MD2B - Acute Leukemias

Introduction

Leukemia is a malignant, marrow-based neoplasm of hematopoietic or lymphoid cells, called “blasts.” The key feature of leukemia is the presence of blasts circulating in the blood. Acute leukemia consists of at least 20% blasts in the blood and can be rapidly fatal if untreated. The two main types of acute leukemia are named for the stem cell of origin: acute lymphoblastic leukemia (ALL) if it involves lymphocytes, and acute myeloid leukemia (AML) if it involves myelocytes. Of note, both lymphocytes and myelocytes are subtypes of white blood cells. While ALL and AML are clinically similar in that they both typically present with symptoms secondary to cytopenias (lowered cell counts), there are significant laboratory features and prognostic factors that can be used to distinguish ALL from AML and to dictate therapy, as discussed below.

Acute Lymphoblastic Leukemia (ALL)

Classification by Immunophenotype [1]

Epidemiology, Etiology, and Pathogenesis

• Most common malignancy in children; accounts for 80% of acute leukemia in children, 56% of acute leukemia in adolescents, and 20% of acute leukemia in adults [2]
• Incidence of ALL in children is 2500 to 3500 new cases per year in the US, accounting for 26% of cancers under 14 years old, with a peak incidence seen between ages 2 – 5 in industrialized countries [2, 3]
• Incidence is 20% higher in boys than girls, 100% higher in whites than blacks [3]
• 5-year survival for ALL in children is 90% [4]
• Etiology is not well-established
• Hereditary link is likely, as siblings of leukemia patients typically show a threefold higher risk of developing disease
• Increased risk is highly associated with Down syndrome (15X), as well as neurofibromatosis 1, ataxia-telangiectasia, and atomic bomb survivors [5, 6]

Clinical Presentation

• History: Generally, cytopenia-related symptoms, such as fatigue, dyspnea, infections, bruising, weight loss, as well as bone pain
• Physical Exam: Pallor, petechiae, fever, lymphadenopathy, palpable liver (64%), palpable spleen (61%) [7]
• Labs: Cytopenias (white blood cells, red blood cells and/or platelets)
• Diagnostic Studies: peripheral smear, bone marrow biopsy, immunohistochemistry/molecular genotyping
• Clinical Pearl: The characteristic presentation of T cell ALL is an older age boy with mediastinal mass and leukocytosis

Staging

While ALL does not have conventional staging like solid tumors, it can be specified by treatment response [8]:

• In remission - patient has received induction treatment to induce remission and now has normocellular bone marrow, no signs or symptoms of the disease, no signs or symptoms of central nervous system leukemia or other extramedullary infiltration, and all normal hematologic laboratory values
• Minimal residual disease – when a patient’s blood counts are normal with standard tests, but more sensitive tests can detect residual cancer cells in the bone marrow
• Active disease – defined as any failure since starting treatment, including relapses or detection of over 5% blasts in the blood

Prognosis 

• 20% of childhood ALL patients eventually relapse [7]
• Nearly 80% of adult patients will achieve remission, but 30-60% of patients will relapse [9]
• Factors associated with poor prognosis include:
  • Age <2 y or >9 y
  • High WBC counts [10]
  • T-cell phenotype
  • Low ploidy
  • Presence of (9;22) chromosomal translocations [11]
  • Presence of disease in CNS or testes [12]
  • Poor early response to treatment

Treatment [13]

• Risk assessment is critical to achieving cure with an acceptable degree of toxicity. Generally, patients with higher-risk disease receive more aggressive therapy
• Treatment is highly complex and depends on the specific protocol used as well as the patient’s risk for relapse. In general, treatment includes:
  • CNS-Directed Therapy:
    • Intrathecal chemotherapy and/or cranial radiation depending on risk of relapse. Intrathecal chemotherapy is injected directly into the CSF via spinal tap
  • Chemotherapy is delivered in specific phases:  
    • Remission induction high-dose chemotherapy. Four-to-six-week regimens with at least two rounds of induction, which usually includes prednisone or dexamethasone, vincristine, L-asparaginase, +/- an anthracycline, followed by a treatmentresponse assessment
    • Consolidation and/or intensificationtherapy for up to 8 months and then maintenance therapy for 2-3 years
    • Allogenic transplantation, transplant of new blood cells from a healthy donor, is of particular benefit in high-risk disease (chromosomal translocations) and after poor response to initial therapy
• Survival rates have improved dramatically owing to advances in molecular genetics, utilization of risk stratification in disease management and targeted therapies
• Targeted therapies such as tyrosine kinase inhibitors can be used in patients with Ph-positive disease. Other targeted agents are still being explored including Janus kinase inhibitors, monoclonal antibodies to B- and T-cell surface antigens, and CAR-T cell therapy [14]

