1 / 53

Chronic Lymphoproliferative Disorders

Downloading this presentation or using any of the diagrams, charts or photographs for any purpose other than studying for the Blood-Hematopoiesis-Lymphatics course is prohibited. Chronic Lymphoproliferative Disorders.

awena
Download Presentation

Chronic Lymphoproliferative Disorders

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Downloading this presentation or using any of the diagrams, charts or photographs for any purpose other than studying for the Blood-Hematopoiesis-Lymphatics course is prohibited.

  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

More Related