The event-free survival (EFS) for pediatric acute lymphoblastic leukemia (ALL) has shown remarkable improvement in the past several decades. In Korea also, a recent study showed 10-year EFS of 78.5%. Much of the improved outcome for pediatric ALL stems from the accurate identification of prognostic factors, the designation of risk group based on these factors, and treatment of appropriate duration and intensity according to risk group, done within the setting of cooperative clinical trials. The schema of first-line therapy for ALL remains mostly unchanged, although many groups have now reported on the elimination of cranial irradiation in all patients with low rates of central nervous system relapse. Specific high risk subgroups, such as Philadelphia chromosome-positive (Ph+) ALL and infant ALL continue to have significantly lower survival than other ALL patients. The introduction of tyrosine kinase inhibitors into therapy has led to enhanced outcome for Ph+ ALL patients. Infant ALL patients, particularly those with
Acute lymphoblastic leukemia (ALL) is the most common cancer in the pediatric age group and is responsible for the most cancer-related deaths in children and adolescents. In Korea, the age-standardized incidence rate of ALL is approximately 28 patients per million in the 0–14 year old age group
Well-established prognostic variables include patient factors such as age, initial presenting white blood cell (WBC) count, the genetic and immunophenotypic characteristics of the leukemic blast, and individual response to therapy.
In precursor B cell (Pre-B) ALL, patient age at diagnosis and presenting WBC count are independent prognostic factors. Patients diagnosed between the ages of 1 and 10 have a superior outcome compared with those <1 year old or ≥10 years old. Infant ALL is particularly known to have poor survival with a 4-year EFS of 47% according to a multinational study
The 10%–15% of patients with T-ALL had previously been considered to have worse outcome than those with Pre-B ALL. However, survival is now similar between the 2 patient groups with appropriate treatment intensification of T-ALL patients
Genetic abnormalities of the leukemic blast, including aneuploidy and recurrent translocations and deletions, are important factors in the determination of risk group and outcome in Pre-B ALL. Those that predict excellent prognosis include
Recurrent genetic abnormalities associated with poor prognosis include
Patients with
Advances in next generation sequencing technology, including whole genome and whole exome sequencing, have aided in the identification of genetic abnormalities with prognostic relevance. One of the most critical abnormalities detected through these methods has been alteration of
The prognostic relevance of genetic abnormalities in T-ALL remains mostly unclear. In terms of incidence,
Early response to treatment may be measured by the clearance of peripheral blasts after one week of prophase steroid, which may be utilized in risk group assignment. Those with a good response to steroid, that is a peripheral blast count <1,000/mm3, have better survival compared with those with a poor response to steroid (a peripheral blast count ≥1,000/mm3)
MRD remains the most important prognostic factor in pediatric ALL. Current methods of measuring MRD include polymerase chain reaction (PCR) for immunoglobulin (Ig)/T-cell receptor (TCR) rearrangements, flow cytometry to detect aberrant immunophenotypes, and PCR for recurrent genetic fusions such as real-time quantitative (RQ)-PCR for
Initial therapy consists of about 4 weeks of remission induction during which steroid (prednisolone or dexamethasone), vincristine, asparaginase, and intrathecal chemotherapy are given. An anthracycline, such as daunorubicin, may be administered to patients deemed high risk at diagnosis. The first intrathecal therapy, often consisting of triple therapy of methotrexate (MTX), cytarabine and hydrocortisone, is given immediately after diagnosis. This initial treatment, done to diagnose and treat central nervous system (CNS) leukemia as well as for CNS prophylaxis, is crucial to the long-term outcome of the patient as a traumatic lumbar puncture (TLP) at this step results in a greater incidence of relapse
Asparaginase toxicity is a major impediment to chemotherapy schedule adherence, especially for adolescent patients. Aside from drug hypersensitivity, major side effects include pancreatitis, hyperglycemia, hypertriglyceridemia, coagulopathy, and thrombosis. Besides patients who show clear toxicity, drug efficacy may be compromised in asymptomatic patients due to silent inactivation
After remission induction, each patient should be classified into a risk group indicating the overall risk for relapse, based on the prognostic factors at diagnosis, and response to initial therapy, including prophase steroid response and MRD at the end of remission induction (
The consolidation phase is marked by continued CNS prophylaxis. In the past, CNS treatment was done mostly with cranial irradiation. However, the long-term neurologic and endocrine complications associated with this method of treatment have led to the omission of cranial irradiation for the majority of patients. Instead, CNS treatment for most patients consists of intensive intrathecal and systemic therapy incorporating agents such as high dose MTX
Afterwards, patients receive an 8-week delayed intensification phase of treatment which utilizes drugs that were used in both remission induction and consolidation. The overall risk group of the patient is important in determining the number of intensification courses administered, with standard risk patients receiving one course of treatment to minimize toxicity
The final phase of treatment is maintenance therapy which on average takes about 2 years for completion. The key component of this phase is antimetabolite therapy, including daily oral mercaptopurine and weekly oral MTX. Some institutions add pulses of vincristine and steroid every 4 weeks to this regimen. CNS prophylaxis should continue during maintenance therapy. As this period of treatment is prolonged and requires daily intake of medication, patient compliance is a critical issue, especially for adolescent patients. Patient noncompliance and high variability of metabolite levels within each patient, caused by varying drug doses and periods of treatment interruption, may result in an increased risk of relapse
