Pediatric Acute Lymphoblastic Leukemia Treatment & Management

Leukemia is a systemic disease, and treatment is primarily based on chemotherapy. Thus, surgical care is generally not required in the treatment of acute lymphoblastic leukemia, except for the placement of a central venous catheter. Such catheters are used for administering chemotherapy, blood products, and antibiotics, and for obtaining blood samples.

Different forms of acute lymphoblastic leukemia (ALL) require different approaches for optimal results. Acute lymphoblastic leukemia treatment typically consists of a remission-induction phase, intensification (consolidation) phase, and continuation therapy targeted at eliminating residual disease. The addition of cyclophosphamide and intensive treatment with asparaginase is also beneficial in the treatment of T-cell acute lymphoblastic leukemia. Mature B-cell ALL needs to be treated like disseminated Burkitt lymphoma, with short-term intensive chemotherapy, including high-dose methotrexate (MTX), cytarabine, and cyclophosphamide over a 6-month period.

Initially transfer children to a facility in which they can be in the care of a pediatric oncologist, preferably a center that participates in multi-institutional clinical trials. Immediately admit any patient who is neutropenic and who develops chills or fever to administer intravenous (IV) broad-spectrum antibiotics. Frequent hospitalizations may be required to deal with complications of acute lymphoblastic leukemia therapy, including the need for blood transfusions or antibiotics.

Because of the use of MTX, avoid folate supplementation.

Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome, which refers to the metabolic derangements caused by the systemic and rapid release of intracellular contents as chemotherapy destroys leukemic blasts. Because some cells can die before therapy, such metabolic changes can occur even before therapy begins.

Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism of purines), hyperphosphatemia, hypocalcemia, and hyperkalemia. Hyperuricemia can lead to crystal formation with tubular obstruction and acute renal failure requiring dialysis. Therefore, electrolyte and uric acid levels should be closely monitored throughout initial therapy.

To prevent complications of tumor lysis syndrome, patients should initially receive intravenous (IV) fluids at twice the maintenance rates, without potassium.

Sodium bicarbonate may be added to the IV fluid to achieve moderate alkalinization of the urine (pH level, 7.5-8) to enhance the excretion of uric acid. A urine pH level higher than this should be avoided to prevent crystallization of hypoxanthine or calcium phosphate.

The standard prophylactic treatment for malignancy-associated hyperuricemia includes allopurinol. By blocking the enzyme xanthine oxidase, allopurinol blocks uric acid formation. Patients at high risk for tumor lysis still need to excrete preexisting uric acid, which is unaffected by the use of allopurinol.

Rasburicase, a recombinant urate oxidase, has demonstrated increased efficacy in pediatric patients at high risk for tumor lysis by catalyzing the enzymatic oxidation of uric acid to a much more urine soluble product, allantoin. Its expense means that use is usually limited to patients at high risk of tumor lysis syndrome (eg, T-cell leukemia with hyperleukocytosis).

The phases and duration of chemotherapy for acute lymphoblastic leukemia (ALL) are briefly discussed in this section.

Phases of therapy

The treatment of childhood acute lymphoblastic leukemia, with the exception of mature B-cell acute lymphoblastic leukemia, has 5 components: induction, consolidation, interim maintenance, delayed intensification, and maintenance.

The goal of induction is to achieve remission, previously defined as less than 5% blasts in the bone marrow. Induction therapy generally consists of 3 or 4 drugs, which includes a glucocorticoid, vincristine, asparaginase, and possibly an anthracycline. This type of therapy induces complete remission based on morphology in more than 98% of patients. However, the measurement of minimal residual disease (MRD) by flow cytometry or polymerase chain reaction (PCR) has been shown to be much more specific and sensitive than the morphologic examination of blast cells, and the goal is to have less than 0.1% and preferably less than 0.01% at the end of induction.

Current childhood acute lymphoblastic leukemia clinical trials incorporate MRD as a criterion for determining rapid early responder versus slow early responder status during induction chemotherapy. Based on MRD measurements, treatment may be intensified in patients with high amounts of residual blasts at the end of induction therapy (>1%).

