Continuing Education Activity

Acute lymphocytic leukemia (ALL) is a malignancy of B or T lymphoblasts characterized by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors which ultimately leads to the replacement of bone marrow elements and other lymphoid organs resulting in a characteristic disease pattern. ALL accounts for approximately 2 percent of the lymphoid neoplasms in the United States and occurs slightly more frequently in males than females, and three times as frequently in Caucasians as in African-Americans. Patients typically present with symptoms related to anemia, thrombocytopenia, and neutropenia due to the replacement of the bone marrow with the tumor. Symptoms can include fatigue, easy or spontaneous bruising and/or bleeding, and infections. Additionally, B-symptoms, such as fever, night sweats, and unintentional weight loss are often present but may be mild, and hepatomegaly, splenomegaly, and lymphadenopathy can be seen in up to half of adults on presentation. Central nervous system (CNS) involvement is common and can be accompanied by cranial neuropathies or symptoms, predominantly meningeal, related to increased intracranial pressure. This activity examines when acute lymphocytic leukemia should be considered on differential diagnosis and how to properly evaluate it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Identify the epidemiology of acute lymphocytic leukemia.
• Outline the exam findings typically seen in patients with acute lymphocytic leukemia.
• Review the management of acute lymphocytic leukemia.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by acute lymphocytic leukemia.

Introduction

Acute Lymphocytic Leukemia (ALL) is a malignancy of B or T lymphoblasts characterized by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors which ultimately leads to the replacement of bone marrow elements and other lymphoid organs resulting in a typical disease pattern characteristic of Acute Lymphocytic Leukemia. ALL accounts for approximately 2 percent of the lymphoid neoplasms diagnosed in the United States. Acute Lymphocytic Leukemia occurs slightly more frequently in males than females, and three times as frequently in Whites as in Blacks. Patients with Acute Lymphocytic Leukemia typically present with symptoms related to anemia, thrombocytopenia, and neutropenia due to the replacement of the bone marrow with the tumor. Symptoms can include fatigue, easy or spontaneous bruising/bleeding, and infections. B-symptoms, such as fever, night sweats, and unintentional weight loss are often present but may be mild. Hepatomegaly, splenomegaly, and lymphadenopathy can be seen in up to half of adults on presentation. Central nervous system (CNS) involvement is common and can be accompanied by cranial neuropathies or symptoms, predominantly meningeal, related to increased intracranial pressure.[1][2][3]

Etiology

The etiology of Acute Lymphocytic Leukemia is unknown. However, certain environmental factors have been implicated in the etiology of Acute Lymphocytic Leukemia such as exposure to benzene, ionizing radiation, or previous exposure to chemotherapy or radiotherapy.

Genomic studies have noted that somatic, polymorphic variants of ARD5B, IKZF1 (the gene encoding Ikaros) and CDKN2A are associated with an increased risk of ALL (odds ratio 1.3 to 1.9). Other rare germline mutations in PAX5, ETV6, and particularly p53 can also strongly predispose to the development of leukemia.

Acute lymphoblastic Leukemia is not considered a familial disease and no screening programs have been developed to test for it in childhood. 

Epidemiology

It is diagnosed in about 4000 people in the United States each year with the majority being under the age of 18. It is the most common malignancy of childhood. The peak age of diagnosis is between two and ten years of age. Acute Lymphocytic Leukemia is more common in children with Trisomy 21 (Down syndrome), neurofibromatosis type 1, Bloom syndrome, and ataxia telangiectasia. All are common in children between two and three years of age. Prognosis is diminished in children when diagnosed in infants less than one year of age and in adults. It is more favorable in children. Association of the MLL gene in children at 11q23 chromosome is associated with poor prognosis. Acute Lymphocytic Leukemia is a disease with low incidence overall in population studies. The incidence of Acute Lymphocytic Leukemia is about 3.3 cases per 100,000 children. Survival rates for ALL have improved dramatically since the 1980s, with a current five-year overall survival rate estimated at greater than 85 percent.

