Eduovisual
Blood & Lymphoreticular
Chronic lymphocytic leukemia: diagnosis and watch-and-wait
— Median age at diagnosis ~70; M:F ≈ 2:1; rare in East Asia.
— Strongest risk factor is family history (2–7× increased risk in first-degree relatives); also associated with monoclonal B-cell lymphocytosis (MBL), the obligate precursor state.
— No proven environmental cause; Agent Orange exposure is VA service-connected for veterans (board favorite).
— Most patients are diagnosed incidentally on routine outpatient CBC showing absolute lymphocytosis — recognizing this and choosing the right next step is high-yield.
— Management hinges on a watch-and-wait paradigm for asymptomatic disease, which collides intuitively with the urge to "treat the number."
— Persistent absolute lymphocyte count (ALC) ≥ 5,000/µL in an adult, especially > 50 y.
— Painless lymphadenopathy, splenomegaly, or fatigue out of proportion to exam.
— Recurrent sinopulmonary infections from hypogammaglobulinemia.
— New autoimmune cytopenias (AIHA, ITP) in an older adult.
— Incidental lymphocyte-predominant CBC during preoperative or annual visit.
— Monoclonal B-cell count ≥ 5 × 10⁹/L in peripheral blood, sustained ≥ 3 months, with characteristic immunophenotype.
— Below 5 × 10⁹/L without lymphadenopathy/organomegaly/cytopenia = MBL, not CLL.
— Same phenotype but presenting with nodal disease and < 5 × 10⁹/L circulating cells = small lymphocytic lymphoma (SLL) — same disease, different compartment.
Board pearl: An asymptomatic 68-year-old with ALC 18,000 on a routine CBC and no adenopathy does not need a bone marrow biopsy — order peripheral blood flow cytometry first.
— Asymptomatic incidental lymphocytosis (~70–80%): CBC ordered for an unrelated reason (preop, annual exam, fatigue workup) returns with ALC 15–50k.
— Painless, symmetric lymphadenopathy: cervical, supraclavicular, axillary, inguinal — rubbery, mobile, non-tender, slowly enlarging over months.
— B symptoms (less common at diagnosis): unintentional weight loss ≥ 10% in 6 months, drenching night sweats, fevers > 100.5°F without infection, extreme fatigue (ECOG ≥ 2).
— Early satiety / LUQ fullness from splenomegaly.
— Recurrent infections: pneumonia, sinusitis, herpes zoster — reflecting hypogammaglobulinemia and T-cell dysfunction.
— Autoimmune cytopenia: new jaundice + anemia (warm AIHA, ~10%) or isolated thrombocytopenia (ITP).
— Duration of any palpable nodes; tempo of growth (rapid growth → consider Richter transformation).
— Prior CBCs — slow rising lymphocyte count over years strongly supports CLL over reactive lymphocytosis.
— Infection history (zoster, pneumonia frequency, sinus disease) — clue to immune compromise.
— Vaccination status: pneumococcal, influenza, recombinant zoster (Shingrix), COVID — critical baseline.
— Family history of lymphoid malignancy.
— Medication review: drugs causing lymphocytosis (rare) and any prior chemo/radiation.
— Lymphocyte doubling time (LDT) < 6 months = active disease, treatment indication.
— Stable count over years = consistent with indolent CLL appropriate for observation.
Key distinction: Reactive lymphocytosis (viral, pertussis, stress) typically resolves over weeks and shows polyclonal, morphologically varied lymphocytes; CLL shows monomorphic small mature lymphocytes with smudge cells persisting > 3 months. Always repeat the CBC before committing to a workup.
— Most patients look well; pallor, jaundice, or cachexia suggest advanced disease or AIHA/transformation.
— Document ECOG performance status at every visit — it drives treatment decisions and fitness for therapy.
— Palpate cervical, supraclavicular, axillary, epitrochlear, inguinal regions bilaterally; record size of largest node in each region (in cm).
— CLL nodes: rubbery, mobile, non-tender, symmetric, slowly progressive.
