Having a child diagnosed with Acute lymphoblastic leukemia (ALL) is a frightening experience. The disease is very aggressive and can cause a life-threatening complications, but there are some things you can do to prepare for it. These tips include ensuring you have the right insurance coverage and knowing what to expect after treatment.
Despite advances in pediatric cancer treatments, children’s survival rates for acute lymphoblastic leukemia (ALL) are still lower than in developed countries. Several factors contribute to poor outcomes. These include treatment-related mortality, relapses, and inadequate supportive care. These factors should be addressed in order to improve outcomes. A pediatric oncology unit dedicated to treating ALL in a country with limited resources could dramatically improve long-term outcomes.
One of the most important factors contributing to treatment failure in children with ALL is relapse. Relapses include the presence of localized leukemic infiltrates at any site. In addition to early responses to therapy, several well-defined prognostic factors have been used to predict relapse. These include the biological and genetic features of leukemic blasts and the timing of the onset of therapy.
Another important factor contributing to treatment failure in children with ALL is the high rate of abandonment. This can occur when a patient is unable to continue therapy or is abandoned due to inadequate supportive care. This can lead to organ failure, infection, and bone marrow suppression. Fortunately, better supportive care has led to improved outcomes.
In addition, improving laboratory diagnostic capabilities has led to more precise risk-directed treatment regimens. Moreover, a number of biologically targeted therapies have been used to treat pediatric ALL. This is a promising area of research. However, a lack of recent data on treatment outcomes in Ghana is a concern.
One of the primary treatments for ALL is L-asparaginase. This molecule depletes L-asparagine in cerebrospinal fluid. This is correlated with plasma L-asparaginase activity. The molecule has been studied in a small study that included 87 children with ALL. The study was conducted to determine whether the molecule affects treatment outcomes in childhood ALL.
Another study evaluated the relationship between L-asparaginase activity and outcomes in a small cohort of children with ALL. Researchers studied the relationship between asparaginase activity and plasma L-asparagine depletion levels, the presence of anti-asparaginase antibodies, and the occurrence of hypersensitivity reactions.
A study conducted by the Children’s Cancer Group compared the outcome of children treated with two different forms of L-asparaginase. Native asparaginase and polyethylene glycol conjugated asparaginase were tested.
Cytogenetic abnormalities confer a worse prognosis
Identifying chromosomal abnormalities is important in the diagnosis and treatment of acute lymphoblastic leukemia (AML). Chromosomal abnormalities are known to have a negative impact on the prognosis of AML. Several studies have identified a correlation between chromosomal abnormalities and clinical features of AML. AML has improved in terms of prognosis and treatment outcomes over recent years.
Cytogenetic abnormalities are common in AML and account for around 40% of childhood AML. The main cytogenetic abnormalities are listed in the current WHO classification. Some of the cytogenetic abnormalities are found only in infants, while others are found in both pediatric and adult patients. The following is a review of the chromosomal abnormalities identified in pediatric AML:
The most common cytogenetic abnormalities found in pediatric AML include t(5;11)(q22;q34), trisomy 8, and loss of 17p. These abnormalities are associated with a poor prognosis in the pediatric AML population.
The KMT2A gene rearrangement occurs in approximately 15-20% of pediatric AML. It is more frequent in infant AML and M0 subtypes. Patients with KMT2A gene rearrangements and MLLT4 have poor prognoses. This gene is associated with poor outcomes in older patients as well.
Several studies have investigated the impact of CEBPA mutations in cytogenetically normal AML. These studies identified gene expression signatures and correlated them with mutations. The impact of CEBPA mutations was found to be only favorable if there were no chromosomal abnormalities associated with them.
Translocation t(6;9) (p22;q34) is found in 1-2% of AML FAB subtypes. This rearrangement leads to a fusion of the DEK gene at 9q34. The DEK gene encodes a nuclear phosphoprotein. The t(6;9) abnormality is present in both M2 and M4 subtypes of AML.
Other types of cytogenetic abnormalities are also found in pediatric AML. These include chromosomal gains and losses and other unbalanced abnormalities. These abnormalities are associated with a low prognosis in AML but may be offset by intensified therapy.
Cytogenetic abnormalities are also correlated with the leukemic cell lineage. These factors are considered risk factors in the current WHO classification of pediatric AML. It is recommended that patients with primary cytogenetically normal AML be evaluated for chromosomal abnormalities.