Pathophysiology

Acute Lymphocytic Leukemia is thought to occur after damage to DNA causes lymphoid cells to undergo uncontrolled growth and spread throughout the body. Splenomegaly and hepatomegaly occur due to sequestration of platelets and lymphocytes in the spleen and liver as the white blood cells are not typical the spleen reacts to them by trying to remove them from the blood. [4][5][6]

Histopathology

On peripheral blood smears of Acute Lymphocytic Leukemia patients, lymphoblasts vary in size. Various CD cytokines must be tested to evaluate for what kind of Acute Lymphocytic Leukemia the patient has developed

History and Physical

The most common presenting symptoms of Acute Lymphocytic Leukemia are nonspecific and may be difficult to distinguish from common, self-limited diseases of childhood. In a meta-analysis, more than half of children with childhood leukemia had at least one of the following five features on presentation: palpable liver, palpable spleen, pallor, fever, or bruising. ALL patients typically present with symptoms of night sweats, easy bruising, skin pallor, unexplained lymphadenopathy, weakness, weight loss, hepatosplenomegaly, or difficulty breathing. Some patients may present with Superior Vena Cava Syndrome. Bone pain, mental changes, and oliguria may also be present. ALL can also present with testicular enlargement, musculoskeletal pain, mediastinal mass, and incidentally found peripheral blood cell abnormalities. 

Evaluation

Acute Lymphocytic Leukemia diagnosis should be explored initially with a laboratory evaluation consisting of a CBC, electrolyte and renal panel, and LDH level. Additionally, imaging such as a chest x-ray for symptoms of shortness of breath may be obtained. If abdominal fullness, tenderness or abdominal mass are symptoms, then a CT scan of the abdomen and pelvis should be obtained. This can also help with the staging of the disease.

NCCN diagnosis guidelines:

• Have presence of more than 20% bone marrow lymphoblasts
• Hematoxylin and eosin-stained bone marrow clot and biopsy sections
• Morphology of bone marrow aspirate assessed with Wright/Giemsa
• Complete flow cytometric immunophenotyping
• Baseline evaluation of the leukemic clone

Lumbar puncture is used to evaluate CNS involvement. The fluid is checked for the presence of lymphoblasts.

Treatment / Management

Children who are suspected of having Acute Lymphocytic Leukemia should be referred to a pediatric center that specializes in cancer for evaluation and treatment.

For children with Acute Lymphocytic Leukemia, induction therapy consists of anthracycline, vincristine, 1-asparaginase, and a corticosteroid.

Today consolidation therapy is widely used and include therapy with a variety of chemotherapeutic drugs with good results.

Maintenance therapy utilizes oral 6-mercaptopurine or methotrexate delivered once weekly or once monthly.  Successful treatment of children with Acute Lymphocytic Leukemia involves administration of a multidrug regimen that is divided into several phases (i.e., induction, consolidation, and maintenance) and includes therapy directed to the central nervous system (CNS).

Most treatment protocols take two to three years to complete.

CNS prophylaxis is done via an intrathecal approach. Patients often require 8-16 intrathecal treatments.

If the patient has Ph-chromosome positive ALL, the current treatment includes the use of tyrosine kinase inhibitors like imatinib, nilotinib, dasatinib or ponatinib. Several trials have shown a good response to these agents.

Stem cell transplantation can sometimes be used as a treatment in which patient's normal source of blood cells (bone marrow) is replaced by healthy young blood cells (stem cells) from a healthy well-matched donor. However, with improvements in chemotherapy, the role of transplantation is declining in ALL.

Recently CAR-T cell therapy has been investigated in ALL with excellent results. Several studies show high rates of remission. Unfortunately, CART is also associated with serious toxicity that includes cerebral edema and cytokine release syndrome, which can be fatal.

All blood products must be irradiated prior to transfusion to prevent transfusion-related graft versus host disease, which is universally fatal.

