Leukemia: Types, Anatomy, and Development

• Leukemia is a disease of the hemopoietic system
• Leukemia is classified based on the speed of progression and cell types involved
• Acute progresses quickly, marked by increased proliferation of undifferentiated cells
• Chronic progresses more slowly, marked by uncontrolled proliferation of mature cells
• Acute and chronic are subdivided into myelogenous and lymphocytic types
• Myelogenous leukemia arises from hemopoietic stem cells
• Lymphocytic leukemia arises from other cell populations in the bone marrow (lymphoid cells/lymphocytes)
• Four main subtypes of leukemia are determined by: Natural history of the disease, Degree of cellular maturation, Dominant cell lines
• The four main leukemia types are ALL, CLL, AML (AKA ANLL), and CML

Leukemia Types

• ALL is acute lymphocytic leukemia
• CLL is chronic lymphocytic leukemia
• AML is acute myelogenous leukemia
• CML is chronic myelogenous leukemia

Anatomy and Development

• Leukemia develops during hemopoiesis or lymphopoiesis that begins with pluripotent stem cells
• Pluripotent stem cells differentiate into myeloid or lymphoid stem cells
• Myeloid stem cell pools provide progenitors for erythrocytes, monocytes, eosinophils, basophils, neutrophils, and platelets
• Lymphoid stem cell pools provide progenitors for classes of lymphocytes (B-cells and T-cells)
• Stem cells normally mature into functional blood cells and lymphocytes.
• Leukemia development results in uncontrolled and accelerated progenitor production, leading to incomplete or defective maturation.

Acute vs. Chronic Leukemia

• Acute leukemia involves rapid proliferation of undifferentiated stem cells
• Leukemic cells accumulate in the bone marrow, impairing normal production of RBCs, WBCs, and platelets
• This results in anemia, neutropenia and thrombocytopenia, leading to fatigue, pallor, bleeding, and infection
• Chronic leukemia cells are mature and accumulate in bone marrow, blood, lymph nodes, liver, and spleen
• This leads to enlarged organs and decreased bone marrow function

Acute Lymphocytic Leukemia (ALL) Epidemiology

• ALL is the most common pediatric malignancy
• 80% of children with acute leukemia have the ALL subtype
• Peak incidence occurs at ages 2-3 and is uncommon over 15 years old
• ALL is more common in males
• It is more common in Hispanics compared to Caucasians and African Americans
• Caucasians are more likely to have ALL compared to African Americans

ALL Etiology

• The cause of ALL is unknown
• A higher incidence (10-15x) is observed among Japanese atomic bomb survivors, suggesting a link to ionizing radiation
• Chemicals like benzene, hydrocarbons, and alkylating chemotherapy agents can contribute
• There is a heredity component, with a 20% risk within 1 year if one twin gets ALL
• Down syndrome is associated with a 10-30 times higher risk of ALL
• HTLV (human T-Lymphotrophic virus) can be a factor

ALL Prognostic Indicators

• A patient can expect complete remission 75% of the time
• Poor prognosis is associated with individuals under 1 year old or over 10, and adults over 50 years old
• A WBC count under 10,000 indicates a favorable prognosis, 20,000-49,000 is medium, and over 50,000 is the least favorable prognosis
• Poor prognosis also occurs if the CNS is involved, there is a mediastinal mass, massive organomegaly, or abnormal DNA content

ALL Clinical Presentation

• Clinical presentation depends on the cells suppressed due to increased production of white cells crowding out other cells
• Anemia (low RBCs) results in flu-like malaise, fatigue, and pallor
• Thrombocytopenia (low platelets) causes bleeding gums, epistaxis, petechiae, ecchymosis, menorrhagia, and excessive bleeding after dental procedures
• Neutropenia (low WBCs) increases susceptibility to respiratory, dental, sinus, perirectal, and urinary tract infections
• Other symptoms include liver, spleen, and testicular enlargement
• Arthritic pain is a symptom
• Symptoms rarely occur more than 6 weeks before acute diagnosis
• Vomiting, headaches, papilledema (optic swelling), or neck stiffness may indicate CNS involvement

ALL Detection and Diagnosis

• CBC shows thrombocytopenia and anemia in 2/3 of patients
• WBC can be low or high; abnormally high WBC indicates poor prognosis
• Immunophenotyping can establish a diagnosis in 90% of patients using an electron microscope and stains
• Protein molecules and markers are looked at
• Bone marrow biopsy is necessary to determine the amount of leukemic blast cells
• If greater than 25% leukoblasts are present, it is positive for leukemia

ALL Pathology

• ALL is characterized by uncontrolled proliferation of lymphoblasts
• Proliferation limits the production of other cells by overcrowding and inhibiting their growth and differentiation

ALL Treatment

• Treatment options include RT, chemotherapy, and BMT
• Four main ways to treat leukemia with radiation: TBI, Helmet field, CNS, testes
• Extramedullary leukemia is most common for relapse with main sites of relapse in the CNS and testes

Total Body Irradiation (TBI)

