L 17 Hematologic Malignancies Lecture

Hematologic Malignancies

Types of Hematologic Malignancies

  • Acute Leukemia
      - Acute Myeloid Leukemia (AML)
      - Acute Lymphoblastic Leukemia (ALL)

  • Lymphoma
      - Non-Hodgkin
      - Hodgkin

  • Myeloproliferative Neoplasms
      - Chronic Myeloid Leukemia (CML)
      - Polycythemia Vera
      - Essential Thrombocythemia
      - Primary Myelofibrosis (Chronic Idiopathic Myelofibrosis)

  • Myelodysplastic Syndrome (MDS)

Acute Leukemia

Acute Myeloid Leukemia (AML)

  • Description: AML is a hematologic malignancy characterized by an increase in the number of myeloid cells (myeloblasts) in the bone marrow and an arrest in their maturation, frequently leading to hematopoietic insufficiency, which may occur with or without leukocytosis.

Epidemiology

  • Median Age at Diagnosis: 60 years

Etiology

  • Risk Factors:
      - Radiation
      - Chemical Exposure: Benzene
      - Drugs: Chemotherapeutic agents

Clinical Presentation

  • Related to Cytopenia:
      - Anemia: Leads to Fatigue and Dyspnea
      - Leukopenia: Results in Fever and Infections (e.g., pneumonia)
      - Thrombocytopenia: Causes Bleeding

  • Features Related to Tumor Infiltration:
      - Hepatosplenomegaly
      - Leukemia Cutis
      - Lymphadenopathy
      - Bone Pain
      - Gingival Hyperplasia
      - CNS Involvement: Cranial Neuropathy (not myeloid-related, only lymphoid)
      - Other Organs: Granulocytic Sarcoma

  • Features Related to Leukocytosis:
      - Hyperleukocytosis (>100,000): Leads to leukostasis
      - Pulmonary Infiltrates and Insufficiency
      - Mental Status Changes
      - Visual Impairments: Blindness
      - Metabolic Changes
      - Tumor Lysis Syndrome: Usually seen with therapy due to the release of chemicals from tumor cells

Laboratory and Radiologic Studies

  • Complete Blood Count (CBC) with Manual Differential Count:
      - Hallmark: Pancytopenia and circulating blast cells (absent in 10% of cases)

  • Bone Marrow Exam: Required after any observed pancytopenia, involving flow cytometry and cytogenetics for diagnosis.
      - Differential Diagnosis (DDX):
        - AML vs ALL vs Myeloproliferative Neoplasm vs Myelodysplastic Syndrome

  • Bone Marrow Morphology:
      - Pathognomonic of AML: >20% blasts present in the marrow
      - Myeloid Leukaemia: Presence of Auer rods – flow cytometry and cytogenetics still needed for confirmation of AML.

Cluster Differentiation (CD) Antigens and Flow Cytometry

  • Definition: Surface marker cell-membrane proteins (glycoproteins) or receptors (antigens) that allow for the identification of different cell lines at various stages of development.

  • Importance: Identification of malignant cells helps in determining the tissue origin of leukemia.

  • Flow Cytometry in Acute Leukemia: Helps differentiate if blast cells are myeloid, lymphoid, or bi-phenotypic.   - Antigen Markers:
        - AML cells show positivity for CD 13 or CD 33
        - B lineage cells express CD19

Other Laboratory Tests

  • Chem 7 Test

  • Clotting Tests

  • Viral Studies

  • RBC Counts

  • Human Leukocyte Antigen (HLA) Typing: To match patients and donors.

Treatment for AML

  1. Acute Promyelocytic Leukemia (APL):

  2. Non-APL AML:
       - Induction Chemotherapy: Critical for AML
       - Supportive Care:
         - Blood Bank Support
         - Prophylactic Antibiotics/Antivirals
       - Day 14 Bone Marrow Assessment:
         - <5% blast cells; administration of G-CSF to increase white blood cell count
       - Complete Remission:
         - Achievable in 80-90% of adults under 60 years
       - Consolidation Therapy: Determined by prognostic group after remission
       - Relapse Treatment: Options include Allogeneic/Autologous Stem Cell Transplant (SCT), innovative approaches    

