chromatin. Smudge cells are common but are neither specific nor sufficient for diagnosis. ### Important mimic: mantle cell lymphoma Mantle cell lymphoma can also express CD5. An atypical phenotype, strong B-cell antigen expression, absent CD23 in a suspicious context, cyclin D1 positivity, or a **CCND1 rearrangement/t(11;14)** should prompt a lymphoma-directed diagnostic pathway rather than assuming CLL. ### Bone marrow and lymph-node biopsy Bone marrow biopsy is **not routinely required to establish typical CLL** when peripheral blood findings are diagnostic. It is useful when unexplained cytopenias need clarification or another marrow disorder is suspected.[1] Lymph-node biopsy is appropriate when SLL needs tissue confirmation, another lymphoma is plausible, or Richter transformation is suspected. ## Baseline evaluation For a newly diagnosed patient, document: - CBC with differential and blood film; - renal and liver function; - lymph-node and spleen burden; - symptoms and functional status; - medication list and major comorbidities; - infection history and vaccination status; - immunoglobulin level when recurrent infection or treatment planning makes it useful; - hemolysis studies when anemia may be immune-mediated: reticulocyte count, bilirubin, LDH, haptoglobin, and direct antiglobulin testing. Routine CT surveillance is not required for a stable asymptomatic patient. Cross-sectional imaging is useful when symptoms, bulky disease, treatment planning, or suspected transformation justify it.[1,2] ## Staging ### Rai staging | Stage | Findings | |---|---| | 0 | Lymphocytosis only | | I | Lymphocytosis plus lymphadenopathy | | II | Lymphocytosis plus splenomegaly and/or hepatomegaly, with or without lymphadenopathy | | III | Lymphocytosis plus anemia, classically hemoglobin <11 g/dL | | IV | Lymphocytosis plus thrombocytopenia, classically platelets <100 × 10^9/L | ### Binet staging | Stage | Criteria | |---|---| | A | Fewer than 3 involved lymphoid areas; no anemia or thrombocytopenia | | B | 3 or more involved lymphoid areas; no anemia or thrombocytopenia | | C | Anemia and/or thrombocytopenia regardless of involved areas | Staging describes burden and prognosis; **stage alone is not a treatment trigger**. Establish why a cytopenia is present before attributing it to CLL.[1] ## When to start treatment Treatment is indicated for **active disease**. The 2018 iwCLL criteria remain foundational and are incorporated into current consensus pathways.[1-3] At least one of the following supports treatment: 1. **Progressive marrow failure**, typically worsening anemia and/or thrombocytopenia attributable to CLL. Hemoglobin <10 g/dL or platelets <100 × 10^9/L are commonly used thresholds, but a stable platelet count below 100 does not automatically mandate therapy.[1] 2. **Massive, progressive, or symptomatic splenomegaly**, classically ≥6 cm below the left costal margin when massive.[1] 3. **Massive, progressive, or symptomatic lymphadenopathy**, classically ≥10 cm in longest diameter when massive.[1] 4. **Progressive lymphocytosis**, such as ≥50% increase over 2 months, or lymphocyte-doubling time <6 months after excluding other causes of lymphocytosis.[1] 5. **Autoimmune anemia or thrombocytopenia poorly responsive to corticosteroids** or otherwise requiring CLL-directed therapy.[1] 6. **Symptomatic or functionally important extranodal involvement**.[1] 7. **Disease-related symptoms**, including one or more of: ≥10% unintentional weight loss in 6 months, substantial fatigue limiting usual function, fever ≥38.0°C for at least 2 weeks without infection, or night sweats for at least 1 month without infection.[1] Do not start CLL therapy for hypogammaglobulinemia alone, a rising lymphocyte count that does not meet progression criteria, or a high absolute lymphocyte count without another treatment indication.[1] > **Clinical pearl:** Early targeted treatment of asymptomatic patients outside a specific evidence-based indication has not replaced observation as standard care. “Watch and wait” is active surveillance, not therapeutic neglect.[1-3] ## Pretreatment workup Before systemic therapy, obtain or update: - FISH including del(17p); - TP53 mutation testing; - IGHV mutation status if never measured; - CBC, renal and liver function; - hepatitis B screening before anti-CD20 therapy; - pregnancy assessment when relevant; - vaccination and infection-risk review; - cardiovascular history, blood pressure, arrhythmia history, bleeding history, anticoagulant/antiplatelet use when a BTK inhibitor is being considered; - tumor burden and renal function when venetoclax will be used. Treatment selection should also consider prior therapies, reason for discontinuation, drug interactions, frailty, kidney function, preference for continuous versus fixed-duration therapy, access, and local regulatory indications.