— Red flags for Richter transformation: rapidly enlarging asymmetric node, fixed/matted, tender, B symptoms, sudden LDH rise.
— Splenomegaly in ~25–55% — measure span below costal margin in cm; check for splenic rub or tenderness (splenic infarct).
— Hepatomegaly in ~15–25%; ascites is uncommon and should prompt transformation workup.
— Leukemia cutis: violaceous papules/plaques (rare).
— Petechiae/purpura → thrombocytopenia (marrow infiltration or ITP).
— Jaundice/scleral icterus → AIHA.
— Herpes zoster scars or active dermatomal vesicles — immune dysfunction marker.
— Stage 0: lymphocytosis only — low risk, median survival > 10 yr.
— Stage I: + lymphadenopathy — intermediate.
— Stage II: + hepato- and/or splenomegaly — intermediate.
— Stage III: + anemia (Hgb < 11) — high.
— Stage IV: + thrombocytopenia (plt < 100k) — high.
— Cytopenias must be from marrow infiltration, not autoimmune destruction, to count for staging.
Step 3 management: Exam findings drive whether you observe or refer urgently — diffuse bulky adenopathy + B symptoms + cytopenia means heme/onc consult now, not a routine 6-month recheck.
— CBC with differential: absolute lymphocyte count ≥ 5,000/µL sustained ≥ 3 months is the entry criterion.
— Peripheral blood smear: monomorphic small mature lymphocytes with condensed chromatin, scant cytoplasm, and pathognomonic "smudge" (Gumprecht) cells — fragile lymphocytes crushed during slide preparation.
— A bone marrow biopsy is not required for diagnosis if flow is diagnostic.
— Classic CLL phenotype: CD5+, CD19+, CD20 dim, CD23+, CD43+, sIg dim, kappa or lambda light-chain restricted, FMC7−, CD10−, cyclin D1−.
— Matutes/CLL score (5-point): assigns 1 point each for CD5+, CD23+, sIg weak, CD79b/CD22 weak, FMC7−; score 4–5 = CLL, ≤ 3 suggests another B-cell neoplasm.
— CMP (creatinine, LFTs, uric acid — TLS risk baseline).
— LDH — rising LDH out of proportion to bulk suggests transformation.
— Haptoglobin, reticulocyte count, direct antiglobulin test (DAT/Coombs) — screen for AIHA; ~35% of CLL patients have positive DAT, only some have overt hemolysis.
— Quantitative immunoglobulins (IgG, IgA, IgM) — baseline hypogammaglobulinemia predicts infection risk.
— Beta-2 microglobulin — prognostic, part of CLL-IPI.
— Hepatitis B surface antigen, core antibody, hepatitis C, HIV — required before any anti-CD20 therapy (reactivation risk).
— Pregnancy test in reproductive-age women.
— Routine CT is not required in asymptomatic patients; obtain CT chest/abdomen/pelvis if treatment is being considered or to evaluate bulky/asymmetric disease.
Board pearl: Smudge cells on smear + lymphocytosis in an older adult → next step is peripheral blood flow cytometry, not bone marrow biopsy and not CT.
— FISH panel for del(13q), trisomy 12, del(11q) (ATM), and del(17p) (TP53).
— TP53 mutation sequencing — mutations without 17p deletion still confer poor prognosis and chemoimmunotherapy resistance.
— IGHV mutational status: unmutated IGHV (≥ 98% germline homology) = aggressive course; mutated IGHV = indolent, better response to chemoimmunotherapy.
— Karyotype (stimulated) — complex karyotype (≥ 3 abnormalities) is independently adverse.
— TP53 status (4 pts), IGHV unmutated (2), β2-microglobulin > 3.5 (2), Rai I–IV/Binet B–C (1), age > 65 (1).
— Stratifies into low/intermediate/high/very high risk groups — guides therapy choice and counseling.
— Not required for diagnosis in typical CLL.
— Indicated when cytopenias are unexplained — distinguishes marrow infiltration (counts for Rai stage III/IV and treatment indication) from autoimmune destruction (treat with steroids/rituximab, not chemo).
