clin med 2 test 1: heme malignancy ppt

Cancer Generalities

• Cancer is characterized by uncontrolled cell growth and loss of apoptosis (programmed cell death)
• Can occur in any cell in the body
• Cancer originating from a blood cell can be classified as Leukemia (myeloid or lymphoid), Lymphoma (lymphoid tissue), or Myeloma (plasma cells, a type of B cell)

Blood Cell Types and Associated Cancers

• Neutrophils → Acute Myeloid Leukemia
• Lymphocytes → Acute Lymphocytic Leukemia
• Monocytes → Acute Myeloid Leukemia
• Eosinophils → Hypereosinophilic Syndrome
• Basophils → AML, seen in CML and HD
• RBC’s → Acute Erythroid Leukemia (rare)
• Platelets → Acute Megakaryoblastic Leukemia (rare)

Normal Neutrophil Development

• Myeloblast → Promyelocyte → Myelocyte → Metamyelocyte → Band → Neutrophil

Epidemiology of Acute Leukemias

• Typically affects older people, non-Hispanic whites
• Genetic disorders: Down Syndrome, Ataxia telangiectasia, Fanconi Anemia, Li Fraumeni
• Radiation exposure
• Chemical exposure

Epidemiology of Chronic Leukemias

• Ionizing radiation is the only known risk factor
• CML was the first disorder proven to be caused by a genetic translocation [t(9;22)]

Epidemiology of Lymphomas

• Relatives of probands have a 3.5x higher chance of developing lymphoma
• Higher incidence in patients with RA, hemolytic anemia, psoriasis, SLE, Systemic sclerosis, Polyarteritis nodosa, sarcoidosis, Crohn Disease, motor neuron disease, and Celiac disease
• Immunosuppression
• Viral infections (HIV, HTLV, EBV)

Epidemiology of Multiple Myeloma

• Higher incidence in African Americans
• Risk increases with Body Mass Index
• Association with Agent Orange exposure (especially those with MGUS)
• Higher incidence in families (3.5x higher with 1st degree relative)

Myelodysplastic Syndrome (MDS)

• Not a malignancy, but a pre-malignancy of the bone marrow
• Defined as...

Cancer Generalities

• Cancer is characterized by uncontrolled cell growth and loss of apoptosis (programmed cell death)
• Can occur in any cell in the body
• Cancer originating from a blood cell can be classified as Leukemia (myeloid or lymphoid), Lymphoma (lymphoid tissue), or Myeloma (plasma cells, a type of B cell)

Blood Cell Types and Associated Cancers

• Neutrophils → Acute Myeloid Leukemia
• Lymphocytes → Acute Lymphocytic Leukemia
• Monocytes → Acute Myeloid Leukemia
• Eosinophils → Hypereosinophilic Syndrome
• Basophils → AML, seen in CML and HD
• RBC’s → Acute Erythroid Leukemia (rare)
• Platelets → Acute Megakaryoblastic Leukemia (rare)

Normal Neutrophil Development

• Myeloblast → Promyelocyte → Myelocyte → Metamyelocyte → Band → Neutrophil

Epidemiology of Acute Leukemias

• Typically affects older people, non-Hispanic whites
• Genetic disorders: Down Syndrome, Ataxia telangiectasia, Fanconi Anemia, Li Fraumeni
• Radiation exposure
• Chemical exposure

Epidemiology of Chronic Leukemias

• Ionizing radiation is the only known risk factor
• CML was the first disorder proven to be caused by a genetic translocation [t(9;22)]

Epidemiology of Lymphomas

• Relatives of probands have a 3.5x higher chance of developing lymphoma
• Higher incidence in patients with RA, hemolytic anemia, psoriasis, SLE, Systemic sclerosis, Polyarteritis nodosa, sarcoidosis, Crohn Disease, motor neuron disease, and Celiac disease
• Immunosuppression
• Viral infections (HIV, HTLV, EBV)

Epidemiology of Multiple Myeloma

• Higher incidence in African Americans
• Risk increases with Body Mass Index
• Association with Agent Orange exposure (especially those with MGUS)
• Higher incidence in families (3.5x higher with 1st degree relative)

Myelodysplastic Syndrome (MDS)

• Not a malignancy, but a pre-malignancy of the bone marrow
• Defined as...

