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chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia & small lymphocytic lymphoma are the same disease, the first predominates in peripheral blood, the second predominates in lymph nodes. Classification: International Workshop Classification# - Stage A 1) no anemia or thrombocytopenia 2) < 3 areas of lymphoid enlargement* [A(0), A(I), or A(II)] - Stage B 1) no anemia or thrombocytopenia 2) 3 or more areas of lymphoid enlargement* [B(I), B(II)] - Stage C - anemia (hemoglobin < 10 g/dL) &/or thrombocytopenia, regardless of lymphoid involvement # diagnosis requires absolute lymphocytosis of > 5000/uL * spleen, liver, lymph nodes (axillary, inguinal, cervical) Rai classification: - Stage 0: peripheral & bone marrow lymphocytosis* - Stage 1: lymphocytosis & lymphadenopathy - Stage 2: lymphocytosis & splenomegaly - Stage 3: lymphocytosis & anemia (hemoglobin < 11 g/dL) - Stage 4: lymphocytosis & thrombocytopenia * peripheral lymphocytosis > 15,000/uL bone marrow lymphocytosis > 40% Epidemiology: 1) most common form of leukemia in patients > 60 years 2) accounts for 30% of all leukemias 3) 90% of patients are > 50 years of age - median age of diagnosis in 70 years 4) more common in men than women 5) rare in Asia 6) B-cell form NOT associated with exposure to radiation, drugs or chemicals Pathology: 1) majority of patients have clonal proliferation of B-cells 2) neoplastic lymphocytes express high levels of bcl-2 rendering them resistant to apoptosis 3) thrombocytopenia is IgG-mediated 4) > 40% lymphocytosis on bone marrow biopsy 5) aberrant expression of CD5 (T-cell marker) Genetics: 1) trisomy 12 is the most common chromosomal abnormality - generally associated with an indolent course [6] 2) abnormalities in chromosomes 13 & 14 may also be seen 3) chromosomal deletions: [4] - 17p deletion associated with poor prognosis - 11q deletion associated with better prognosis - 17p13 deletion associated with p53 deletion (median survival 3 years) [2] 4) defects in ARL11 may be a cause of susceptibility to chronic lymphocytic leukemia 5) chromosomal translocation t(X;11)(q21;q23) involving ARHGAP20 with BRWD3 associated with B-cell CLL 6) defects in ZAP70 (median survival 3 years) [2] 7) other implicated genes TBRG1, CLLU1, ARHGAP27, TRIM13 (possibly) Clinical manifestations: 1) many cases asymptomatic on presentation - diagnosis incidental identified by lymphocytosis 2) lymphadenopathy - painless - most common reason for presentation [6] - may wax & wane 3) hepatosplenomegaly, generally painless 4) weight loss, fatigue may be noted 5) fever with Richter's syndrome 6) slowly progressive 7) B symptoms (fever, night sweats, weight loss), massive lymphadenopathy & hepatosplenomegaly associated with transformation 8) manifestations of an acquired immunodeficiency in a small precentage of patients [6] - infections - hemolytic anemia, immune thrombocytopenia, pure red cell aplasia (see Laboratory) - excessive reaction to insect bites [6] Diagnostic criteria: - CLL is diagnosed by an absolute increase in mature lymphocytes of > 5000/uL for 3 months & demonstrating clonality of peripheral blood B-lymphocytes by flow cytometry Laboratory: 1) complete blood count (CBC) with differential a) absolute lymphocytosis of > 5000/uL b) thrombocytopenia (<5%) c) anemia 2) peripheral smear - small mature-appearing lymphocytes - smudge cells often present 3) direct antiglobulin test (positive in 10-30%) - associated with poor response to treatment & poor prognosis [21] 4) serum albumin & total protein shows hypogammaglobulinemia (50%) - IgG in serum 5) flow cytometry: a) B-lymphocyte phenotype: CD19+, CD20+, CD23+, CD5+* b) blood ZAP70 positive patients have higher rates of clonal evolution [4] c) next test after peripheral smear [2,25] 6) serum beta-2 microglobulin > 3.5 mg/L associated with poor prognosis (median survival 13 months) [2] 7) Ig heavy chain gene rearrangement for clonality & prognosis 8) bone marrow biopsy a) not required for