— Indicated for SLL diagnosis (tissue-predominant disease) or to rule out Richter transformation when a node is rapidly enlarging, asymmetric, or PET-avid.
— PET-CT is not for staging CLL but is excellent for identifying the most FDG-avid node (SUV > 10) to biopsy when transformation is suspected.
— HBV (sAg, core Ab), HCV, HIV; consider CMV serology before alemtuzumab (rarely used now).
Key distinction: IGHV mutational status is fixed for life — check it once. FISH and TP53 should be re-checked before each new line of therapy because clones evolve, especially after chemoimmunotherapy.
— Progressive marrow failure: Hgb < 10 g/dL or platelets < 100k from marrow infiltration.
— Massive/progressive/symptomatic splenomegaly (≥ 6 cm below costal margin).
— Massive nodes (≥ 10 cm) or progressive/symptomatic lymphadenopathy.
— Progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months (only if starting ALC > 30k and no other cause).
— Autoimmune cytopenia poorly responsive to corticosteroids.
— Symptomatic extranodal involvement (skin, kidney, lung).
— Disease-related symptoms: unintentional weight loss ≥ 10% in 6 mo, ECOG ≥ 2 fatigue, fevers > 2 wk without infection, night sweats > 1 mo.
— Absolute lymphocyte count itself, however high (even 200k) — leukostasis is rare in CLL because cells are small and non-adherent.
— Stable bulky nodes without symptoms.
— Positive DAT without hemolysis.
— Hypogammaglobulinemia alone.
— Patient/family anxiety about "the number."
— Visit + CBC every 3 months for the first year, then every 6–12 months if stable.
— Annual influenza vaccine; pneumococcal (PCV20 or PCV15→PPSV23); recombinant zoster vaccine (Shingrix); COVID-19 boosters; avoid live vaccines (MMR, varicella, live zoster, yellow fever).
— Annual skin exam (↑ non-melanoma skin cancer risk) and age-appropriate cancer screening.
Step 3 management: A 65-year-old with Rai 0 CLL, ALC 40k, no symptoms → no treatment, no chemo, no rituximab. Order vaccines, schedule 3-month follow-up, and reassure.
— BTK inhibitors (continuous, oral):
– Acalabrutinib (± obinutuzumab) — preferred over ibrutinib due to lower atrial fibrillation and hypertension rates.
– Zanubrutinib — similar profile, also preferred.
– Ibrutinib — older, more cardiotoxicity (AF, HTN, bleeding); largely supplanted.
— BCL-2 inhibitor + anti-CD20 (fixed duration, 12 months):
– Venetoclax + obinutuzumab — high rates of undetectable MRD, time-limited therapy.
— Ibrutinib/acalabrutinib/zanubrutinib: atrial fibrillation, hypertension, bleeding (hold 3–7 days perioperatively), arthralgias, diarrhea, infections.
— Venetoclax: tumor lysis syndrome — requires weekly ramp-up dosing, aggressive hydration, allopurinol/rasburicase, and inpatient monitoring for high-risk patients (bulky nodes, high ALC, renal dysfunction).
— Obinutuzumab/rituximab: infusion reactions, HBV reactivation (screen and treat HBcAb+ patients with entecavir prophylaxis).
— PJP prophylaxis (TMP-SMX) and antiviral prophylaxis (acyclovir/valacyclovir) for many regimens.
— IVIG for recurrent serious infections + IgG < 400–500 mg/dL.
Board pearl: A patient starting venetoclax with bulky adenopathy needs TLS prophylaxis with hydration, allopurinol, and weekly dose ramp-up — not a single full dose at home.
— Rarely indicated in CLL because lymphocytes are small and rarely cause leukostasis even at counts > 500k.
— Contrast with AML/CML blast crisis, where leukapheresis is used for symptomatic hyperleukocytosis.
— Reserved for symptomatic splenomegaly unresponsive to systemic therapy, or refractory autoimmune cytopenia failing steroids, rituximab, and IVIG.
