Leukemia and Lymphoma

• Hematological malignancies include leukemia and lymphoma.
• Leukemia involves cancer cells primarily in the bone marrow and blood.
• Lymphoma involves cancer cells tending to be in lymph nodes and other tissues.

Leukemia Types and Characteristics

• Acute leukemias are highly proliferative disorders with rapid progression.
• Acute leukemias have symptoms of hematopoietic insufficiency.
• Chronic leukemias have a slower clinical progression.
• Chronic leukemias exhibit a late onset of symptoms.
• Chronic leukemias maintain partial differentiation potential.
• Leukemia's classification is based on lineage, either lymphoid or myeloid.

Diagnosing Leukemia

• Newly diagnosed leukemia patients require an aspirate of the liquid marrow.
• A bone marrow core biopsy is also needed for newly diagnosed patients.
• Bone marrow aspiration removes a small amount of tissue in liquid form for examination.
• A bone marrow biopsy removes a small sample of bone marrow for testing.
• Examining the size, shape, and traits of white blood cells helps classify them.
• Determining the percentage of cells in the bone marrow aids in diagnosis.

Acute Myeloid Leukemia (AML) - Epidemiology

• AML is more common in the elderly, with 54% of cases affecting those ≥ 65 years old.
• AML accounts for approximately 13-14% of leukemia cases in the first 10 years of life.
• AML accounts for about 36% of leukemia cases in older children.
• AML is often fatal.
• Death can occur from neutropenia-associated infections.
• Death can also occur from thrombocytopenia-associated bleeding.
• Intracranial hemorrhage is also a cause of death.

Etiology of AML

• De novo AML has an unknown cause.
• Secondary AML may be related to a history of radiation therapy.
• Secondary AML is related to alkylating agents like melphalan, busulfan, and cyclophosphamide.
• Secondary AML is related to carbo- and cisplatin.
• Secondary AML is related to topoisomerase II inhibitors such as etoposide and doxorubicin.
• Secondary AML has a worse prognosis than de novo AML.

Clinical Presentation of AML

• Anemia causes fatigue, malaise, weakness, pallor, palpitations, dyspnea on exertion (DOE), and shortness of breath (SOB).
• Thrombocytopenia results in easy bruising, petechiae, ecchymosis, heavy or prolonged menses, epistaxis, gingival bleeding, and conjunctival hemorrhage.
• Neutropenia can lead to infection.
• Signs of infection may be absent secondary to low WBC.
• Skin manifestations include skin infiltration, like "Leukemia cutis" or "Granulocytic sarcoma."
• Pain can be generalized bone pain, with increased WBC, and from leukemic infiltration of tissue.
• Leukocytosis or myelosuppression can cause hyperviscosity syndrome.
• Symptoms may include visual changes, mucosal bleeding, and neurological symptoms.
• Constitutional and cardiopulmonary symptoms may occur.
• Gum hypertrophy might be present.
• Increased serum LDH is indicative.
• CNS manifestations are uncommon in AML.

Diagnosing AML

• Diagnosis involves taking patient history and conducting a physical examination.
• Diagnostics include CBC with differential, platelet count, and chemistry profile.
• Includes performing PT, PTT, and fibrinogen tests
• Examination of peripheral blood smear aids diagnosis.
• The presence of Auer rods strongly suggests AML.
• Requires bone marrow biopsy with cytogenetics.
• Includes immunophenotyping.
• MRI of the brain and/or lumbar puncture is performed if there are neurologic symptoms.
• Neurologic symptoms include lethargy, confusion, or focal neurological defects in patients with WBC >40k.
• Human Leukocyte Antigen (HLA) typing is done for potential allogeneic transplantation candidates.

AML Management

• The primary goal of therapy is achieving complete remission (CR).
• Complete remission is defined by an absolute neutrophil count > 1 X 109.
• Platelet count > 100 X 109 are required for complete remission.
• Patient independence of transfusions indicates complete remission.
• Bone marrow with less than 5% blasts is required for complete remission.
• Absence of blasts with Auer rods is expected for complete remission.
• Absence of extramedullary disease is also needed.

AML Treatment Stages

• AML treatment is divided into: remission induction therapy and post-remission therapy.
• Post-remission therapy may comprise: conventional chemotherapy, or allogeneic hematopoietic stem cell transplantation (HSCT).