HSCT should be reserved for AYA patients with Acute lymphoblastic leukemia
HSCT is a treatment option for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL). The indications for HSCT are higher than those for younger children, although treatment-related morbidity is still higher for AYAs. The prognosis for AYA patients with ALL is poor. AYAs are at risk for relapse. AYAs are also at risk for increased chemotherapy-related toxicities. A multidisciplinary team approach is important for effective treatment.
AYAs with ALL typically receive adult regimens. Adult-based regimens include high-dose chemotherapy and allogeneic HSCT. The combination of high-dose chemotherapy and allogeneic HCT has shown long-term DFS in 30%-40% of patients. However, high-dose therapy has not been shown to be better than non-marrow ablative dose-intensification strategies.
The Children’s Cancer Group (CCG) and the Cancer and Leukemia Group B (CLGB) have performed clinical trials for HSCT for children. These trials have shown that HSCT can be beneficial for children with relapsed/refractory ALL. In addition, HSCT is a good choice for patients in the accelerated phase of the disease. HSCT should be performed before progression and before the appearance of complications. This strategy may be advantageous for older adults but may have to be reconsidered in the presence of an accelerated disease.
In an attempt to improve the outcomes of AYAs with ALL, researchers are pursuing pediatric-inspired approaches. Pediatric-based regimens typically include fewer myelosuppressive agents, steroids, and CNS prophylaxis. Pediatric-based regimens have shown impressive improvements in EFS, but further progress is needed. In addition, new targeted agents are being evaluated in frontline trials. Inotuzumab ozogamicin, a CD22-targeted antibody, is being evaluated for AYA ALL. Inotuzumab has shown impressive activity in the treatment of relapsed/refractory ALL.
Treatment-related morbidity and mortality after HSCT are significant. Poor graft function, defined as incomplete recovery of blood counts after SCT, is one of the major causes of morbidity. There are several options for the management of poor graft function, including infusion of additional hematopoietic stem cells (PBSC), immunosuppression, and augmentation of chemotherapy.
There is a large population of adolescents and young adults (AYAs) with ALL. Treatment approaches for these patients vary considerably. While the results from these studies were impressive, more studies are needed to better identify high-risk patient populations and improve outcomes for all AYAs with ALL.
IKZF1 deletion in B-ALL
Among the many molecular aberrations observed in B-cell precursor acute lymphoblastic leukemia (B-ALL), IKZF1 deletions are particularly detrimental. They are associated with an increased risk of treatment failure, relapse, and death. They are also associated with an increased number of fusion transcripts. IKZF1 deletions are most common in patients with concurrent BCR-ABL1.
In the present study, we assessed the predictive value of the recently defined IKZF1plus microdeletion profile in 373 children with BCP-ALL. We compared clinical characteristics, including age at diagnosis, gender, and WBC count, among subjects with IKZF1 deletions and subjects with wild-type IKZF1 expression. The 5-year cumulative incidence of relapse (CIR) for IKZF1 deletions was compared with that for the wild-type group. The risk for relapse in subjects with IKZF1 deletions was higher, with a 5-year CIR of 13.5% vs. 11% for the wild-type group. However, in BCR-ABL1 negative disease, this risk was not significant.
IKZF1 deletions were detected in a total of 242 patients in the initial study. Patients were identified through a multiplex ligation-dependent probe amplification (MLPA) assay. These assays identify IKZF1 breakpoint sequences (RSS-12RSS-23RSS). However, IKZF1 is also a common gene to undergo deletions in a non-allelic manner.
IKZF1 deletions in subjects with Down syndrome were associated with increased relapse risk. The risk was higher than the risk in matched controls in the IKZF1 deleted group, but lower in subjects receiving chemotherapy or allotransplantation. However, subjects undergoing allotransplantation were not matched to standard risk treatment groups in the NOPHO trial.
IKZF1 deletion was associated with higher levels of treatment failure, relapse, and mortality, but not with lower levels of non-relapse mortality. IKZF1 deletion was more common in subjects with BCR-ABL1 than in subjects without BCR-ABL1. However, in subjects with BCR-ABL1, the risk for treatment failure and relapse was higher in subjects with IKZF1 deletion.
IKZF1 deletions are associated with an increased risk of treatment failure and relapse in childhood B-cell precursor acute lymphoblastic (BCP-ALL) leukemia. These aberrations should be assessed for prognostic significance in ALL subgroups. Continued research will likely contribute to improved treatment strategies. These results suggest that individualized primary therapy may be beneficial to patients with ALL.
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