Acute Leukemias

• Without treatment, acute leukemias are fatal, and death can occur within hours, days, or weeks
• Acute leukemias are the most dangerous malignancies, requiring immediate referral to a hematologist without delay
• These patients are the sickest in the hospital, and prompt identification of findings is crucial

Signs and Symptoms of Acute Leukemia

• CBC with "BLAST" in the differential, which is never normal in peripheral blood
• Severe fatigue associated with anemia, cardiac damage, SOB, liver enzyme elevation, and renal insufficiency
• High white cell count (>50-100K), which may require leukapheresis to reduce leukostasis

Epidemiology of Acute Leukemia

• AML is the most common acute leukemia in adults, while ALL is the most common in children
• Incidence increases with age, with a median age of 65 years old
• Incidence is similar between races
• Almost all cases are associated with acquired gene mutations, with unknown underlying causes
• Environmental factors like exposure to chemotherapy, RT, chemicals, benzene exposure, and smoking are contributing factors
• Germline mutations, Trisomy 21, Fanconi's anemia, and CHIP (Clonal Hematopoiesis of Indeterminate Significance) are also associated with acute leukemia

Clinical Presentation of Acute Leukemia

• Anemia
• Fevers
• Bleeding/bruising or DIC
• Bone/Joint pains
• Skin manifestations
• Pallor
• Petechiae
• Ecchymosis
• Rare: gingival hyperplasia (monocytic), oral candida, herpetic lesions
• CNS involvement: confusions, CNS hemorrhage, meningitis (monocytic)
• Hepatomegaly and splenomegaly (10%), usually indicating ALL or prior MPN
• Metabolic/electrolyte abnormalities:
  • Hyperphosphatemia
  • Hypocalcemia
  • High uric acid
  • Hyperkalemia
  • High LDH

Why Acute Leukemia is so Dangerous

• Acute Leukemia cells are "sticky," causing blockages in capillaries and vasculature, leading to infarctions in organs
• Leukemic blasts take over the bone marrow, preventing normal growth and production of WBCs, RBCs, and platelets
• Doubling time for malignant cells can be hours, allowing them to quickly take over the entire marrow space

When to Suspect Acute Leukemia

• When "blasts" are seen in the WBC differential, immediately contact a hematologist
• Sudden changes in WBC count can indicate leukemia or infection and medication use
• WBC count elevation may require discussion with a specialist, especially if there are signs of hyperviscosity:
  • Changes in mentation and vision
  • Bleeding from gums or increased spontaneous bruising
  • Chest pains
  • Renal failure (from TLS!)
  • Shortness of breath
  • Chest pains

Treatments for AML/ALL

• Treatment of acute leukemia always involves chemotherapy (unless palliative care)
• Cytoreduction may be necessary, using Hydroxyurea (in AML) or steroids (in ALL), and Leukopheresis
• Fit patients will need to undergo chemotherapy:
  • AML: "7 + 3" (High dose Ara C plus anthracycline)
  • ALL: Chemotherapies with steroids as the backbone, depending on age and type of lymphocyte (B or T cell)
• Many patients will require a CONSOLIDATION BONE MARRROW TRANSPLANT after achieving remission
• CAR-T therapy is now used in some leukemias
• Not everyone will be eligible for chemotherapy treatment, and many will not be eligible for bone marrow transplant
• Supportive care is offered for those who are not eligible for intensive chemotherapy