Prognosis for AML in Adults

  • Complete Remission Rate: 70-80% success in those < 60 years

  • Specific Subtype Prognosis (AML M3):
      - M3 is the most curable subtype
      - Genetic mutation: t(15;17)
      - DIC Treatment: Administered with all-trans retinoic acid to promote proper maturation of M3 cells, with complication management
      - Long-term Remission Rate: >90%

Acute Lymphoblastic Leukemia (ALL)

  • Epidemiology:
      - 80% of acute leukemias in children
      - 20% of adult leukemias
      - Commonly occurs in ages 3-7 years

  • Symptomatology: Similar fatigue symptoms as AML

  • Diagnosis: Flow cytometry of marrow aspirate shows lymphoblasts

  • Treatment: Combination chemotherapy with CNS prophylaxis due to lymphoblast hiding in the CNS

  • Remission Rate: 90% achievable

Lymphoma

Overview of Lymphoma Types

  • Subtypes:
      - B Cell Lymphomas:
        - Precursor B cell neoplasms
        - Mature B cell neoplasms
        - Includes: CLL/SLL, Hairy Cell Leukemia, Follicular Lymphoma (translocation t(14;18) leading to bcl-2 overexpression), Diffuse Large B Cell Lymphoma
      - T Cell Lymphomas:
        - Precursor T cell neoplasms
        - Mature T cell neoplasms
        - Includes: Mycosis Fungoides / Sezary Syndrome

Risk Factors for Lymphoma

  • Viral: EBV

  • Bacterial: H. pylori

  • Autoimmune diseases

  • HIV Infection

  • Organ Transplantation

Classification: Hodgkin vs Non-Hodgkin Lymphoma

  • Types of Lymphomas:
      - Hodgkin Lymphoma
      - Non-Hodgkin Lymphoma: Can be B lymphoma or T lymphoma

Chronic Lymphocytic Leukemia (CLL)

  • Definition: Hairy cell leukemia, B lymphocytes malignancy with a mean age of 70 years.

  • Clinical Features: Fatigue, incidental finding, autoimmune hemolytic anemia, splenomegaly

  • CBC Findings: Increased mature lymphocytes and possible smudge cells

  • Diagnosis: Flow cytometry needed to confirm CLL (polyclonal reaction indicates viral infection)

  • Rai Staging:
      - Stage 0: Follow-up required without therapy
      - Progressive Disease: Requires therapy
      - Biologic & Stem Cell Therapy available

  • Prognosis:
      - Varies with stage
      - Stage 0-1: 10-15 years survival
      - Stage III-IV: 2-year survival rates >90%

Diagnostic Features of Lymphoma

  • Clinical Features:
      - Indolent: Painless lymphadenopathy (isolated or widespread)
      - Intermediate Stage: Constitutional symptoms such as fever, night sweats, or weight loss

  • Laboratory Diagnosis: Requires tissue biopsy (excisional of entire lymph node or fine needle aspiration)
      - Flow Cytometry Application: Determine if cells are monoclonal and if they belong to B-cells or T-cells

Staging Evaluation for Non-Hodgkin Lymphoma

  • Evaluation Methods:
      - Physical Exam
      - Documentation of B symptoms
      - Laboratory evaluation: CBC, Liver Function Tests (LFT), uric acid, calcium
      - Bilateral Bone Marrow Biopsy required

Staging Classifications

  • Hodgkin Lymphoma: Lugano Classification

  • Non-Hodgkin Lymphoma: Also follows Lugano Classification but does not use “B” symptoms for staging

  • Stages of Lymphoma:
      - Stage I: Involvement of 1 side/1 lymph node
      - Stage II: Involvement of 2+ nodes on the same side
      - Stage III: Involvement of nodes on both sides
      - Stage IV: Disseminated disease

Treatment of Non-Hodgkin Lymphoma

  • Rituximab: An anti-CD20 monoclonal antibody

  • MALT Lymphoma: Associated with H.pylori, t(11;18) translocations do not respond to antibiotics

  • Aggressive Lymphomas: Require combination chemotherapy

  • Prognosis:
      - Low risk: 80% survival
      - High risk: 50% survival

Hodgkin Lymphoma

  • Epidemiology: Two peaks in age distribution: 20s-30s and another peak >50 years

  • Clinical Features: Palpable nontender lymphadenopathy and presence of B symptoms (fever, night sweats, weight loss)
      - Fever of Unknown Origin (FUO): Pel-Ebstein fever - cyclical fever patterns

Diagnosis

  • Method: Made via excisional lymph node biopsy identifying Reed-Sternberg cells.