— Pre-splenectomy: vaccinate ≥ 2 weeks before against encapsulated organisms (pneumococcus, meningococcus ACWY + B, Hib).
— Excisional biopsy preferred over FNA when transformation is suspected — architecture matters for diagnosing diffuse large B-cell lymphoma (Richter).
— Now rarely needed in the targeted-therapy era; consider for double-refractory disease (failed BTKi and venetoclax) or after Richter transformation in young, fit patients.
— Give before starting therapy when possible (responses are far better).
— Annual inactivated influenza, PCV20 (or PCV15 followed by PPSV23 ≥ 8 weeks later), recombinant zoster (Shingrix, 2 doses), COVID-19 primary series and boosters.
— Contraindicated: live attenuated vaccines (MMR, varicella, live zoster, yellow fever, intranasal flu, BCG, oral typhoid).
— IVIG (400 mg/kg every 3–4 weeks) for recurrent serious infections + IgG < 400–500.
— PJP and HSV/VZV prophylaxis on most active therapies.
CCS pearl: When ordering venetoclax initiation in CLL on a CCS case, also order: IV fluids, allopurinol, electrolyte panel q6–8h, telemetry, and an inpatient bed for the first dose if TLS risk is high.
— Use CIRS (Cumulative Illness Rating Scale), creatinine clearance, and ECOG to categorize as "go-go," "slow-go," or "no-go."
— Even "no-go" patients are usually candidates for targeted therapy (BTKi or venetoclax-obinutuzumab) — chemoimmunotherapy is what we avoid, not treatment itself.
— Pre-existing atrial fibrillation, uncontrolled HTN, or anticoagulation need → prefer acalabrutinib or zanubrutinib over ibrutinib, or choose venetoclax-obinutuzumab (no cardiotoxicity signal).
— On a BTKi: monitor BP at every visit; treat HTN aggressively; hold BTKi 3–7 days before any surgery/procedure for bleeding risk.
— Venetoclax: CrCl < 80 mL/min increases TLS risk — admit for ramp-up, aggressive hydration, frequent labs.
— Allopurinol dose-adjust; rasburicase preferred if uric acid is high or risk is high (avoid in G6PD deficiency).
— BTK inhibitors: minimal renal adjustment needed.
— Ibrutinib/acalabrutinib/zanubrutinib: reduce dose in moderate-severe hepatic impairment.
— Venetoclax: caution and dose adjustment in severe hepatic dysfunction.
— HBV reactivation with anti-CD20: screen all patients; treat HBsAg+ or HBcAb+ with entecavir or tenofovir during and ≥ 12 months after therapy.
— BTKi and venetoclax are CYP3A4 substrates — avoid strong inhibitors (azoles, clarithromycin, grapefruit) and inducers (rifampin, phenytoin, St John's wort); dose-adjust with moderate inhibitors.
— Warfarin + ibrutinib historically avoided due to bleeding; DOACs are preferred when anticoagulation is needed.
Step 3 management: A 78-year-old with AF on apixaban and Rai III CLL needing therapy → acalabrutinib or venetoclax-obinutuzumab, not ibrutinib, and definitely not FCR.
— Essentially does not exist — CLL is a disease of older adults. A child with lymphocytosis has ALL, infection, or pertussis, not CLL.
— A young adult (< 50) with apparent CLL warrants careful review of flow cytometry to exclude mantle cell lymphoma (CD5+, CD23−, cyclin D1+, t(11;14)) or leukemic marginal zone lymphoma.
— Historically offered FCR (fludarabine, cyclophosphamide, rituximab) if IGHV-mutated and TP53 wild-type — can produce very long remissions (potential "cures") but with risk of secondary MDS/AML and infections.
— Most US practice has shifted to targeted therapy even in this group; counsel on tradeoffs.
— Fertility counseling and sperm/oocyte banking before chemoimmunotherapy.
— CLL during pregnancy is rare. Watch-and-wait is feasible if asymptomatic.
