Chronic Lymphoproliferative Disorders

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2. Chronic Lymphoproliferative Disorders • Variety of conditions featuring neoplastic proliferations of mature lymphocytes in blood

3. Chronic Lymphoproliferative Disorders Mature B-cell disorders B-cell chronic lymphocytic leukemia (CLL) B-cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Lymphoplasmacytic lymphoma Leukemic phase of non-Hodgkin lymphoma Plasma cell leukemia

4. Chronic Lymphoproliferative Disorders Mature T-cell / NK cell disorders T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T-cell leukemia/ lymphoma Sezary syndrome

5. B-Cell Chronic Lymphocytic Leukemia (CLL) • Most common adult leukemia in U.S. & Western Europe: • ~30% of all leukemias • Predominantly older age group: • Median age ~55-60 years at diagnosis • Does occur at younger ages • Men > Women

6. CLL: Biologic Heterogeneity • CLL is biologically heterogeneous • Pre-germinal center variant: • “Unmutated” immunoglobulin gene (IgH) • More aggressive • Post-germinal center variant: • “Mutated” immunoglobulin gene (IgH) • Less aggressive • Appearance and phenotype generally the same

7. B-Cell CLL: Etiology • No known cause in the majority of patients • Possible genetic predisposition: • Increased incidence in relatives of CLL patients • Possible occupational or chemical exposure: • Reported increased incidence in agricultural workers

8. B-Cell CLL: Clinical • Frequently asymptomatic: Unexpected finding on routine CBC • Symptoms (when present) nonspecific: • Fatigue, weight loss, fever, night sweats • Physical exam: Often unremarkable: • Lymphadenopathy may be present, but usually not marked • May have hepatosplenomegaly

9. B-Cell CLL: Diagnosis • Lymphocytosis (>5,000/mL) • Immunophenotyping by flow cytometry: • Immunoglobulin light chain restriction (korl light chain, but not both) • Characteristic phenotype • Bone marrow examination: • Traditionally done, but may not be required

10. B-Cell CLL: Blood Smear • Lymphocytosis of small, mature-appearing lymphocytes: • Very condensed nuclear chromatin (“Soccer ball” nuclei) • Numerous “smudge” cells (smashed lymphocytes)

11. B-CLL: Blood Smear Low power

12. B-CLL: Blood Smear “Smudge Cell”

13. B-CLL: Bone Marrow Biopsy

14. B-Cell CLL: Phenotype* • Expression of B-cell markers (CD19, CD20) • Expression of CD5 (T-cell marker) • Dim surface immunoglobulin, with light chain restriction • Other markers: CD23+, FMC-7-, CD38 variable: • CD38 expression may be adverse indicator * This could appear on the USMLE….

15. B-CLL: Laboratory Findings • Anemia and/or thrombocytopenia: • ~30% at diagnosis, usually mild • Absolute neutrophil count usually normal; percent neutrophils decreased • Direct antiglobulin (“Coombs’ ”) test: • ~1% positive at diagnosis; increases with duration of disease • Other labs usually unremarkable

16. B-Cell CLL: Differential Diagnosis • Reactive lymphocytosis: • Viral & other infections • Drugs • Monoclonal B-cell lymphocytosis (MBL) • Prolymphocytic leukemia, T/NK-cell leukemias, hairy cell leukemias • Other non-Hodgkin lymphomas with blood involvement: • Mantle cell, follicular lymphomas, others

17. Monoclonal B-Cell Lymphocytosis (MBL) • Presence of a small monoclonal B-cell population in blood • By definition, less than 5,000 clonal lymphocytes/mL (< 5 x 109/L) • Other criteria: • Normal physical exam (no lymphadenopathy or hepatosplenomegaly) • No B symptoms • No autoimmune or infectious disease

18. Monoclonal B-Cell Lymphocytosis (MBL) • Relatively common; increases with age: • Estimated >4% of people over 40 • Majority have same phenotype as CLL • MBL probably precedes all cases of CLL • However: Majority of MBL never transform to CLL • No treatment for MBL