[2,3] ## First-line systemic therapy Contemporary treatment is usually built around a **BTK inhibitor** or a **venetoclax-containing fixed-duration regimen**. Exact selection varies by jurisdiction and by the patient's biology and comorbidities.[2,3] ### Covalent BTK inhibitors Acalabrutinib and zanubrutinib are widely used second-generation covalent BTK inhibitors. They are generally favored over first-generation ibrutinib when a covalent BTK strategy is chosen because comparative data show favorable efficacy and/or tolerability profiles in relevant settings.[2,3,7] Important class toxicities include: - bleeding; - atrial arrhythmia and other cardiovascular events; - hypertension; - infection; - cytopenia; - peri-procedural bleeding risk; - drug interactions, particularly CYP3A interactions. Assess blood pressure and cardiac symptoms longitudinally. Peri-procedural interruption depends on bleeding risk and the specific product label. ### Venetoclax-based fixed-duration therapy Venetoclax is a potent BCL-2 inhibitor capable of deep remissions, but TLS prevention is essential.[4] For CLL/SLL, the standard dose ramp is: | Week | Venetoclax dose | |---|---:| | 1 | 20 mg once daily | | 2 | 50 mg once daily | | 3 | 100 mg once daily | | 4 | 200 mg once daily | | 5 and thereafter | 400 mg once daily when this is the regimen target | Before initiation: - measure lymph-node size and absolute lymphocyte count; - assess kidney function; - correct clinically important electrolyte abnormalities; - provide hydration and antihyperuricemic prophylaxis according to TLS risk; - review CYP3A/P-gp interactions; - plan chemistry monitoring at the label-specified intervals; - use inpatient monitoring for patients whose TLS risk and renal function warrant it.[4] > **Caution:** Venetoclax should not be started at the full treatment dose. The ramp, prophylaxis, and laboratory schedule are safety-critical components of therapy.[4] ### Acalabrutinib plus venetoclax On **February 19, 2026**, the U.S. FDA approved acalabrutinib plus venetoclax for adults with CLL/SLL.[5] In the approved fixed-duration schedule: - acalabrutinib: **100 mg approximately every 12 hours**, for up to 14 28-day cycles; - venetoclax: begins in cycle 3 with the standard 5-week escalation, then **400 mg once daily through cycle 14**.[5] The pivotal AMPLIFY population excluded del(17p) and TP53-mutated disease, so treatment decisions in TP53-disrupted CLL require careful use of evidence specific to that high-risk group.[5] ### TP53-disrupted disease For del(17p) and/or TP53-mutated CLL, avoid relying on chemoimmunotherapy. Continuous BTK-inhibitor strategies and other targeted approaches are preferred, with selection tailored to prior exposure, comorbidities, and local approvals.[2,3] ## Relapsed or refractory CLL/SLL Management depends on what the disease has already seen, whether prior therapy failed from resistance or intolerance, duration of prior response, TP53 status, and patient-specific toxicities.[2,3] ### Progression during a covalent BTK inhibitor Resistance to one covalent BTK inhibitor is generally not managed by simply switching to another covalent BTK inhibitor. Options may include venetoclax-based therapy, a noncovalent BTK inhibitor, cellular therapy, or a clinical-trial strategy depending on prior exposure and jurisdiction.[2,3,6] ### Intolerance to a covalent BTK inhibitor If the prior drug was stopped for intolerance rather than disease resistance, switching to another better-tolerated covalent BTK inhibitor may be reasonable in selected patients.[2,3] ### Pirtobrutinib Pirtobrutinib is a noncovalent BTK inhibitor. On **December 3, 2025**, the U.S. FDA granted traditional approval for adults with relapsed/refractory CLL/SLL previously treated with a covalent BTK inhibitor. The recommended dose is **200 mg orally once daily**.[6] ### Cellular therapy Lisocabtagene maraleucel is a CD19-directed CAR-T therapy with a U.S. indication for selected adults with relapsed/refractory CLL/SLL after at least two prior lines that included a BTK inhibitor and a BCL-2 inhibitor; the indication was granted under accelerated approval based on response and durability data.[8] Referral to a center experienced in cellular therapy is appropriate when the patient approaches this treatment space, because candidacy, bridging therapy, infection risk, cytokine-release syndrome, neurologic toxicity, and prolonged cytopenia require specialist planning. ## Autoimmune cytopenias ### Autoimmune hemolytic anemia Consider AIHA when anemia is accompanied by reticulocytosis, indirect hyperbilirubinemia, low haptoglobin, elevated LDH, and a compatible direct antiglobulin test. Exclude bleeding, marrow failure, renal disease, and nutritional deficiency. Initial therapy is usually directed at the autoimmune process. CLL-directed therapy is appropriate when autoimmune cytopenia is poorly controlled, recurrent, or accompanied by another active-disease indication.