diagnosis b) useful to distinguish CLL marrow infiltration from ITP [2] 9) see ARUP consult [7] * CD5+ is a T-cell marker Radiology: - computed tomography (CT): a) thorax, abdomen, pelvis b) assess lymph node & visceral involvement c) not useful for asymptomatic patient [2] Complications: 1) increased incidence of solid tumors a) lung b) skin (basal cell & squamous cell) 2) secondary chemotherapy-induced acute non-lymphocytic leukemia 3) transformation into aggressive form of large-cell lymphoma (Richter's syndrome of Richter transformation) 4) autoimmune disorders a) warm autoantibody-mediated hemolytic anemia b) autoimmune pure red cell aplasia - positive direct antibody test (DAT) rules out aplastic anemia [6]* c) immune thrombocytopenic purpura (ITP) d) leukocytoclastic vasculitis [24] 5) humoral immune dysfunction (hypogammaglobulinemia) with infections due to: a) Staphylococcus aureus b) Streptococcus pneumonia c) Pseudomonas d) Neisseria meningitidis e) Haemophilus influenza f) Klebsiella g) Pneumocystis h) cytomegalovirus i) Candida j) Herpes simplex k) Herpes zoster * given DAT positive in 10-30% of patients with CLL, taken with a 'grain of salt' Management: 1) treat fever as infection (Richter's syndrome is exception) 2) recurrent infections - prophylactic intravenous immune globulin for gamma-globulin levels < 0.3 g/dL - raise serum IgG to > 0.6 g/dL [2] 3) observe stage 0 or stage A patients - do not treat asymptomatic patients with good prognosis regardless of leukocyte count [2] 4) criteria for treatment of CLL a) fever, weight loss, & night sweats b) symptoms due to lymphadenopathy c) hepatosplenomegaly d) worsening cytopenia e) treat patients with Rai stages III or IV or international workshop stage C f) patients with poor prognostic features [2] 5) ibrutinib for untreated older patients (>=65 years) [16] - may be superior to ofatumumab [11] - superior to treatment with bendamustine + rituximab [16] - ibrutinib + venetoclax may be useful for untreated patients with CLL [18] - ibrutinib + rituximib no better than ibrutinib alone [16] - may increase risk of infection during first 6 months of treatment 6) zanubrutinib (Brukinsa) for untreated older patients (>=65 years) [22] - may be superior to bendamustine-rituximab [22] 7) acalabrutinib (Calquence) FDA-approved for treatment of CLL [23] 8) rituximab-based chemotherapy a) fludarabine, cyclophosphamide, rituximab yields bestresponse [2] (ibrutinib + rituximib better) [17] b) pentostatin, cyclophosphamide, rituximab [5] (see PCR regimen) c) idelalisib in combination with rituximab for treatment failure d) venetoclax +rituximab may be superior to bendamustine + rituximab [13] 9) other chemotherapy regimens a) chlorambucil with or without prednisone or fludarabine b) fludarabine is treatment of choice for patients who have relapse after chlorambucil &/or prednisone c) cladribine d) alemtuzumab (Campath-1H) treatment of refractory leukemia (B-CLL) {FDA approved 2001} e) ofatumumab in previously treated CLL f) obinutuzumab, in combination with chlorambucil, as an option for adults with untreated CLL unable to tolerate full-dose fludarabine-based therapy, only if: bendamustine-based therapy is not suitable (NDG, NICE) 10) radiation therapy for localized painful or massive lymph nodes 11) splenectomy for persistent cytopenia or symptoms related to splenomegaly 12) allogeneic stem cell transplantation is only curative therapy a) patients < 60 years of age b) good performance status c) stage III/IV disease [2,8,12] 13) thrombocytopenia is treated with glucocorticoids 14) restage for aggressive relapse or transformation 15) prognosis is dependent on genetic factors a) course is chronic in 60% of patients b) median survival time is 5 years from onset of treatment c) median survival once anemia or thrombocytopenia develops is 18 months [6] 16) suitability for elective surgery dependent upon symptoms & performance status - asymptomatic patients with good preformance status may proceed to elective surgery [2]