19. B-CLL: Distinction from Small Lymphocytic Lymphoma (SLL) • Distinction based on presence or absence of blood involvement: • CLL: >5,000/mL clonal lymphocytes • SLL: <5,000/mL clonal lymphocytes • Phenotype, appearance in lymph node & bone marrow identical • Considered one disease in WHO classification: B-CLL/SLL

20. B-CLL: Staging • Two systems: Rai and Binet: • Rai (or modified Rai) used in U.S. • Binet used in Europe • Both use lymphadenopathy & bone marrow compromise as significant variables • Both helpful in predicting prognosis: • However, some patients with low stage at diagnosis follow aggressive course

21. Rai Staging System for CLL 0 = lowest; IV = highest Don’t memorize this table - Learn the general concept

22. Binet Staging System for CLL A= Low; B = Intermediate; C = High Don’t memorize this table - Learn the general concept

23. B-CLL: Clinical Course • Majority have indolent course: • Median survival >10 years • Some patients live >20 years without treatment, with few problems • Minority of patients have aggressive course: • Survival only a few years Older patient with stage 0 CLL may have normal life expectancy for age

24. B-CLL: Predictors of Aggressive Course • Rapid lymphocyte doubling time*: • Doubling time < 12 months • Presence of cytogenetic abnormalities • Diffuse involvement of bone marrow • Bone marrow compromise: • Advanced Rai or Binet stage * Rate of increase in lymphocyte count is more important than the lymphocyte count itself

25. CLL: Predictors of Aggressive Course • Unmutated immunoglobulin heavy chain gene (versus mutated IgH gene) • Expression of CD38 • Expression of ZAP-70 • Specific chromosomal abnormalities: • p53 gene mutations • Trisomy 12 • ATM gene mutations

26. B-CLL: Complications • Infections • Cytopenias • Autoimmune disorders • Mass effects: • Due to bulky lymphadenopathy • Transformation to histologically aggressive disease You need to know these.

27. B-CLL: Infections • Most frequent cause of death • Predominantly due to hypogammaglobulinemia: • Poor opsonization • Impaired response to new antigenic challenges • Respiratory tract = most common site: • Other mucosal surfaces also

28. B-CLL: Infections • Bacterial infections most common • Organisms: • Strep. pneumoniae • H. influenzae • Staph.aureus • Gram-negative enterics • Pseudomonas species

29. B-CLL: Infections • Patients treated with fludarabine prone to opportunistic infections: • Pneumocystis carinii • Listeria • Mycobacteria • Nocardia • Aspergillus • Herpes viruses

30. B-CLL: Cytopenias • Multi-factorial • Replacement of bone marrow • Autoimmune phenomena: • Immune hemolytic anemia; pure red cell aplasia • Immune thrombocytopenia (rare) • Hypersplenism • Treatment

31. B-CLL: Autoimmune Phenomena • Predominantly directed against blood cells • Positive direct antiglobulin (“Coombs’ ”) test common • Hemolytic anemia less common: • Resembles idiopathic warm autoimmune hemolytic anemia • Immune thrombocytopenia occurs, but uncommon

32. B-CLL: Histologic Transformation • Development of large cell lymphoma (Richtersyndrome): • Occurs in ~3-5% of patients • Poor response to therapy; short survival • Prolymphocytic transformation: • Majority of lymphocytes in blood larger, with prominent nucleoli • Histologic transformation uncommon You need to know about Richter syndrome

33. B-CLL: Treatment • Some patients never require treatment for CLL • Indications for treatment: • Rapid lymphocyte doubling time • Bulky lymphadenopathy • Bone marrow compromise • Autoimmune phenomena • Lymphocytosis per se is not an indication for treatment