— If treatment is necessary, defer to second/third trimester; rituximab has been used; BTKi, venetoclax, and fludarabine are teratogenic/embryotoxic — avoid.
— Effective contraception required during and after therapy (BTKi ≥ 1 month, venetoclax ≥ 30 days, fludarabine ≥ 6 months).
— First-degree relatives have elevated risk but routine screening is not recommended outside research protocols — there is no early intervention that changes outcomes.
— CLL is presumptively service-connected for Vietnam-era veterans exposed to Agent Orange — counsel patients to file a VA claim; this is a real Step 3 patient-advocacy item.
— Avoid live vaccines (yellow fever — affects travel plans).
— Skin protection and annual dermatology screening — non-melanoma skin cancers are 2–8× more common.
Board pearl: A 35-year-old with CD5+ lymphocytosis — think mantle cell lymphoma, not CLL, and confirm with cyclin D1 staining and FISH for t(11;14).
— Mechanisms: hypogammaglobulinemia, T-cell dysfunction, neutropenia from therapy or marrow infiltration, complement dysfunction.
— Common: encapsulated organisms (S. pneumoniae, H. influenzae), HSV/VZV reactivation, PJP (on therapy), influenza, COVID-19 (impaired vaccine response), invasive fungal disease on BTKi (rare aspergillosis).
— Manage low threshold for empiric antibiotics; IVIG for recurrent serious infections + IgG < 400–500.
— Warm AIHA (~5–10%) — DAT+, spherocytes, elevated indirect bilirubin, low haptoglobin, high reticulocyte count, high LDH; treat with prednisone 1 mg/kg, add rituximab or IVIG if refractory.
— ITP — isolated thrombocytopenia with normal marrow megakaryocytes (or increased); treat like primary ITP.
— Pure red cell aplasia — rare; consider parvovirus B19 PCR.
— Autoimmune cytopenias do not count for Rai staging but are themselves an indication to treat when refractory to steroids.
— Transformation to diffuse large B-cell lymphoma (90%) or rarely Hodgkin lymphoma.
— Clues: rapidly enlarging asymmetric node, B symptoms, abrupt LDH rise, hypercalcemia, extranodal disease.
— Diagnose with excisional biopsy of the most PET-avid node (SUV > 10).
— Prognosis poor (median survival 6–12 months for clonally related DLBCL); treat with R-CHOP ± novel agents; consider allo-SCT in responders.
— Increased risk of non-melanoma skin cancer (BCC, SCC — often aggressive), melanoma, lung cancer, and therapy-related MDS/AML after fludarabine-based regimens.
— Highest risk with venetoclax initiation in bulky disease; rare with BTKi.
Key distinction: Sudden LDH rise + asymmetric rapidly growing node in a CLL patient is Richter until proven otherwise — get a biopsy, not just more imaging.
— Febrile neutropenia (ANC < 500 + temp ≥ 38.3°C or ≥ 38.0°C sustained) — broad-spectrum antibiotics within 1 hour (cefepime or pip-tazo); add vancomycin if line, soft tissue source, or hemodynamic instability.
— Severe AIHA with hemodynamic compromise or Hgb < 7 — admit, IV methylprednisolone, transfuse cautiously (cross-match difficulties — call blood bank early), consider IVIG and rituximab.
— Suspected Richter transformation with B symptoms, hypercalcemia, or organ compromise — admit for expedited biopsy and staging.
— Tumor lysis syndrome during venetoclax ramp-up — IV fluids, rasburicase if uric acid > 8 (avoid in G6PD), monitor electrolytes q6h, renal consult if oliguric.
— Serious infection in a hypogammaglobulinemic patient (pneumonia with hypoxia, meningitis, bacteremia).
— New diagnosis with cytopenias or B symptoms.
— Suspected transformation.
— Disease meeting iwCLL treatment criteria.
— Planning for therapy initiation (FISH, TP53, IGHV, vaccines, infectious screen).
— Hematology/oncology — primary disease management.
— Infectious disease — recurrent or atypical infections, prophylaxis planning.