Staging Evaluations for Hodgkin Lymphoma

  • Required Evaluations:
      - History and Physical
      - CBC, ESR, Chem 7
      - LDH Levels
      - Chest CT Scan
      - Bone Marrow Biopsy

Hodgkin Lymphoma Treatment

  • Standard Treatment: Chemotherapy

  • Prognosis:
      - Stages IA-IIA: 10-year survival rates >90%
      - Poorer outcomes seen in older patients and those with bulky disease

Plasma Cell Disorders

Spectrum of Disorders

  • Monoclonal Gammopathy of Undetermined Significance (MGUS): Transformation to myeloma at a rate of 1% per year

  • Smoldering Myeloma

  • Multiple Myeloma

  • Plasma Cell Leukemia

  • Other Plasma Cell Disorders: Waldenström Macroglobulinemia

Multiple Myeloma

  • Clinical Features: Most commonly occurs in individuals 65 years and older
      - Symptoms:
        - Anemia (73%)
        - Bone Pain (58%)
        - Elevated Creatinine Levels (48%)
        - Hypercalcemia (28%)
        - Weight Loss (24%)

Diagnostic Evaluations for Multiple Myeloma

  • CBC with Differential: Red cell rouleaux formation

  • BUN and Creatinine Levels

  • Serum Protein Electrophoresis (SPEP) and Immunofixation

  • Urine Tests:
      - 24-hour urine collection for Bence-Jones Protein quantitation and 24-hour protein electrophoresis

  • Findings: Monoclonal immunoglobulin spike (M protein)
      - Subtype Confirmation: Serum immunofixation identifies specific immunoglobulin subtype (e.g., IgG, IgM, IgA, IgD, IgE)

Diagnosis of Multiple Myeloma

  • Requirements:
      - Clonal bone marrow plasma cells ≥10%
      - Defining Events:
        - Evidence of end-organ damage:
          - Hypercalcemia
          - Renal insufficiency
          - Anemia
          - Bone lesions
          - Clonal plasma cells must be ≥60%
          - Involved : uninvolved serum free light chain ratio ≥100
          - Presence of ≥1 focal lesions on MRI studies

Treatment of Multiple Myeloma

  • Approaches:
      - Chemotherapy, Autologous Hematopoietic Cell Transplantation (HCT), and/or combination therapy
      - Management of Hypercalcemia and Hyperuricemia: Treated aggressively
      - Outcome Factors: Age, performance status, comorbidities influence prognosis
      - Survival Rate: Average of >7 years but robust factors can improve outcomes
      - Management of Vertebral Collapse: Vertebroplasty or kyphoplasty recommended
      - Bisphosphonates: Utilized for management and prevention

Waldenström Macroglobulinemia

  • Definition: Lymphoplasmacytoid malignancy characterized by the secretion of IgM antibodies

  • Clinical Characteristics:
      - Unlike myeloma, disease primarily localized to lymph nodes, resulting in enlargement
      - Symptoms:
        - IgM myeloma display IgM plasma cells and may cause lytic lesions and associated Bence-Jones proteins in urine
      - Common age range: 60s to 70s
      - Symptoms include fatigue, hyperviscosity, anemia, mucosal gastrointestinal bleeding, visual impairments, altered consciousness, and no significant bone tenderness typically seen

Laboratory Diagnosis for Waldenström Macroglobulinemia

  • Findings:
      - Presence of Anemia
      - Rouleaux Formation: Seen in peripheral RBCs
      - Abnormal Plasmacytic Lymphocytes
      - Monoclonal IgM Identified on SPEP
      - Bone Radiographs: Often normal

Hyperviscosity Syndrome

  • Symptoms: Fatigue, headaches, blurred vision, mucosal bleeding, impaired mentation/coma, transient paresis

  • Physical Features: Tortuous retinal veins -