The number of patients receiving HCT in first CR is decreasing, with recent studies showing 1.2%–6.6% of patients treated with upfront HCT
A study of a large number of patients enrolled in the UK Medical Research Council ALL97/99 trial showed a Ph+ ALL incidence of 3%
Despite major improvement in survival, Ph+ ALL remains a very high risk subtype of ALL with increased risk of relapse either with or without transplant. Although the results of the COG study provide evidence that HCT may not be necessary in first CR for Ph+ ALL patients, further follow-up on a larger number of patients is necessary to clarify this issue. Data from adult patients show that MRD, as measured by RQ-PCR for
Infant ALL continues to have dismal outcome despite chemotherapy intensification and treatment with HCT. Cooperative studies showed long-term EFS of less than 50%
Infants without
Patients aged 15 and above face special issues compared with other ALL patients. Depending on the medical department to which they are transferred for care, these patients may be treated under high risk pediatric ALL protocols, or may be given chemotherapy commonly administered by adult hematologists. Although this age group may be more susceptible to the side effects of chemotherapy than younger patients, several studies have shown superior EFS compared with historical controls with acceptable toxicity when treated with pediatric regimens
Children with Down Syndrome (DS) have a 20 fold greater risk for ALL compared with non-DS children
Relapse is the most important cause of treatment failure in ALL, and a leading cause of cancer-related death in children. Long-term follow-up of a large number of relapsed patients showed survival rates ranging from 10% to over 50% depending on important prognostic factors such as site of relapse, duration of first remission, and initial risk group
As current therapeutics fail a significant portion of relapsed patients, novel treatment strategies may be the best option for this group of patients. Immunotherapy has proven to be an effective and highly promising approach for both relapsed and refractory patients, with survival rates superior to those observed with conventional chemotherapy, although longer follow-up is necessary. One of the most important agents in this regard is blinatumomab, a bispecific T-cell engager antibody that directs CD3+ effector memory T cells to CD19+ target cells including Pre-B ALL blasts
Immunotherapy utilizing autologous T cells transduced to express a receptor with specificity for CD19 has been extremely effective in relapsed/refractory ALL patients. Reported rates of CR after CAR T-cell therapy in this group of patients range from 70%–90%
With the remarkable improvement in survival of pediatric ALL compared to the past, much of the current focus is on maintaining high survival rates while limiting the long-term toxicities of treatment. Significant long-term effects include neurocognitive impairment, endocrine complications, cardiac dysfunction, and the risk for secondary malignancies
Neurocognitive sequelae will have a profound effect on the adult survivor's ability to function in society. The decrease in the dose of cranial irradiation currently administered compared to the past, and the elimination of cranial irradiation in many patients contribute to lessening such toxicities. One study found that patients who received 18-Gy cranial irradiation and intrathecal chemotherapy had similar neurocognitive complications to those who received intensive triple intrathecal chemotherapy with omission of cranial irradiation
Endocrine complications, such as the metabolic syndrome and short stature, may result from the use of steroids, as well as cranial irradiation. Again, the elimination of cranial irradiation in many patients may aid in minimizing these toxicities. In our study of patients treated with dexamethasone-based chemotherapy and without cranial irradiation, random glucose and body mass index decreased significantly at 12 months posttreatment completion compared to values measured during chemotherapy
Although patients treated on current protocols receive less of a cumulative anthracycline dose than in the past, these patients are still at risk for asymptomatic abnormalities of cardiac function that may progress to overt heart dysfunction with long-term follow-up
The findings from large cooperative trials have resulted in a remarkably improved survival rate for children with ALL. The key areas for future work should include studies to improve the outcome of high risk ALL, including Ph+ ALL and infant ALL, the implementation of novel therapies to treat patients who relapse, whose outcome still remains extremely poor, and the attempt to identify and minimize long-term toxicities from treatment.
Risk group | Criteria |
---|---|
Low | All of the following: |
Age ≥1 and <10 years old | |
Initial WBC count <50,000/mm3 | |
Trisomies of 4, 10, 17 or ETV6/RUNX1 (+) | |
Standard | As above, except lack of trisomies of 4, 10, 17 or ETV6/RUNX1 (+) |
High | Any of the following: |
Age≥10 and <15 years old | |
Initial WBC count ≥50,000/mm3 and <100,000/mm3 | |
Initial CNS* or testicular involvement | |
Precursor B cell ALL with poor prephase steroid response† | |
| |
| |
MRD (+) at end of remission induction‡ | |
T-cell ALL with good prephase steroid response | |
Very high | Any of the following: |
Age ≥15 years old | |
Initial WBC count ≥100,000/mm3 | |
| |
Infant ALL | |
Hypodiploidy with <45 chromosomes | |
T-cell ALL with poor prephase steroid response | |
CR not achieved after first remission induction |
ALL, acute lymphoblastic leukemia; WBC, white blood cell; CNS, central nervous system; MRD, minimal residual disease; CR, complete remission.
*CNS 3 (elevated CSF WBC (≥5 cells/µL) and cytology showing lymphoblasts) is the criterion for diagnosis of CNS involvement. †Poor prephase steroid response indicates a peripheral blast count ≥1,000/mm3 after 7 days of steroid treatment. ‡MRD not measured for all patients, but measured using reverse trancription-polymerase chain reaction or real-time quantitative-polymerase chain reaction for patients with recurrent genetic abnormalities.