— Dermatology — annual skin screening; aggressive SCC/BCC.
— Cardiology — pre-BTKi baseline if AF history, manage on-therapy AF/HTN.
— Transfusion medicine — refractory AIHA, alloantibody complexity.
— Document vaccination status, IgG level, performance status, and follow-up appointment within 1–2 weeks for any CLL patient discharged after an infection.
CCS pearl: A CLL patient admitted with pneumonia — order blood cultures, sputum, urine antigen, HIV/HBV/HCV serologies if not done, IgG level, and CT chest before empiric antibiotics within the first hour; arrange ID and heme follow-up before discharge.
— CD5+ like CLL but CD23−, FMC7+, cyclin D1+, t(11;14).
— Younger patients, GI tract involvement (lymphomatous polyposis), aggressive course.
— Critical not to miss — treatment is completely different (R-CHOP/cytarabine or BTKi-based).
— CD5−, CD10−, CD23−; may circulate (splenic MZL with villous lymphocytes).
— Splenomegaly with minimal nodal disease; associations with H. pylori (gastric MALT), HCV (splenic MZL), Sjögren (parotid MALT), Chlamydia psittaci (ocular adnexal).
— CD10+, BCL2+, t(14;18); CD5−, CD23 variable; nodal predominance.
— Pancytopenia + massive splenomegaly without lymphadenopathy; dry tap on marrow.
— CD11c+, CD25+, CD103+, CD123+; BRAF V600E mutation; treat with cladribine.
— Older patients, very high WBC, massive splenomegaly, > 55% prolymphocytes on smear, FMC7+, CD5 variable.
— IgM monoclonal gammopathy, hyperviscosity (epistaxis, blurred vision, headache), MYD88 L265P mutation.
— Same disease as CLL, but presents with predominant lymphadenopathy and < 5,000/µL circulating monoclonal B cells. Treated by the same criteria.
— Precursor: < 5,000/µL monoclonal B cells, no adenopathy/organomegaly/cytopenia.
— Progression to CLL ~1–2% per year; observe with annual CBC.
Key distinction: CD5+ CD23+ = CLL; CD5+ CD23− cyclin D1+ = mantle cell. Always confirm CD23 and cyclin D1 status before committing to a CLL diagnosis.
— EBV (infectious mononucleosis): young patient, pharyngitis, posterior cervical adenopathy, splenomegaly, atypical (Downey) lymphocytes (large, abundant blue cytoplasm conforming around RBCs), positive heterophile (Monospot); transaminitis common.
— CMV: similar mono-like illness, heterophile-negative.
— Acute HIV (seroconversion): febrile illness, rash, mucosal ulcers — check HIV RNA, not just antibody.
— Pertussis: marked lymphocytosis (20–50k) with paroxysmal cough in adults/children — small mature lymphocytes; PCR diagnostic.
— Acute viral hepatitis, rubella, mumps, adenovirus.
— Bordetella pertussis (above).
— Bartonella, brucellosis, syphilis, TB (less commonly lymphocytic).
— Post-trauma, post-surgery, post-seizure, sickle cell crisis, status asthmaticus — resolves in hours to days.
— DRESS syndrome, certain antiepileptics.
— Mild persistent lymphocytosis, Howell-Jolly bodies on smear.
— Can produce relative or mild absolute lymphocytosis.
— Chronic mild polyclonal lymphocytosis.
— T- or NK-cell, often associated with rheumatoid arthritis and neutropenia; characteristic LGLs on smear; STAT3 mutations.
— HTLV-1 endemic regions (Japan, Caribbean); flower cells, hypercalcemia, lytic bone lesions.
Board pearl: Lymphocytosis + paroxysmal cough in a young adult or child = pertussis; lymphocytosis + pharyngitis + splenomegaly in a teen = EBV mono. Neither needs flow cytometry — get the targeted test.
— Annual inactivated influenza vaccine (high-dose for ≥ 65).
— Pneumococcal: PCV20 alone, or PCV15 followed by PPSV23 ≥ 8 weeks later.