Special Case of AML: Acute Promyelocytic Leukemia (APML) aka M3

• Has the special t (15;17), Retinoid Acid Receptor Alpha (RAR-A)
• Presents with DIC and will die of bleeding complications if not found early
• MUST START ATRA IMMEDIATELY IF SUSPECTED until confirmation tests return
• Auer Rods are needlelike crystals diagnostic of APML
• APML has an EXCELLENT prognosis but a difficult initial course

Advanced Treatments

• Bone Marrow Transplant
• Chimeric Antigen Receptor T cell (CART) therapy:
  • Type of immunotherapy
  • FDA approved for B-ALL, B-NHL, Mantle Cell Lymphoma, follicular Lymphoma, and Multiple Myeloma
  • Some good results, especially in B-ALL with CR 70-94%, but some will relapse regardless of initial response
  • Major side effects: Fever, Cytokine Release Syndrome (CRS), and long-term B cell aplasia leading to hypogammaglobulinemia and cytopenia

Chronic Leukemia Types

• Chronic Myeloid Leukemia (CML) is characterized by the presence of the BCR-ABL translocation t(9;22).
• CML is often associated with elevated White Blood Cell (WBC) count, potentially high Platelet (PLT) count, and almost normal Hemoglobin (Hb) levels.
• Splenomegaly is always present in CML.
• Tyrosine kinase inhibitors are used to treat CML.
• CML can progress to an accelerated phase (with 30% blasts) which is treated similarly to Acute Myeloid Leukemia (AML).

Chronic Lymphocytic Leukemia (CLL)

• CLL is characterized by a VERY elevated WBC count (in the hundreds of thousands).
• The Complete Blood Count (CBC) report often includes the presence of "smudge cells".
• New treatments for CLL involve oral medications.
• Depending on the disease stage, patients with CLL can have a normal life expectancy.

Chronic Leukemias General Characteristics

• Chronic Leukemias are not usually emergencies and can be managed over a long period.
• Patients are at increased risk of infections, especially in CLL, which may be mitigated by monthly IVIG infusions.
• Splenomegaly in CML can lead to feelings of fullness even when eating small meals.

Treatment of Chronic Leukemias

• Imatinib was the first Tyrosine Kinase Inhibitor (TKI) approved for CML treatment.
• Historically, CLL treatment involved chemotherapy, but new oral medications are now available.

Lymphomas

• Hodgkin Lymphoma (HL) presentation: lymphadenopathy, fatigue, pruritus, with peak ages at 20-24 and 80-84 years old
• HL treatment: complex chemotherapy, radiation therapy, or a combination of both, with bone marrow transplantation (BMT) and CART therapy as options
• "Owl Eye cells" are associated with HL

Non-Hodgkin Lymphoma (NHL)

• Affects all races, ages, and socioeconomic strata, with increased risk for those exposed to chemicals, radiation, HIV, EBV, and with breast implants
• Presentation: lymphadenopathy, fever of unknown origin, and possible association with autoimmune disorders, immunodeficiencies, and H. pylori infection
• Physical exam: enlarged lymph nodes (LN), spleen, and CNS involvement
• Diagnosis: requires excisional biopsy of LN (FNA's are poor), with examination of CBC, renal function, and uric acid levels
• Treatment: depends on NHL type, with options including radiation, chemotherapy, immunomodulators, and BMT/CART

Rituximab

• Monoclonal Ab against CD20 Ag, optimizing B cells for Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity
• Used in B cell (CD 20+) Lymphomas, commonly with R-CHOP/CHOP or R-EPOCH chemotherapy regimens

Plasma Cell Dyscrasias

• MGUS: 1%/year progression rate to multiple myeloma
• Smoldering myeloma and multiple myeloma are complications of MGUS
• Waldenström macroglobulinemia: a type of lymphoma
• Amyloidosis: a complication of plasma cell dyscrasias
• CRAB Criteria: calcium elevation, renal failure, anemia, bone lesions
• Pitfalls of MM: worsening anemia, renal failure, hypercalcemia, and increased thirst and urination frequency
• Bone lesions with pathological fractures are common in MM
• When to refer a patient: anemia with renal insufficiency +/- hypercalcemia, or lytic lesions on imaging