Induction Therapy Considerations

• Remission induction therapy can be intensive or low-intensity, based on patient co-morbidities.
• Intensive chemotherapy aims to achieve CR.
• Low-intensity chemotherapy aims to alter the natural course of the disease.

Treatment - Patients Under 60

• Recommended remission induction chemotherapy includes cytarabine and an anthracycline.
• Using conventional '7+3' chemotherapy is the typical treatment.
• A repeat bone marrow assessment is done around day 21 after starting therapy.
• A repeat bone marrow is done to assess cytoreduction.
• If there are significant residual leukemic blasts for a second cycle of the same therapy is immediately started.
• The treatment plan proceeds to consolidation therapy with documented CR.
• Consolidation therapy is determined by the prognostic risk assessment.
• Salvage chemotherapy (re-induction) is given if CR is not obtained.
• Palliative or best supportive care is provided to patients who fail to achieve CR after salvage chemotherapy.
• If post remission therapy is not administered, >80% of AML patients will relapse.
• 2 broad categories of post remission therapy is chemotherapy consolidation or allogeneic HSCT, using cells from a healthy donor.
• Consolidation chemotherapy should begin within 2 weeks.
• This is following hematologic recovery after induction.
• It also happens after confirmed bone marrow evaluation demonstrating complete remission.
• Consolidation chemotherapy is reserved for patients who are ineligible for transplant.
• Consolidation chemotherapy is also done while preparing for transplant.
• High-dose cytarabine for 3-4 cycles is the gold-standard for post-remission therapy for those age 60 or younger with favorable or intermediate risk.
• Neurotoxicity, associated with high-dose cytarabine can lead to loss of gross motor ability.
• Neurotoxicity also can cause irreversible damage.
• Cerebellar toxicity manifests as ataxia, nystagmus, and dysarthria.

AML - Treatment - Older Patients

• Lower-intensity therapy with Azacitidine or Decitabine is used in patients older than 60 or with therapy-related AML.

Refractory or Relapsed AML Management

• Resistant disease is either persistent disease.
• Persistent disease occurs after intensive chemotherapy.
• Relapse appearance of AML occurs after achievement of CR within 6 months after initiation of intensive chemotherapy.
• Reappearance of disease at a later time point is called relapse.
• The only curative option for relapsed/refractory (r/r) leukemia patients is allogeneic HSCT.
• In the salvage setting anthracyclines often cannot be re-applied.
• Alternative approaches are used such as higher doses of cytarabine with chemomodulation by fludarabine or cladribine.

Cytarabine

• Cytarabine can cause a flu-like syndrome.
• It is characterized by fever, myalgia, bone pain, maculopapular rash, conjunctivitis, malaise, and occasionally chest pain.
• Symptoms may begin 6-12 h after IV administration.
• It occurs more commonly after large doses, but can occur with small doses.
• A hypersensitivity mechanism is often responsible.
• Symptoms resolve within 24 hours when the drug is discontinued.
• Corticosteroids may be used for treatment and prophylaxis.
• therapy may be continued with corticosteroid prophylaxis.
• A risk of neurotoxicity is increased.
• Increased when with high doses (greater than 1 g/m2), advanced age, and renal dysfunction.
• Neurotoxicity can be cerebellar syndrome (nystagmus, dysarthria, and ataxia).
• Discontinue the drug immediately if cerebellar toxicity occurs.
• Palmar-plantar erythrodysesthesia leading to desquamation can occur with intermediate or high-dose therapy.
• Prophylactic topical steroids and/or skin moisturizers may be used.
• Cytarabine > 1,000 mg/m2/dose IV over 1-4 hours for > 2 doses leads to corneal toxicity.
• Corneal toxicity affects approximately 80% of patients who do not receive eye drops.
• This occurs due to high water solubility and high concentrations achieved in tear glands and aqueous humor.
• Ocular toxicity includes excessive tearing, pain, photophobia and sensation of foreign body.
• Prevention involves artificial tears and topical corticosteroids- Dexamethasone 0.1% instill 2 drops into both eyes every 4 hours up to 48 hours.
• Dexamethasone and diclofenac drops are superior to dexamethasone drops alone
• Treatment of cytarabine-induced ocular toxicity involves drug discontinuation and topical corticosteroids.
• Permanent damage is rare from cytarabine induced ocular toxicity.