— Recombinant zoster vaccine (Shingrix): 2 doses, age ≥ 19 with immunocompromise (all CLL patients qualify).
— COVID-19 primary series and boosters per current CDC schedule for immunocompromised.
— Hepatitis B vaccination if susceptible (3- or 4-dose series).
— Avoid all live vaccines: MMR, varicella, live zoster (Zostavax — withdrawn), yellow fever, intranasal flu, BCG, oral typhoid.
— Counsel household contacts to be fully vaccinated.
— Annual full-body skin exam by dermatology — skin cancers in CLL are aggressive and frequent.
— Age-appropriate: colon (start 45, every 10 yr if average risk), breast (40–74), cervical, lung CT for eligible smokers, prostate per shared decision-making.
— Routine BP, lipid, A1c screening; statin and antihypertensive management.
— Bone density screening if on long-term steroids for autoimmune cytopenia.
— IgG < 400–500 mg/dL plus recurrent serious bacterial infections (≥ 2 in a year requiring antibiotics or hospitalization).
— Dose: 400 mg/kg every 3–4 weeks; target trough IgG > 500.
— Sun protection (SPF 30+, broad-brim hats).
— Smoking cessation, alcohol moderation.
— Exercise per general guidelines; no specific restrictions.
— Handwashing, mask use during high-transmission respiratory illness seasons.
Step 3 management: At every CLL visit, document: ALC trend, nodes/spleen exam, performance status, vaccination status, IgG level annually, and skin exam date — these are the items that move the needle in long-term outcomes.
— First year: CBC with differential + clinical exam every 3 months.
— After stable year: every 6–12 months indefinitely.
— Bring forward sooner if new symptoms (B symptoms, rising nodes, new infections, fatigue).
— CBC with differential (track ALC trend and doubling time).
— Symptom screen: B symptoms, fatigue (ECOG), infections, easy bruising/bleeding, early satiety.
— Exam: weight, BP, nodes (all stations), spleen/liver, skin.
— Annual: CMP, LDH, quantitative IgG, DAT if new anemia.
— Annual dermatology and age-appropriate cancer screening.
— BTK inhibitors: BP and pulse at every visit; ECG if palpitations; CBC monthly initially; watch for atrial fibrillation, bleeding, infections, arthralgias.
— Venetoclax: TLS labs during ramp-up (uric acid, K, phos, Ca, Cr, LDH q6–24h depending on risk); CBC for neutropenia.
— Anti-CD20 (rituximab/obinutuzumab): HBV monitoring (HBV DNA q1–3 mo if HBcAb+); infusion reaction prevention.
— "CLL is often a chronic disease, not an acute crisis. Many patients live a normal lifespan without ever needing chemotherapy."
— "We do not treat the number, we treat symptoms and complications."
— "Treatment is dramatically better than 10 years ago — most patients now get pills, not infusions."
— Discuss prognosis honestly using CLL-IPI when relevant; offer clinical trials.
— Screen for depression/anxiety — the "cancer-but-no-treatment" paradox causes real distress.
— Support groups (LLS, CLL Society); written materials; family involvement.
— Discuss early, especially in older patients — code status, healthcare proxy, goals of care.
Board pearl: A patient calls anxious about an ALC that rose from 25k to 32k over 6 months with no symptoms — reassure and continue surveillance; this does not meet doubling-time criteria and is not a treatment trigger.
— Patients may struggle accepting "we know you have cancer, but we won't treat it." Document a clear consent conversation: rationale (no survival benefit to early treatment, toxicity avoidance), monitoring plan, what would trigger treatment, and patient's understanding.
— Offer a second opinion without defensiveness — it builds trust and is often diagnostic of patient anxiety needs.
— CLL patients often see multiple specialists (PCP, heme/onc, derm, ID, cardiology). Ensure medication reconciliation at every transition — BTKi and venetoclax have severe CYP3A4 interactions (azoles, macrolides, grapefruit, statins) that primary teams may miss.
