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H. Inaba and C.G. Mullighan
Table 3. Risk factors in pediatric acute lymphoblastic leukemia
Factor
Patient and clinical characteristics Age at diagnosis
Sex
Race
Down syndrome
WBC counts at diagnosis CNS involvement at diagnosis Testicular involvement Immunophenotype
Cytogenetic and genetics
Minimal residual disease
Better
1 to <10 years Female Caucasian, Asian No
<50 × 109/L CNS 1
No
B-ALL
High hyperdiploidy (51-65 chromosomes) ETV6-RUNX1: t(12;21)(p13.2;q22.1) NUMT1 rearrangement
Negative
Continuously decreasing and becoming negative
Worse
<1 year or ≥10 years
Male
African American, Hispanic Yes
≥50 × 109/L
CNS 2 and CNS 3, traumatic tap with blasts Yes
T-ALL
Hypodiploidy (<44 chromosomes) KMT2A rearrangement: t(v;11q23.3) BCR-ABL1: t(9;22)(q34.1;q11.2) (Ph+) BCR-ABL1-like (Ph-like)
TCF3-HLF: t(17;19)(q22;p13)
MEF2D rearrangement
Intrachromosomal amplification of chromosome 21 (iAMP21) BCL2 or MYC rearrangements
Positive
Increasing and/or persistently positive while monitored
WBC: white blood cell; CNS: central nervous system; ALL: acute lymphoblastic leukemia; Ph: Philadelphia chromosome.
nance (or continuation), and lasts for 2-2.5 years. Most conventional chemotherapeutic agents were developed before 1970, and the optimal dosages and schedules for combination chemotherapy were developed with dose adjustments based on tolerability, response evaluation with MRD, and individualized pharmacodynamic and pharmacogenomic studies, but with limited use of the biological features of ALL cells obtained through genomic analyses. Allogeneic hematopoietic cell transplantation (HCT) has been used for patients at very high risk. In the last decade, molecularly targeted agents and immunother- apy have emerged as novel therapeutic strategies.
Survivors treated before 1990 experienced late effects in multiple organ systems (e.g., reproductive, neurologi- cal, or gastrointestinal effects or infections), but those treated on more recent protocols have experienced pre- dominantly musculoskeletal effects, possibly due to more intensive use of dexamethasone and asparaginase.96 In addition, cranial radiotherapy-induced hypothalamic dys- function has given way to impaired glucose metabolism and obesity as the use of radiotherapy has been reduced. The recent pattern of late effects could be managed by prevention or intervention as well as by rational reduc- tion of conventional chemotherapy combined with mol- ecularly targeted therapy and immunotherapy.
Remission-induction therapy
Remission-induction therapy consists of three drugs (glucocorticoid [prednisone or dexamethasone], vin- cristine, and asparaginase) or four drugs (the 3 aforemen- tioned drugs plus anthracycline) administered over 4-6 weeks and induces complete remission (CR) in approxi- mately 98% of pediatric patients.
Compared to prednisone, dexamethasone has a longer half-life and better CNS penetration, which improves CNS disease control.97 In randomized studies comparing prednisone and dexamethasone, patients who received
dexamethasone had better event-free survival (EFS) than did those who received prednisone at a prednisone-to- dexamethasone dose ratio of <7 (Table 1).1,97 However, OS was similar in both arms, except in one study that found dexamethasone beneficial in patients with T-ALL who had a good prednisone-prophase response.1 Furthermore, dexamethasone is associated with more fre- quent adverse effects, such as infection, bone fracture, osteonecrosis, mood/behavior problems, and myopathy. When the dose ratio was >7, there was no difference in outcomes with the two glucocorticoids.97 Therefore, the dose, schedule, and type of glucocorticoid are determined based on the patient’s age, relapse risk, and treatment phase. Bacterial infection can be reduced with prophylac- tic antibiotics, such as levofloxacin during neutropenia.98,99 Alternate-week dexamethasone administration, as opposed to a continuous schedule, can reduce the risk of osteonecrosis.100 Adding hydrocortisone to dexametha- sone can reduce neuropsychological adverse effects, pos- sibly by reducing the cortisol depletion in the cerebral mineralocorticoid receptors.101
Vincristine does not typically cause significant myelo- suppression and is given weekly during induction therapy and as monthly or tri-monthly pulses with glucocorti- coids during continuation at doses of 1.5-2.0 mg/m2. However, its adverse effects include peripheral sensory and motor neuropathy, and the dose is typically capped at 2.0 mg. A GWAS in children with ALL revealed that a polymorphism within the promoter region of CEP72 was associated with increased incidence and severity of vin- cristine-related peripheral neuropathy.102
In many countries, polyethylene glycol (PEG)- Escherichia coli L-asparaginase (pegaspargase) has replaced native E. coli L-asparaginase, compared with which pegas- pargase has a longer half-life and a lower incidence of hypersensitivity. Compared with intramuscular native E. coli L-asparaginase, intravenous pegaspargase was similar-
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