[1-3] ### Immune thrombocytopenia ITP should be distinguished from marrow-infiltration thrombocytopenia, hypersplenism, infection, drug effect, thrombotic microangiopathy, and other causes. A disproportionate platelet decline with relatively preserved other cell lines may support the diagnosis. Treatment is individualized according to bleeding risk, platelet count, response, and concurrent CLL activity. ## Infection prevention and supportive care CLL itself and its therapies impair humoral and cellular immunity. ### Vaccination Use age- and risk-appropriate **non-live vaccines**, ideally before highly immunosuppressive therapy when feasible. Influenza, COVID-19, pneumococcal, and recombinant zoster vaccination are commonly relevant. Vaccine responses may be blunted, but vaccination remains worthwhile.[2,3] Avoid live vaccines in significantly immunocompromised patients unless a specialist has established that the product is safe in the specific circumstance. ### Hypogammaglobulinemia Low immunoglobulin concentration alone is not an indication for immunoglobulin replacement. Consider replacement in selected patients with recurrent or severe bacterial infections plus clinically important hypogammaglobulinemia despite appropriate preventive measures.[2,3] ### Anti-CD20 therapy and hepatitis B Screen for hepatitis B before anti-CD20 monoclonal antibody therapy. Patients with evidence of current or prior infection may require antiviral prophylaxis or close virologic monitoring according to hepatology/infectious-disease guidance. ### Secondary malignancy and skin cancer CLL is associated with increased risk of secondary malignancy, particularly nonmelanoma skin cancer. Continue standard cancer screening and encourage regular skin surveillance and sun protection.[2,3] ## Richter transformation Richter transformation most commonly represents transformation to an aggressive large B-cell lymphoma. Suspect it when there is: - rapid growth of one or a few lymph-node regions; - new or rapidly worsening constitutional symptoms; - disproportionate LDH elevation; - hypercalcemia; - new extranodal disease; - abrupt clinical deterioration despite otherwise indolent CLL. PET/CT can help identify the most metabolically active site, but diagnosis requires tissue biopsy. Excisional or core biopsy of the most suspicious accessible lesion is preferred over assuming that CLL progression explains the presentation.[2,3] ## Monitoring during observation For patients without a treatment indication, follow-up frequency depends on disease trajectory and clinical risk. At each visit, assess: - CBC trend; - lymph-node and spleen burden; - constitutional symptoms; - recurrent infection; - autoimmune cytopenia features; - medication and vaccination status; - skin and other malignancy risk. Do not use routine serial CT solely to follow stable asymptomatic CLL.[1-3] ## Monitoring during treatment Monitoring depends on regimen but commonly includes: | Therapy | Key monitoring | |---|---| | BTK inhibitor | CBC, bleeding, blood pressure, atrial arrhythmia/cardiac symptoms, infection, interactions, peri-procedural plan | | Venetoclax | TLS risk before start, scheduled electrolytes/creatinine during escalation, CBC, infection, interactions | | Anti-CD20 monoclonal antibody | Infusion reactions, CBC, infection, hepatitis B reactivation risk | | Cellular therapy | Cytopenia, infection, cytokine-release syndrome, neurologic toxicity, prolonged immune suppression | Persistent cytopenia on treatment should not automatically be attributed to drug toxicity; assess disease progression, infection, autoimmune causes, marrow disease, and nutritional factors as appropriate. ## Response and progression Clinical response integrates blood counts, lymph-node/spleen burden, symptoms, and, in selected settings, marrow assessment. Minimal residual disease testing can provide prognostic information and is incorporated into some fixed-duration strategies and trials, but it should be used only where the result has a defined clinical role.[2,3] A transient rise in peripheral lymphocytes can occur after starting a BTK inhibitor because malignant cells redistribute from lymphoid tissue into blood. Isolated early redistribution lymphocytosis with improving nodes and symptoms is not necessarily disease progression.[2] ## Special populations ### Older adults and frailty Chronologic age alone should not determine treatment. Account for frailty, falls, cognition, polypharmacy, renal function, cardiac disease, anticoagulation, infection history, and the burden of frequent monitoring. Fixed-duration and continuous therapies have different practical tradeoffs.