— On hospital discharge after infection: document IgG level, vaccine status, follow-up appointment within 1–2 weeks, and hold BTKi 3–7 days before any planned procedure.
— A CLL patient inadvertently given a live vaccine (MMR, live zoster, yellow fever) is a patient safety event — report to VAERS, monitor closely, and the institution should review immunization screening protocols.
— All cellular blood products in CLL should be irradiated (prevent transfusion-associated GVHD) and CMV-safe (leukoreduced or CMV-seronegative) if CMV-seronegative. This is a sentinel-event-level issue if missed.
— CLL itself is reported to state cancer registries by treating institutions (no individual reporting duty).
— Veterans with CLL and Vietnam-era service have presumptive service-connected disability for Agent Orange — clinicians should inform patients to file with the VA.
— First-degree relatives have increased risk; counsel but do not order routine screening outside research.
— Ethically, patients with CLL should be informed of trial options at each decision point — particularly for relapsed/refractory disease and Richter transformation.
— In Richter transformation or double-refractory disease, early palliative care referral improves quality and may extend survival.
Step 3 management: Before any anti-CD20 therapy, screen for HBV (sAg and core Ab) — failure to do so leading to fatal HBV reactivation is a documented preventable harm and a board-favorite safety question.
Board pearl: When in doubt on Step 3 about an asymptomatic CLL vignette, the answer is almost always "observation and follow-up in 3 months" plus vaccinate appropriately.
— A 68-year-old man has CBC at annual physical: WBC 32k, ALC 25k, Hgb 13.5, plt 220k. Asymptomatic. Exam normal.
— Next step? → Peripheral blood flow cytometry (not bone marrow, not CT, not start treatment).
— Follow-up question: flow confirms CD5+/CD19+/CD23+. Management? → Observation with CBC every 3 months.
— Smear shows numerous "smudge cells" with monomorphic small lymphocytes.
— Diagnosis? → CLL.
— Known CLL patient now has Hgb 8.5, plt 75k, fatigue, 5 kg weight loss.
— Action? → Initiate first-line therapy (acalabrutinib or venetoclax-obinutuzumab); check FISH/TP53/IGHV first.
— CLL patient with new jaundice, Hgb 7, ↑ retic, ↑ indirect bili, ↓ haptoglobin, DAT positive.
— Treatment? → Prednisone 1 mg/kg; this AIHA alone is NOT an indication for CLL-directed chemotherapy unless refractory.
— Stable CLL patient develops rapidly enlarging cervical node, fevers, weight loss, LDH 800.
— Next step? → Excisional biopsy of the most FDG-avid node on PET-CT.
— CLL patient asks about shingles vaccine.
— Recommend? → Recombinant zoster vaccine (Shingrix), 2 doses; avoid live attenuated zoster.
— Patient starting venetoclax with bulky nodes develops K 6.2, phos 7, uric acid 11, Cr rising.
— Management? → IV fluids, rasburicase, hold venetoclax, telemetry, electrolyte correction.
— 55-year-old man with CD5+ lymphocytosis, CD23 negative, cyclin D1 positive.
— Diagnosis? → Mantle cell lymphoma, not CLL.
— Recurrent sinopulmonary infections (3 in past year), IgG 380.
— Intervention? → IVIG replacement.
— CLL patient needs RBCs.
— Order? → Irradiated, leukoreduced products.
Key distinction: The high-yield Step 3 trap is treating an asymptomatic high lymphocyte count — the right answer is almost always observe and vaccinate, not chemotherapy.
CLL is a chronic, indolent CD5+/CD19+/CD23+ B-cell leukemia diagnosed by peripheral blood flow cytometry alone; the cornerstone of management is watch-and-wait with infection prevention until iwCLL criteria for treatment are met, at which point modern targeted therapy (BTK inhibitors or venetoclax-obinutuzumab) — not the lymphocyte count itself — drives outcomes.
Board pearl: On Step 3, the most common right answer for an asymptomatic patient with newly diagnosed CLL is "observation with CBC every 3 months and age-appropriate vaccination" — recognizing this restraint is the entire teaching point.