Splenectomy is rarely required for Acute Lymphocytic Leukemia. Splenectomy can help boost platelet count but does not affect the outcome of leukemia itself. Splenectomy can be performed for severe symptoms that are not amenable to chemotherapy treatment such as abdominal pain. Radiation can also be used in cases of the enlarged spleen to try and reduce the size of the spleen in most cases. [7][8][9]

Tumor lysis syndrome is a life-threatening complication that occurs in patients receiving chemotherapy. It is characterized by hyperuricemia, elevated potassium and phosphate and decreased levels of calcium. Renal failure is invariably present.

Differential Diagnosis

• B cell lymphoma
• Acute myeloid leukemia
• Non-hodgkin lymphoma

Staging

Current World Health Organization Classification of ALL[10]

B-lymphoblastic leukemia/lymphoma

• B-lymphoblastic leukemia/lymphoma, NOS
• B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
• B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);  BCR-ABL1
• B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged
• B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);  ETV6-RUNX1
• B-lymphoblastic leukemia/lymphoma with hyperdiploidy
• B-lymphoblastic leukemia/lymphoma with hypodiploidy
• B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3);  IL3-IGH
• B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);  TCF3-PBX1
• Provisional entity: B-lymphoblastic leukemia/lymphoma,  BCR-ABL1-like
• Provisional entity: B-lymphoblastic leukemia/lymphoma with  iAMP21

T-lymphoblastic leukemia/lymphoma

• Provisional entity: Early T-cell precursor lymphoblastic leukemia
• Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma

Prognosis

Only about 30% of adults with ALL can be cured today. Criteria for good prognosis include:

• Age of less than 30
• No abnormal cytogenetics
• WBC count less than 30,000
• Complete remission within 4 weeks

Poor prognostic factors include:

• Age of more than 60
• Presence of abnormal cytogenetics (t(9:22), t(4:11)
• Failure to achieve remission within 4 weeks
• Precursor B-cells more than 100,000

Pearls and Other Issues

Despite improvements in supportive care, death resulting from treatment toxicity remains a challenge. It is important to watch out for Tumor Lysis Syndrome which occurs when chemotherapy causes cancer cells to lyse releasing certain intracellular elements such as potassium, calcium, uric acid, and phosphorus. These elements, in large numbers, resulting in toxicity that can often lead to renal failure. Pretreatment with fluids and steroids typically prevents Tumor Lysis Syndrome. However, if it occurs, aggressive fluid therapy is the treatment. 

Even after treatment, Acute Lymphocytic Leukemia can come back (relapse). Relapses can occur as far back as 21 years. IT is important to address other issues associated with cancer treatment in a young child including providing psychological support to child, parents, and family. 

Enhancing Healthcare Team Outcomes

Like all malignancies, the management of acute leukemia is with an interprofessional team dedicated to the management of cancer patients; the an interprofessional team includes an oncologist, internist, infectious disease expert, and a hematologist. The primary care provider and nurse practitioner may be responsible for follow up after treatment and report back to the interprofessional team. These patients need close monitoring as they are prone to infections, coagulation dyscrasias, and relapse. Team conference should be held while the patient is being treated and any problems should be conveyed to the team.

The pharmacist should educate the patient on chemotherapy medications, their adverse effects, and benefits. The dietitian should encourage a healthy diet. To prevent infections, the nurse practitioner should encourage hand washing, washing of fruits and vegetables and maintaining good personal hygiene.

The oncology nurses should monitor the patient for adverse effects of the drug including tumor lysis syndrome. Patients should be given consistent messages and one should avoid offering unrealistic expectations. To improve outcomes, the team should keep updated on the latest clinical trials.

Outcomes

Despite improvements in supportive care, death resulting from treatment toxicity remains a challenge. It is important to watch out for Tumor Lysis Syndrome which occurs when chemotherapy causes cancer cells to lyse releasing certain intracellular elements such as potassium, calcium, uric acid, and phosphorus. These elements, in large numbers, resulting in toxicity that can often lead to renal failure. Pretreatment with fluids and steroids typically prevents Tumor Lysis Syndrome. However, if it occurs, aggressive fluid therapy is the treatment.

Even after treatment, Acute Lymphocytic Leukemia can come back (relapse). Relapses can occur as far back as 21 years. It is important to address other issues associated with cancer treatment in a young child including providing psychological support to child, parents, and family.