[2,3] ### Kidney impairment Reduced kidney function materially increases venetoclax TLS risk and may alter monitoring intensity. Renally cleared concomitant drugs and contrast exposure also require review. ### Cardiovascular disease [Atrial fibrillation](/library/atrial-fibrillation), ventricular arrhythmia history, uncontrolled hypertension, heart failure, and antithrombotic therapy influence BTK-inhibitor selection. Coordinate anticoagulation and bleeding-risk management rather than stopping indicated stroke prevention without a plan. ### Pregnancy CLL during pregnancy is uncommon. Treatment decisions require maternal-fetal medicine and hematology input because teratogenicity, fetal exposure, treatment timing, and maternal disease urgency differ among agents. Avoid extrapolating routine nonpregnant regimens without specialist review. ## Disposition and referral Most newly diagnosed asymptomatic CLL is managed as an outpatient. Urgent hospital-based care is appropriate for: - severe infection or sepsis; - hemodynamically important anemia or bleeding; - severe autoimmune hemolysis; - symptomatic bulky organ compromise; - suspected TLS; - serious treatment toxicity; - suspected Richter transformation with rapid clinical decline. Hematology referral is appropriate for all newly diagnosed CLL/SLL when diagnosis, prognostic testing, surveillance intensity, or treatment planning is not already being managed by a hematology service. ## Decision pathway **CLL/SLL confirmed** → **Is there an iwCLL active-disease indication?** → **No:** observation, infection prevention, vaccination, CBC and symptom/organ-burden follow-up. → **Yes:** update del(17p)/TP53; obtain IGHV if never done; assess kidney, cardiac, bleeding, infection, drug-interaction, and TLS risks. → **Select targeted strategy** based on biology, comorbidity, prior therapy, patient preference, local approvals, and access. → **Venetoclax planned?** Perform formal TLS risk stratification and label-specified escalation/monitoring. → **Relapse after covalent BTK inhibitor?** Distinguish resistance from intolerance; consider a different mechanism rather than automatic within-class substitution for resistance. → **Abrupt focal progression or disproportionate systemic deterioration?** Biopsy for suspected Richter transformation. ## Recent guideline and regulatory developments > **Current practice:** Contemporary consensus emphasizes targeted therapy, repeat TP53/del(17p) assessment before each treatment line when relevant, and selection based on prior drug class exposure rather than a fixed chemotherapy sequence.[2,3] > **Current practice:** U.S. FDA approval of fixed-duration acalabrutinib plus venetoclax on February 19, 2026 expanded first-line all-oral treatment options. The pivotal untreated population excluded del(17p)/TP53-mutated disease, which matters when applying the evidence.[5] > **Evidence note:** Pirtobrutinib received traditional U.S. approval on December 3, 2025 for relapsed/refractory CLL/SLL previously treated with a covalent BTK inhibitor, providing a noncovalent BTK option after that class.[6] ## References 1. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. *Blood.* 2018;131(25):2745-2760. PMID: 29540348. DOI: 10.1182/blood-2017-09-806398. https://ashpublications.org/blood/article/131/25/2745/37141/iwCLL-guidelines-for-diagnosis-indications-for 2. National Cancer Institute. **Chronic Lymphocytic Leukemia Treatment (PDQ®)–Health Professional Version.** Continuously updated. https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq 3. Lymphoma Research Foundation Workshop Panel. Consensus recommendations from the 2024 Lymphoma Research Foundation workshop on treatment selection and sequencing in CLL/SLL. *Blood Adv.* 2025. DOI: 10.1182/bloodadvances.2024014474. https://ashpublications.org/bloodadvances/article/9/2/349/518050/Consensus-recommendations-from-the-2024-Lymphoma 4. U.S. Food and Drug Administration. **VENCLEXTA (venetoclax) tablets, prescribing information.** Revised May 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/208573s032lbl.pdf 5. U.S. Food and Drug Administration. FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. February 19, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-venetoclax-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma 6. U.S. Food and Drug Administration. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. December 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic 7. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. *N Engl J Med.* 2023;388(4):319-332. PMID: 36511784. DOI: 10.1056/NEJMoa2211582. https://pubmed.ncbi.nlm.nih.gov/36511784/ 8. U.S. Food and Drug Administration. FDA grants accelerated approval to lisocabtagene maraleucel for chronic lymphocytic leukemia and small lymphocytic lymphoma. March 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-chronic-lymphocytic-leukemia-and-small7:["$","$L17",null,{"article":{"id":"medical-chronic-lymphocytic-leukemia","title":"Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma","slug":"chronic-lymphocytic-leukemia","description":"Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are blood-predominant and tissue-predominant manifestations of the same mature B-cell neoplasm. 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