Acute Myeloid Leukemia (AML)

Epidemiology, Etiology and Pathogenesis

• There are approximately 20,000 cases of AML per year in the US [15]
• AML accounts for 80-90% of adult acute leukemias, 15% of childhood leukemias, 31% of leukemias in adolescents, and all neonatal acute leukemias [2]
• Etiologic factors are thought to include exposure to carcinogens and mutagens, such as benzene, alkylating agents, and ionizing radiation; inherited genetic conditions such as Fanconi anemia and Down syndrome; and viruses
• Pathogenesis involves clonal evolution through multiple steps. AML etiology and pathogenesis is considered similar to myelodysplasia, (also known as MDS, refractory anemia, preleukemia or smoldering leukemia), which is a clonal abnormality of pluripotential stem cells with defective maturation and ineffective hematopoiesis

Clinical Presentation

• History: Present with cytopenia-related symptoms, as with ALL
• Physical Exam: Pallor, petechiae, fever, organ involvement
• Labs: Cytopenias common; considered a medical emergency if WBC count is >100,000 or there are DIC-type indices
• Diagnostic Studies: Peripheral smear, bone marrow biopsy, neurologic exam

Staging 

Similar to ALL in that there is no clear-cut staging system. Patients are classified as:

• Untreated - newly diagnosed leukemia with no prior treatment, abnormal bone marrow with more than 20% blasts, signs and symptoms of the disease, and typically abnormal hematologic cell counts
• In remission - a normal peripheral blood cell count and normocellular marrow with less than 5% blasts, no signs or symptoms of the disease, and no signs or symptoms of central nervous system leukemia or other extramedullary infiltration
• Relapsed or refractory - evidence of disease after achieving remission or unsuccessful treatment

Prognosis

• The three most important prognostic factors are: age, WBC count, and cytogenetics [16]
• Patients with the following cytogenic abnormalities have a more favorable prognosis [16]:
  • t(8;21), inv(16)/t(16;16), t(15;17)
• Factors associated with a poor prognosis [16,17] include:
  • Age >60 y/o
  • Comorbid conditions (Performance Status)
  • WBC > 100,000
  • CNS involvement
  • Disease secondary to MDS, chemo or XRT
  • CD34 +
  • MDR-1 positive
  • Complex karyotypic abnormalities

Treatment

• AML chemotherapy is administered in two basic phases, induction, and post-remission
• Induction is given using daunorubicin/cytarabine + anthracycline with 70-80% complete remission rate, but also 100% relapse rate if no further therapy is given [18]
• Targeted agents may be considered for patients with certain cytogenic abnormalities
• Post-remission therapy consists of consolidation chemo, giving 40-50% cure rates, or autologous and allogeneic bone marrow transplants, giving improved cure rates of 45-65% [19]
• A retrospective analysis of long-term AML survivors showed a 7% incidence of malignancies secondary to treatment [20], and the incidence increased 5-fold (0.04/100,000 to 0.2/100,000 people) from 2001-2007 to 2008-2014, respectively [21]
• High yield: For APML t(15;17), whose unique fusion product PML-RARα contains retinoic acid receptor, regimens containing all-trans-retinoic acid (ATRA) as a differentiation agent results in remission rates around 90% and a 70% cure rate [22]
  • APML cells can be distinguished on blood smear based on cytoplasmic inclusions known as Auer rods 

Differences between ALL and AML [20,23]

Morphologic Differences

Cytochemical differences

Immunophenotypic differences

• Lymphoid stem cells are TdT+
• Other markers help distinguish B-cell ALL from T-cell ALL
• Some ALL blasts also express myeloid antigens, but the presence of these antigens has no prognostic effect [24]