• Administered with 1200 cGy in 3 days, twice per day (6 treatments total)
• Purpose is to immunosuppress the patient before a bone marrow transplant
• It is given with a low dose rate (100 cGy/min) to spare late-responding tissues like abdominal organs and lungs

Helmet Field

• Treats the meninges prophylactically
• 1800 cGy is given, with 200 cGy per day for nine consecutive days

CNS (Craniospinal Technique)

• Combination of a helmet and posterior spine field
• Used when there are leukemic cells in the CSF
• The helmet is treated to 2400 cGy, and the total spine to 1500 cGy

Testes

• Leukemic cells tend to harbor, so the testes are sometimes treated, especially in combination with TBI
• 400 cGy is given in a single electron treatment

Chemotherapy

• Chemotherapy involves induction, consolidation, and maintenance
• Induction chemotherapty is given immediately after diagnosis and includes prednisone, dexamethasone (Decadron), and vincristine
• Consolidation begins when the patient is in remission, involving intravenous or intrathecal methotrexate and L-aspariginase
• Maintenance involves intravenous mercaptopurine and methotrexate, the best drug to prevent CNS spread

Bone Marrow Transplant (BMT)

• It is a treatment of choice for ALL, CML, and AML
• Bone marrow is harvested from the patient or a matching donor and infused into the patient after their BM has been destroyed by chemo or TBI
• Healthy marrow finds its way into the marrow cavities, and the patient begins normal hemopoiesis
• An identical twin provides the most desirable BMT donor

BMT Types

• An Allogenic transplant = BM is taken from a compatible sibling or other non-related matching donor from the registry
• Risks to the donor are very small
• First, the recipient gets a large dose of chemo alone or in combination with TBI to reduce leukemic cells and immunosuppress the patient so they can’t reject the new marrow
• After infusion, normal cells begin to produce in 2-4 weeks
• Autologous BMT = reinfusion of the patient's own bone marrow that was harvested and frozen when in remission
• Monoclonal antibodies before reinfusion can help remove leukemic cells

Failure of BMT

• Recurrent leukemia can occur, especially after the autologous method
• Graft vs. host disease (rejection) happens in 50% of patients and can range from a slight rash to a progressive life-threatening condition

RT Field Design TBI

• Machine settings are set for the largest field size possible (40 x 40)
• The gantry is positioned laterally
• The patient is placed in a box or on a cart
• Arms are placed over the lungs for compensators
• SSD 5 ft. or more in order to encompass entire body
• Half of the treatment is given to each side of the body
• TLD's at ankles, knees, and thighs are used to check midline doses
• Compensators are placed on a tray over the thinnest parts of the body

RT Field Design Helmet Field

• Field size is large enough to cover all meninges with fall-off around the head
• The inferior border is C2, with eyes and mouth blocked
• Parallel-opposed lateral fields are used

RT Field Design Cranio-Spinal Irradiation

• Patient is prone
• One or two posterior spine fields are used to cover the spine through S2
• The line of divergence determines the collimator angle for the helmet field
• The helmet and spine fields must abut using calculated gap or feathering technique to avoid hot and cold spots

RT Field Design Testes

• Usually in conjunction with TBI
• The patient is supine in lithotomy position
• Clinical setup involves a field size determined by the size of testes
• It is usually treated with electrons

Side Effects from TBI

• Acute side effects include GI issues, mucositis, skin reactions, alopecia, and interstitial pneumonitis
• Chronic side effects include permanent sterility, cataracts, liver fibrosis, and necrosis of genitals, muscles, kidneys

Side Effects from Helmet and CSI

• Acute: Skin reaction and hair loss, Low blood counts, N & V, Malaise, L'Hermittes sign if spine treated.
• Chronic: Neuropsychological and intellectual deficits, Cataracts, Growth retardation, Decreased pituitary function, Myelopathy – irreversible, Benign or malignant secondary tumors

Acute Myelogenous Leukemia (AML) Epidemiology and Etiology

• AML is also known as ANLL
• It usually occurs in patients over the age of 40, with a median age of 67
• 80% of adults with acute leukemia have AML or the myelogenous subtype
• Incidence is higher in white males, particularly older males, and in Jewish populations of Eastern European descent
• Etiology is similar to ALL, including prior radiation exposure, benzene, chemotherapy agents, and Thorotrast

AML Prognosis

• Unfavorable prognostic indicators include being over age 60, in poor health, and impaired organ function
• AML has a worse prognosis than ALL in children
• A WBC count of less than 20,000 is most favorable, and over 50,000 is the least favorable
• Age and chromosome status are two major prognostic indicators for treatment decisions

AML Clinical Presentation

• AML may have abrupt onset or a 1-6 month prodromal period
• Nonspecific flulike symptoms include fatigue, pallor, dyspnea, and anemia
• Petechiae, purpura, epistaxis, gum bleeding, or GI or urinary tract bleeding are symptoms of thrombocytopenia
• Fevers, chills, and susceptibility to infection are signs of neutropenia

AML Detection and Diagnosis

• CBC with differential and platelet count is performed
• Chromosomal abnormalities are seen in 30-50% of patients
• Definitive diagnosis is by bone marrow biopsy
• Presence of Auer rods is essential for diagnosis
• At least 30% myeloblasts are needed to be considered AML