Consolidation therapy is given soon after remission is achieved to further reduce the leukemic cell burden before the emergence of drug resistance and relapse in sanctuary sites (ie, testes, central nervous system [CNS]). In this phase of therapy, the patient is given different drugs (eg cyclophosphamide, cytarabine and/or 6-mercaptopurine [6-MP]). Consolidation therapy appears to improve the long-term survival of patients with standard-risk disease.

In interim maintenance, nonmyelosuppressive chemotherapy (eg, vincristine and intravenous MTX) are administered to maintain remission and allow the bone marrow to recover. This occurs for 4-8 weeks and is followed by delayed intensification, which is aimed at treating any remaining resistant leukemia cells. The addition of intensive reinduction and reconsolidation therapy (collectively known as delayed intensification) is beneficial for patients in all risk groups.

The last (and longest) phase of treatment is maintenance. This consists of intrathecal MTX every 3 months, monthly vincristine and steroid pulses, daily 6-MP, and weekly MTX.

Duration of therapy

Whereas mature B-cell acute lymphoblastic leukemia (ALL) is treated with a 6- to 8-month course of intensive therapy, achieving acceptable cure rates for patients with B-lineage and T-lineage ALL requires approximately 2-2.5 years of continuation therapy. Attempts to reduce this time resulted in high relapse rates after therapy was stopped. In the United States, in current ALL clinical trials, the total duration of therapy for girls is 2 years from the start of interim maintenance; for boys, it is 3 years from the start of interim maintenance.

Most contemporary protocols include a continuation phase based on weekly orally administered MTX given with daily, orally administered 6-MP, and monthly pulses of vincristine and a glucocorticoid. Although these pulses improve outcomes, they are associated with avascular necrosis of the bone and vincristine neuropathy, and the current Children's Oncology Group standard risk ALL trial is evaluating whether these last 2 agents can be given every 3 months. A single-institution trial has shown that patients with high-risk ALL may benefit from intensified continuation therapy that includes the rotational use of drug pairs.

The use of continuous dexamethasone in adolescents has been associated with an unacceptably high rate of osteonecrosis of the hips of around 40%,^[12] and this medication is therefore omitted from induction and continuation therapy in older children.

Central nervous system (CNS) disease is divided into the following:

• CNS 1 - Absence of blasts on cytospin preparation of cerebrospinal fluid (CSF), regardless of the number of white blood cells (WBCs)
• CNS 2 - WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more than 5/mL but negative by Steinherz-Bleyer algorithm findings* (if traumatic tap)
• CNS 3 - WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia, such as facial nerve palsy, brain/eye involvement, and hypothalamic syndrome (Additional intrathecal therapy is only given for CNS 3 disease.)

*If the patient has blasts in the peripheral blood and the lumbar puncture is traumatic (containing ≥5/mL WBCs and blasts), treat as CNS 3 if the CSF WBC count divided by the CSF red blood cell (RBC) count is greater than 2 times the blood WBC count divided by the blood RBC count.

Treatment of subclinical CNS leukemia is an essential component of acute lymphoblastic leukemia therapy.

Cranial irradiation

Although cranial irradiation effectively prevents overt CNS relapse, concern about subsequent neurotoxicity and brain tumors has led irradiation to be replaced with intensive intrathecal and systemic chemotherapy for most patients. This strategy has produced excellent survival outcomes, with CNS relapse rates of less than 2%.

Whether cranial irradiation is necessary for patients with very high-risk acute lymphoblastic leukemia (patients with BCR-ABL or MLL gene rearrangements) is unclear. Pui et al conducted a clinical trial in children with newly diagnosed acute lymphoblastic leukemia and determined that prophylactic cranial irradiation can be safely omitted from treatment to avoid irradiation consequences with effective risk-adjusted chemotherapy.^[13] The investigators reported that patients who did not receive prophylactic cranial irradiation had significantly longer continuous complete remission relative to historical controls. In addition, patients with CNS leukemia or traumatic lumbar puncture with blast cells at diagnosis or those with a high level of minimal residual disease after 6 weeks of remission induction were significantly associated with poorer event-free survival.^[13] Risk factors for CNS relapse included genetic abnormality, CNS involvement at diagnosis, and T-cell immunophenotype.

