Chronic lymphocytic leukemia Magdalena Olszewska-Szopa

Definition Diagnostic criteria: Chronic lymphocytic leukemia (CLL) belongs to B-cell low-grade non-Hodgkin lymphomas. CLL is the most common form of leukemia in adults. International Workshop on CLL (IWCLL) 2008 guidelines Diagnostic criteria: ≥5 x 109 B clonal lymphocytes/L in the peripheral blood for the duration of at least three months.

Epidemiology and risk factors Advanced age Positive family history

Clinical presentation many patients are asymptomatic at the moment of the diagnosis, fatigue, autoimmune hemolytic anemia (AIHA), infections, splenomegaly, hepatomegaly, lymphadenopathy (painless), extra-nodal infiltrates – rarely. B symptoms (general symptoms) Night sweats Weight loss Fever

Physical examination Lymphadenopathy present in 87%: cervical/axillary/inguinal/generalised. Splenomegaly present in 54% Hepatomegaly present in 15% www.gp.online

Laboratory and imaging tests Blood smear Immunophenotyping – diagnosis confirmation and risk factors identification eg ZAP70 and CD38 status Interphase fluorescence in situ hybridization (FISH) - indetifies genetic risk factors eg del17p Serum marker beta-2 microglobulin Concentration of immunoglobulins in the blood Ultrasound of the abdomen and chest radiography CT scans of the chest and abdomen (not mandatory) blood tests -

Laboratory and imaging tests Bone marrow tests usually are not needed. Lymph node biopsy usually is not needed. Biopsies are performed if the peripheral blood smear does not yield diagnostic clues, to confirm the diagnosis, or to differentiate CLL from other diseases (e.g., Hodgkin's disease). Histopathology or immunophenotyping of lymph nodes are performed in case of Richter syndrom suspicion.

Blood smear CLL cells are typically small/medium sized normal looking lymphocytes Gumprecht shadows – smudge cells - typical for CLL ASH Image Bank - American Society of Hematology

Immunophenotyping – flow cytometry The test which is usually done from blood - determines whether the cells are clonal and recognizes their antigens (CD’s). Classical findings: CD19+, CD20weak +, CD23+, light chain restriction (kappa or lambda) Adverse Flow-cytometry factors: High proportion of CLL cells containing ZAP-70 (20% or more) or CD38 (30% or more)

Rai staging and prognostic system: Stage Stage (revised) Findings Median survival Low risk Isolated lymphocytosis > 150 months I Intermediate risk + Lymphadenopathy 101 months II + Hepatomegaly and/or splenomegaly 71 months III High risk + Anemia (Hb < 11 g/dL) 19 months IV + Thrombocytopenia (< 100,000/μL) Leukemia and lymphoma society (2017) Binet staging system: Stage Findings A Hb ≥10 g/dL and thrombocytes ≥100,000/uL and <3 involved nodal areas B Hb ≥10 g/dL and thrombocytes ≥100,000/uL but ≥3 involved nodal areas C Hb <10 g/dL or thrombocytes <1000,000/uL independently of numer of nodal areas involved Adapted from 2008 NCI guidelines

Assesing patient fitness Eastern Cooperative Oncology Group (ECOG) Performance Status Cumulative Illness Rating Scale (CIRS) grade ECOG Fully active, able to carry on all predisease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair

Differential diagnosis SLL – small lymphocytic lymphoma. The same appearance of neoplastic cells. The tissue infiltration is situated in lymph nodes, spleen, or other organs but circulating B lymphocyte count <5 x 10 9/L NHL – other non hodgkin lymphomas. Histopathological tests needed. Reactive lymphocytosis – the cells are not clonal. MBL – monoclonal B cel lymphocytosis. As many as 12% of healthy individuals >40 years of age may have low levels (<5 x 109/L) of circulating monoclonal B cells with no evidence of organ infiltration. MBL progresses to CLL at a rate of 1%–2% of patients per year Other types of chronić leukemias, eg: hairy cell leukemia, prolymphocytic leukemia..

Prognostic factors Serum markers, such as beta2 –microglobulin Genetic markers, including immunoglobulin heavy chain variable region (IgHv), gene mutational status (se: NOTCH1 gene mutation, tp53 mutation) Genetic abnormalities detected by fluorescence in situ hybridization (FISH) or metaphase cytogenetics (se: del 17p) Protein markers, such as zeta-chain-associated protein kinase 70 ([ZAP]- 70), cluster of differentiation CD38, or CD49d. Lymphocyte doubling time shorter than one year Increased fraction of prolymphocytes (an early form of the lymphocyte) in the blood Leukemia and Lymphoma society

Complications Immunosuppression with subsequent infections (most common cause of death) Autoimmune hemolytic anemia (AIHA) (of both the warm and cold agglutinin type) Immune Thrombocytopenic Purpura (ITP) Richter's transformation or Richter's syndrome: transformation into a high-grade NHL (approx. 5% of CLL cases) Secondary malignancies

Treatment Watch and wait strategy - no benefits of early treatment for people with low-risk CLL have been shown. When to Begin Treatment (when at least one of the above is present): Enlarging lymph nodes noted over a series of clinical exams Enlarging liver and/or spleen noted over a series of clinical exams Decreased red blood cell counts (hemoglobin less than 11g/dL) Decreased platelet counts (platelets less than 100,000/uL) Autoimmune anemia and/or thrombocytopenia poorly responsive to standard therapy Lymphocyte doubling time of less than 6 months (only in patients with lymphocytes greater than 30g/L) Presence of CLL B - symptoms

Therapy The therapy may consist of classical drugs and immunotherapy: Purine analogues and alkylating agents Anti-CD20 antibodies Glicocortycosteroids are part of the regimens or are given in monotherapy to eliminate autoimmunologic cytopenias. Targeted therapy is of increasing importance: Bruton kinase inhibitors, PI3K inhibitors, Bcl-2 inhibitors

Therapy Autologous stem cel translantation (ASCT) – due to the lack of efficacy and relatively high risk of late complications ASCT is NOT a part of therapy Allogenic stem cel transplantation (Allo-SCT) – decreasing role in the era of new drugs. Still an option for young high risk or recurrent patients. Surgery or radiotherapy have no role in the therapy