AML Pathology

• AML involves unregulated proliferation of stem cells that have lost their ability to differentiate
• This leads to a gradual accumulation of undifferentiated cells
• Cells do not reach maturity or are defective at maturity

AML Staging and Classification

• The French-American-British (FAB) system is used for staging and classification

AML Treatment

• AML is treated the same as ALL
• Prognosis depends on the patient's age, subtype of cells, and whether the cancer is recurrent
• Recurrent AML has a poor prognosis

Chronic Lymphocytic Leukemia (CLL) Epidemiology

• CLL accounts for 30% of leukemias in the US
• Incidence increases with age, with 65 being the average age of onset
• Half of patients are over 70 years old, and it is rare under 40 years old
• It occurs twice as frequently in males as in females
• Less incidence in Asians, and equal incidence for blacks and whites

CLL Etiology

• Heredity is a factor, with a 2-7 times higher risk if a first-degree relative has it
• Some immunodeficiency syndromes and viruses can be factors
• Chemicals used in the rubber industry may contribute
• Only leukemia is not associated with radiation exposure or benzene

CLL Presentation

• Is frequently asymptomatic and found on routine blood test (WBC over 10,000)
• Fatigue, fever, night sweats, and weight loss can occur
• Lymphadenopathy and an enlarged spleen are very common presentation markers

CLL Detection

• Blood tests can be used for diagnosis
• Enlarged nodes and spleen can be detected
• 50% of patients have chromosome abnormalities

CLL Pathology

• Increased proliferation of leukemic cells in the bone marrow, blood, lymph nodes, and spleen with organ enlargement and decreased bone marrow function

CLL Treatment

• Optimal treatment is not known
• Those with early-stage disease may not benefit from treatment
• Palliative RT can be used for localized masses, lymph tissue, or spleen (most common)
• Splenectomy is an option
• Chemotherapy is used for progressive anemia and thrombocytopenia, using chlorambucil and prednisone

Radiation Therapy (RT) to Spleen

• RT is given to reduce spleen size
• AP/PA fields are set up clinically with a 1 cm margin around the entire spleen
• Simulation is necessary for kidney location
• 500 cGy are given in 5 days

Chronic Myelogenous Leukemia (CML) Epidemiology and Etiology

• About 15% of all leukemias are CML
• It is rare in childhood and before age 35; peaks in the mid-60s
• The etiology is unknown but may be linked to prior radiation exposure or benzene

CML Prognostic Indicators

• Spleen size, platelet count, hematocrit, gender, and percentage of myeloblasts are important factors
• It can transform into acute leukemia after 3-4 years; with a median survival of 2 years afterward

CML Presentation

• Early symptoms are mild and non-specific, including fatigue, heat intolerance, sweating, and easy bruising
• If the spleen is enlarged (90% of cases), there is a vague discomfort in the LUQ, early satiety, and weight loss
• After 3-4 years, it can transform into a blast crisis, in which all organs of the body are invaded by blast cells (several 1000). Symptoms are now fever, bone pain, and weight loss
• The active disease phase includes 10% weight loss in 6 months, fever, extreme fatigue, anemia, thrombocytopenia, organ involvement, and painful enlargement of the spleen

CML Detection and Diagnosis

• It is difficult to diagnose and usually found incidentally
• Can present with mild to moderate anemia
• Myeloblasts are detected in the blood
• Presence of the Philadelphia chromosome is most important

CML Pathology

• Abnormal hemopoietic stem cells; erythropoiesis impaired

CML Treatment

• RT, chemo, BMT
• RT for spleen and TBI
• Immunotherapy with alpha-interferon can cause a gradual reduction of leukocytes, an increase in RBC, and a decrease in spleen size
• Gleevec (moab) is also an immunotherapy drug
• Allogeneic BMT is the only curative treatment for CML, but only 20-30% find a matching donor
• Median survival time is 3.5 years, but anytime from 1-12 years is possible

Role of the Radiation Therapist

• Since chemo is the main treatment, radiation therapists are unlikely to see many leukemia patients
• Special scheduling is needed for RT departments that perform TBI
• Sufficient time is needed to comfort children and parents
• Some pediatric patients will require general anesthesia, which is time-consuming
• Coordination of RT, anesthesia, and nursing schedules can be difficult
• The radiation oncologist may need to adjust the spleen field daily
• Blood counts may be needed before treatment
• As much as 1.5 hours per TBI session are needed, twice per day, leading to scheduling conflicts, so actual tx time is 45 minutes
• Patients are immunocompromised, so disinfect the room and machine and wear a gown, gloves, and mask
• Nausea may interrupt treatment
• Treatment may have to be done on weekends or evenings

Leukemia Outcomes

• ALL had only a 4% survival rate before 1962 but now has a 75-85% 5-year survival rate
• AML has a 50-70% remission rate, with a 5-year survival rate of 21%
• CLL has no definitive cure
• CLL with a 5-year survival rate of 74%
• If CML is accelerated, survival is less than 1 year; after blast crisis, patients may only live a few months