34. B-CLL: Treatment • Traditional: Chlorambucil + prednisone: • Controls WBC count • Few or no complete responses • Fludarabine: Becoming treatment of choice for many hematologists: • Can induce complete responses • However: Myelosuppressive & immunocompromising • Monoclonal antibody therapy (Rituxan)

35. B-CLL: Allogeneic Stem Cell Transplant • Considered for young patients with aggressive disease, histocompatible donor • Potential for cure of disease: • “Graft versus leukemia” effect • Significant morbidity & mortality • Most patients too old for allogeneic transplant

36. Hairy Cell Leukemia (HCL) • Uncommon, distinctive lymphocytic leukemia • Occurs predominantly in older population • Men > women (~3-5 : 1)

37. Hairy Cell Leukemia: Characteristics • Cytopenias: • Leukopenia, anemia, thrombocytopenia • Neutropenia & monocytopenia common • Splenomegaly: Often massive • Distinctive “hairy” lymphocytes in blood: • May be uncommon

38. Hairy Cell Leukemia

39. Hairy Cell Leukemia: Clinical • Nonspecific symptoms: • Fatigue, weakness, lethargy • Abdominal discomfort, early satiety: • Due to splenomegaly • Recurrent pyogenic infections: • Due to neutropenia • Cutaneous infections common

40. Diagnosis of Hairy Cell Leukemia • Flow cytometry: Key diagnostic test • Demonstrate clonality of lymphocytes • Characteristic phenotype • TRAP stain: • “Tartrate-resistant acid phosphatase” • Older test used to diagnose HCL • Neither specific nor 100% sensitive • Might appear on USMLE

41. HCL: Treatment & Survival • Survival previously ~3-5 years • Now: Dramatically effective therapies • Cladribine (2-chlorodeoxyadenosine): • Single 7-day infusion causes durable complete responses in >80% • Others: • Pentostatin (2’-deoxycoformycin): Also effective • Interferon-a: Replaced by Cladribine

42. Adult T-Cell Leukemia/Lymphoma (ATLL) • Lymphocytosis of neoplastic T-cells with multilobated or convoluted nuclei • Common in southern Japan, parts of Caribbean, West Africa • In U.S.: Most common in Southeast: • African-Americans > Caucasians

43. Adult T-Cell Leukemia/Lymphoma

44. ATLL: HTLV-1 • Geographic localization of ATLL corresponds to areas of endemic human T-cell lymphocytotrophic virus-1 (HTLV-1) • First virus proven directly oncogenic in humans • Demonstration of positive serologies for HTLV-1 required for diagnosis of ATLL

45. ATLL: HTLV-1 • RNA retrovirus • Similarities to, but different family from HIV: • Infects same cells (CD4+ lymphocytes) • Encodes many proteins with similar structures & functions

46. Adult T-Cell Leukemia/Lymphoma • May present as leukemia, + lymphadenopathy • May present as lymphoma: • Lymphadenopathy without blood involvement • Most patients eventually develop leukemic picture, if not present at diagnosis

47. Adult T-Cell Leukemia/Lymphoma • Japan: • Median onset: Mid 50’s • Smoldering, indolent and acute forms occur • United States: • Median onset in 30’s • Most cases aggressive • Skin lesions & hypercalcemia common

48. ATLL: Treatment & Survival • Treatment largely ineffective • Standard chemotherapy tolerated poorly: • Treacherous due to immunocompromised state • Survival in U.S. poor: • Median survival <1 year

49. CLL: Take Home Messages • CLL is a clonal proliferation of small, mature-appearing lymphocytes • It is common in the older population • Most cases are indolent, with long survival; a minority are aggressive • It is incurable with conventional therapy • It is essentially the same as small lymphocytic lymphoma (SLL)

50. CLL: Take Home Messages • Primary complications of CLL: • Infections • Bone marrow suppression • Autoimmune diseases: Autoimmune hemolytic anemia • Transformation to high grade lymphoma (Richter syndrome): Uncommon