Optimal treatment for patients with very high-risk acute lymphoblastic leukemia (ALL) has not been determined; however, some centers recommend allogeneic stem cell transplantation (SCT) soon after first remission is achieved. It is important to know that for the subset of patients with BCR-ABL gene rearrangement, the addition of imatinib to intensified chemotherapy produced survival results equivalent to allogeneic SCT.^[14]

For patients without a matched family donor, transplantation of marrow from an unrelated donor would therefore no longer be a reasonable treatment option for that subset, although it may be so for other very-high-risk patients. Results of SCT, often reported from single institutions, have been inconsistent and sometimes disappointing. Large, multi-institutional, controlled trials are clearly needed to determine the effectiveness of this therapy for patients without a matched donor.

In general, relapsed acute lymphoblastic leukemia (ALL) cells acquire resistance to exposed chemotherapy drugs. However, patients who relapse “late” (ie, 6 mo or longer after completion of therapy) can often be re-treated with more intensive chemotherapy. Patients who relapse “early” (ie, either during or just after completing therapy) may benefit from (SCT). It is very important that patients who go for SCT have MRD of less than 0.1%; otherwise, they inevitably relapse. Overall, the outcome of patients with relapse is poor.

A drug targeted at the underlying molecular defect that is unique to certain leukemias can have potent and specific antileukemic activity while producing minimal toxicity to normal cells.^[15]

The best example of molecular targeted therapy is imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, that is standard front-line treatment for Ph-positive chronic myeloid leukemia (CML). Combination regimens with imatinib and conventional chemotherapy have shown efficacy in Ph-positive acute lymphoblastic leukemia, justifying its use as front-line therapy for Ph-positive acute lymphoblastic leukemia^{[16, 14]}

More than 80% of children with acute lymphoblastic leukemia (ALL) now can be cured.^[6] However, the cause of treatment failure in the remaining 20% of patients is largely unknown.

More recently, poor outcome has been correlated with alteration of IKZF1, which encodes the lymphoid transcription factor IKAROS.^[17] In addition, Janus kinase mutations have been associated with a high risk of treatment failure.^[18]

Because of the diverse nature of the disease, use of risk-directed therapy for all patients on the basis of molecular and pharmacogenetic characterization of the leukemic cells at the time of diagnosis is favored.

Studies using microarray gene expression, multiparameter flow-cytometry, quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), genomics, proteomics, and bioinformatics hold promise for providing important clues to the mechanisms behind leukemogenesis and response and resistance to therapy. Future goals include the use of these technologies to identify biologic subsets of acute lymphoblastic leukemia that require specifically targeted therapies.

Numerous consultations may be obtained, depending on the clinical circumstances of patients with newly diagnosed acute lymphoblastic leukemia (ALL), including the following:

• Pediatric oncologist: Refer all patients to a subspecialist to direct their care.
• Pediatric surgeon: Patients require placement of a central venous catheter.
• Psychosocial team: Involve psychologists and social workers in the care of patients with acute lymphoblastic leukemia to aid them and their families in navigating all of the difficult issues surrounding their care.
• Radiation oncologist: Consultation may be appropriate if there is extramedullary disease not responding to induction therapy (eg, testicular involvement) or that associated with high-risk disease (eg, CNS-3 in patients with T-lineage ALL).
• Other subspecialists: Consultations with other specialists (ie, infectious disease specialist, nephrologist) may be appropriate, depending on the clinical circumstances.

Frequent clinic visits are required to administer outpatient chemotherapy, to monitor blood counts, and to evaluate new symptoms. In addition, all patients should be on trimethoprim- sulfamethoxazole (TMP-SMZ) or a similar agent, such as monthly IV pentamidine, to prevent Pneumocystis carinii pneumonia (PCP). Patients with infant leukemia may benefit from being on oral fluconazole prophylaxis to reduce the risk of candidiasis.