Interactions

disease interactions

Related

apoptosis bcl-2 proto-oncogene CLL gene mutation humoral immune dysfunction Richter's syndrome; Richter transformation small lymphocytic lymphoma

Specific

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL) prolymphocytic leukemia T-cell prolymphocytic leukemia (TPLL)

General

chronic leukemia lymphoid leukemia

Database Correlations

OMIM 151400

References

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  5. Kay NE et al, Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007, 109:405 PMID: 17008537
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  7. ARUP Consult: Chronic Lymphocytic Leukemia - CLL The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/chronic-lymphocytic-leukemia
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  13. O'Neil A Venetoclax-Rituximab Outshines Bendamustine Rituximab for Relapsed/Refractory CLL. Response and minimal residual disease- negativity rates superior with the BCL-2 inhibitor. https://www.medpagetoday.com/reading-room/asco/hematologic-malignancies/70005 - Seymour JF, et al Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia - Results from pre-planned interim analysis of the randomized phase 3 Murano Study. American Society of Hematology (ASH17), LBA-2. - Seymour JF, Kipps TJ, Eichhorst B et al Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2018; 378:1107-1120. March 22, 2018 PMID: 29562156 http://www.nejm.org/doi/full/10.1056/NEJMoa1713976 - Fuerst ML Thomas Kipps, MD, PhD, on Fixed-Duration Venetoclax-Rituximab in CLL - Deep remissions in patients with relapsed/refractory disease. MedPage Today. ASCO Reading Room 02.04.2021 https://www.medpagetoday.com/reading-room/asco/immunotherapy/91042 - Kater AP, Wu JQ, Kipps T et al Venetoclax Plus Rituximab in Relapsed CLL: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From MURANO Ph III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054 PMID: 32986498
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  17. Shanafelt TD, Wang XV, Kay NE et al Ibrutinib- Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med 2019; 381:432-443. Aug 1. PMID: 31365801 https://www.nejm.org/doi/full/10.1056/NEJMoa1817073
  18. Jain N, Keating M, Thompson P et al Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia. A Nonrandomized Phase 2 Trial. JAMA Oncol. 2021;7(8):1213-1219, June 10 PMID: 31141631 https://jamanetwork.com/journals/jamaoncology/fullarticle/2780587
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  21. Ahmed SA, Abdallah GEM, Aly MM et al Revisiting Autoimmunity in Chronic Lymphocytic Leukemia: Prognostic Value of Positive Direct Antiglobulin Test in a Retrospective Study and Literature Review. J Blood Med. 2021 Apr 13;12:225-234 PMID: 33880072 PMCID: PMC8053514 Free PMC article
  22. Bassett M Zanubrutinib Wins in First-Line CLL for Older Patients. The BTK inhibitor proves superior to bendamustine-rituximab in phase III trial. MedPage Today July 8, 2022 https://www.medpagetoday.com/hematologyoncology/leukemia/99653 - Tam CS, Brown JR, Kahl BS et al Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncology. 2022. July 7. PMID: 35810754 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00293-5/fulltext
  23. Otto MA FDA Approves Tablet Formulation of Acalabrutinib (Calquence) for CLL, SLL, and MCL. Medscape. Aug 5, 2022 https://www.medscape.com/viewarticle/978732
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