Pocket Oncology (Pocket Notebook Series), 1st Ed.

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Andrew M. Intlekofer and Andrew D. Zelenetz

Definition

• Chronic neoplasm of monoclonal, functionally incompetent, mature B lymphocytes

• MBL (monoclonal B cell lymphocytosis) = premalignant accumulation of clonal B cells present in ∼5% of adults age >60; <5000 clonal B cells/mm3 in blood w/o ↑ LN, ↑ spleen, or cytopenias, progresses to CLL at rate of ∼1% per y

• CLL = >5000 malignant cells/mm3 in blood (see below), ± marrow, ± LN

• SLL = identical to CLL but disease limited to LN

Epidemiology

• 16K cases annually in US, median age 70, male:female 1.7:1

Clinical Presentation

• Sx: Painless LAN, fatigue, recurrent infxn, bleeding, bruising, B sx uncommon (wt loss > 10%, fevers, sweats), ∼25% asx

• PE: LAN, HSM, pallor, rash (leukemia cutis)

Diagnostic Evaluation

• CBC w/diff → ALC > 5000; “smudge cells” & small mature-appearing lymphocytes w/dense chromatin, scant basophilic cytoplasm

• Additional labs: CMP, phos, UA, LDH, B2M (>ULN = poor prognosis), Coombs, retic, hapto, quantitative Ig/IF, HIV, HBV sAg, HBV cAb, HCV Ab

• Peripheral blood flow cytometry → CD19+, CD20+ (dim), CD5+, CD23+, κ/λ restricted, surface Ig+ (dim), CD10–; also CCND1– by IHC

• BM bx unnecessary unless progressive cytopenias; typically shows clusters of malignant lymphocytes w/interstitial or diffuse distribution

• Karyotype, cytogenetics, & FISH (see table below); repeat prior to new tx

• Molecular diagnostics for Ig variable region (IGHV) Mt

• CT scan optional unless concern for impaired/threatened organ function or pre-tx to allow response assessment; FDG PET not recommended except in suspected transformation, typically will show SUV in 3–7 range, SUV >10 c/w transformed disease

Disease Complications

• Immunodeficiency: Due to ↓ Ig & abnl B/T cell fxn, infxn account for 50% death for CLL/SLL pts, usu sinopulmonary infxn; prevent w/nonlive vaccinations, tx = abx, monthly IVIG if recurrent infxn & IgG < 500

• AIHA: Usu w/progressive disease, may be exacerbated by purine analogs; labs ↓ Hgb, ↑ retic, ↓ hapto, +Coombs; tx = steroids

• Pure red cell aplasia (PRCA): Rare <1% pts; labs ↓ Hgb, ↓ retic; BM bx w/absent red cell precursors; r/o parvovirus/CMV/EBV; tx = cyclosporine

• ITP:∼5% pts, unrelated to disease status, BM bx shows nl/↑ megakaryocytes, standard tx for ITP = steroids, IVIG, ritux, splenectomy, or thrombopoietin analogs

• Transformation: 5–10% pts, usu transforms to aggressive large cell lymphoma (Richter’s), heralded by rapid ↑ LN, new B sx, or ↑↑ LDH, dx by FDG PET scan & bx LN w/ ↑ SUV, tx like DLBCL (eg, R-CHOP); also can transform to PLL; rarely Hodgkin or myeloma

• Other: Agranulocytosis; paraneoplastic MPGN; rare leukostasis if WBC > 400K

Principles of Treatment

• CLL is incurable (exception allo-SCT) → consider clinical trial for all pts

• Indications for tx: Rai HR/Binet C or Rai IR/Binet B w/ALC doubling time <6 mos, disease-related sx, progressive/refractory cytopenias

• Observation: ∼1/3 of CLL pts never require tx; routine oncology visits w/PE, CBC, monitor for complications; no survival benefit early tx (JNCI 1999;91:861)

• Radiation: IFRT; used w/curative intent for Ann Arbor stage I SLL; also palliative relief of sx due to compressive adenopathy

• Allogeneic SCT (nonmyeloablative): Consider for fit pts w/short duration of remission or del17p; some pts may achieve cure; no role for ASCT

Specific Treatment Regimens:

• FCR: Preferred 1st-line regimen for younger (age < 70) pts w/good PS, OR 95%, CR 70%, PFS 80 m (Lancet 2010;376:1164)

• FR: Lower tox 1st-line regimen, OR 90%, CR 47%, PFS 42 m (JCO 2011;29:1349)

• PCR: Alternative to FCR, may be better tolerated but likely less efficacious

• BR: 1st line or later; promising but studies of comparative efficacy underway

• Alemtuzumab: Effective for del17p (Blood 2004;103:3278); not effective for bulky LN

• Chlorambucil: Usu reserved for older and/or poor PS pts

• Lenalidomide: 1st line for elderly (Blood 2011;118:3489); used w/rituximab for relapsed/refractory disease (JCO 2013;31:584); can cause “tumor flare”

• Novel agents: Ibrutinib & CAL-101 still in development but appear effective in pts regardless of adverse prognostic features

Treatment Complications:

• TLS: ↑ risk w/ ↑↑ WBC or ↑↑ LN; labs ↑ UA, ↑ Phos, ↓ Ca; PPX w/IVF + allopurinol + phos binder ± rasburicase

• Infxn: Sinopulmonary; neutropenic fever/sepsis, esp after purine analogs

• CMV reactivation: ↑↑ risk w/alemtuzumab tx; tx = gan/famciclovir or foscarnet

• Tx-related MDS/AML: More common after tx w/alkylators

Supportive Care:

• CA screening: ↑ risk of 2nd 1° CA incl skin (aggressive)/colon/lung

• Vaccinations: Influenza q1y & pneumococcal q5y; no live vaccines

• Infectious PPX: For VZV & PJP/PCP; esp postpurine analog or alemtuzumab