Multiple Myeloma (MM) Management

• Oncologist risk stratification and assessment for autologous transplant
• Stem cell collection after 3-6 months of induction chemotherapy, which can be kept for many years
• Auto transplant prolongs the time to first relapse, but MM is not curable with auto transplant; it only prolongs survival
• Treatment aims to improve quality of life and manage symptoms, but there is no current cure for MM

Lymphomas

• Hodgkin Lymphoma (HL) presentation: lymphadenopathy, fatigue, pruritus, with peak ages at 20-24 and 80-84 years old
• HL treatment: complex chemotherapy, radiation therapy, or a combination of both, with bone marrow transplantation (BMT) and CART therapy as options
• "Owl Eye cells" are associated with HL

Non-Hodgkin Lymphoma (NHL)

• Affects all races, ages, and socioeconomic strata, with increased risk for those exposed to chemicals, radiation, HIV, EBV, and with breast implants
• Presentation: lymphadenopathy, fever of unknown origin, and possible association with autoimmune disorders, immunodeficiencies, and H. pylori infection
• Physical exam: enlarged lymph nodes (LN), spleen, and CNS involvement
• Diagnosis: requires excisional biopsy of LN (FNA's are poor), with examination of CBC, renal function, and uric acid levels
• Treatment: depends on NHL type, with options including radiation, chemotherapy, immunomodulators, and BMT/CART

Rituximab

• Monoclonal Ab against CD20 Ag, optimizing B cells for Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity
• Used in B cell (CD 20+) Lymphomas, commonly with R-CHOP/CHOP or R-EPOCH chemotherapy regimens

Plasma Cell Dyscrasias

• MGUS: 1%/year progression rate to multiple myeloma
• Smoldering myeloma and multiple myeloma are complications of MGUS
• Waldenström macroglobulinemia: a type of lymphoma
• Amyloidosis: a complication of plasma cell dyscrasias
• CRAB Criteria: calcium elevation, renal failure, anemia, bone lesions
• Pitfalls of MM: worsening anemia, renal failure, hypercalcemia, and increased thirst and urination frequency
• Bone lesions with pathological fractures are common in MM
• When to refer a patient: anemia with renal insufficiency +/- hypercalcemia, or lytic lesions on imaging

Multiple Myeloma (MM) Management

• Oncologist risk stratification and assessment for autologous transplant
• Stem cell collection after 3-6 months of induction chemotherapy, which can be kept for many years
• Auto transplant prolongs the time to first relapse, but MM is not curable with auto transplant; it only prolongs survival
• Treatment aims to improve quality of life and manage symptoms, but there is no current cure for MM

Myeloid Leukemias

• Acute Myeloid Leukemia (AML): sudden onset, >20% blasts, severe
• Chronic Myeloid Leukemia (CML): characterized by Philadelphia chromosome

Lymphoid Leukemias

• Acute Lymphoblastic Leukemia (ALL): typically affects kids
• Chronic Lymphocytic Leukemia (CLL): typically affects older adults, characterized by smudge cells

Lymphomas

Hodgkin's Lymphoma

• Peaks in young age and old age
• Characterized by "owl eyes" and Reed-Sternberg cells

Non-Hodgkin's Lymphoma

• Affects all ages and races
• Characterized by splenomegaly and implants
• Associated with H. pylori

Multiple Myeloma

• Presents with mild back pain, typically in the mid-thoracic region
• Pain not alleviated when lying down
• Affects middle-aged individuals
• Can cause cord suppression when lying in a supine position

Myelodysplastic Syndrome (MDS)

• A premalignant disorder that will progress to cancer if left untreated
• A precursor to cancer