Page 1179 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 65 Clinical Manifestations and Treatment of Childhood Acute Lymphoblastic Leukemia 1027

hematologic relapse during therapy or shortly thereafter and for those Drug Interactions
with T-cell ALL. Patients with late-onset isolated CNS relapse who
had not received cranial irradiation as initial CNS-directed therapy We have not yet reached a full understanding of the contribution of
have a very high remission retrieval rate, with long-term prognosis genetic polymorphisms to interindividual differences in drug effects
approaching that of newly diagnosed patients. that allows us to translate this new knowledge into clinical practice.
Genome-wide studies using paired diagnosis and relapse samples However, by simply avoiding drug interactions, one can prevent
from the same patients are exploring the genetic basis of relapse. increased toxicity or reduced efficacy of chemotherapy. Phenytoin
Although 90% of the cases exhibit differential gaining or losing and phenobarbital induce the activity of cytochrome P450 enzymes,
genetic lesions from diagnosis to relapse, most relapse samples are significantly increasing the systemic clearance of several antileukemic
clonally related to diagnosis samples. Relapse clones could be present agents that may adversely affect treatment outcome. We substitute
as minor populations at diagnosis and selected during treatment to these anticonvulsants with gabapentin or levetiracetam in patients
receiving antileukemic therapy. On the other hand, azole compounds
emerge in the predominant clone at relapse, displaying alterations of (e.g., fluconazole, itraconazole, ketaconazole, posaconazole) can
genes that have been implicated in treatment resistance. Almost 20% inhibit cytochrome P450 enzymes and increase the toxicities of various
of relapsed cases have sequence or deletion mutations of CREBBP, antileukemic agents, especially vincristine.
which impair histone acetylation and transcriptional regulation of
CREBBP targets, suggesting that the mutations may confer drug
resistance and raising the possibility of using drugs to reverse the
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aberrant epigenetic programs, such as histone deacetylase inhibitors.
The next generation of deep sequencing technologies promises to of esophageal herpes simplex viral infection, candidiasis, or both.
unravel many more, if not the full repertoire of genetic alterations in Oral candidiasis occurs frequently, especially in young children.
leukemia. Azole compounds (e.g., fluconazole, itraconazole, ketaconazole) are
frequently used to treat fungal infections. It should be recognized
that they can inhibit cytochrome P450 enzymes and increase the
SUPPORTIVE CARE toxicities of various antileukemic agents, especially vincristine. On
the other hand, concomitant administration of anticonvulsants that
Stringent supportive care significantly contributes to a favorable ALL induce cytochrome P450 enzymes (e.g., phenytoin, phenobarbital,
outcome, and should be initiated at diagnosis as remission induction carbamazepine) increases the systemic clearance of several antileuke-
is associated with an increased risk from cardiovascular, metabolic, mic agents and may adversely affect treatment outcome. Anticonvul-
and infectious complications. All febrile patients with or without sants that are less likely to induce the activity of cytochrome P450
documented infection should be given broad-spectrum intravenous enzymes (e.g., levetiracetam [Keppra]) are recommended in patients
antibiotics until an infectious disease can be excluded. Rapid turnover receiving chemotherapy. Photosensitive skin rash can occur during
of leukemia cells before and immediately after the initiation of che- antimetabolite therapy. The rashes are erythematous, maculopapular,
motherapy leads to metabolic disturbances including hyperkalemia, similar to atopic eczema, and most prominent on the face. Topical
hyperuricemia, hyperphosphatemia, and secondary hypocalcemia. administration of simple emollients or a weak steroid preparation,
Patients with high levels of uric acid are at risk for the develop- and avoidance of external exposure to sunlight, should improve the
ment of acute kidney injury secondary to uric acid deposition in skin condition. Patients with Down syndrome tolerate methotrexate
the kidneys. All patients require intravenous hydration to prevent or poorly, and appropriate dose adjustment is indicated in them. During
treat hyperuricemia and hyperphosphatemia. Allopurinol, a xanthine each clinic visit, a thorough review of all drugs should be undertaken
oxidase inhibitor, can prevent uric acid formation. Rasburicase, a because of potential adverse interactions among them. In fact, che-
recombinant urate oxidase that breaks down uric acid to allantoin (a motherapy can also interact with various food (e.g., grapefruit) and
readily excretable metabolite with 5- to 10-fold higher solubility than supplements (e.g., St. John’s wort, folic acid). 28
uric acid), is more effective than allopurinol but is associated with
methemoglobinemia or hemolytic anemia in patients with glucose-
6-phosphate dehydrogenase deficiency because hydrogen peroxide is LATE EFFECTS OF TREATMENT
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a byproduct of the uric acid breakdown. Phosphate binders should
also be used to prevent or treat hyperphosphatemia. Transfusions The most problematic late effects of contemporary ALL therapy
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should be administered slowly in patients with severe anemia to include neuropsychologic impairments, bone morbidity, and obesity.
prevent congestive heart failure. In patients with extreme hyperleu- While neuropsychologic deficits are well-recognized side effects of
kocytosis, prompt diagnosis can be established on peripheral blood, cranial irradiation, intrathecal and systemic chemotherapy (especially
and chemotherapy should be urgently initiated (usually steroids with methotrexate) can also cause brain atrophy and spinal cord dysfunc-
gradual introduction of other agents to achieve adequate response tion and contribute to the development of neurocognitive toxicities.
while avoiding massive tumor lysis). Packed red blood cell transfusion Severe CNS toxicity has been attributed to cranial irradiation at doses
should be delayed until after the leukocyte count is decreased to of 2400 cGy or higher, but lower doses have also been associated with
prevent complications of leukostasis, but platelet transfusion should long-term neuropsychologic impairments, especially in younger
be administered to prevent bleeding. All blood products should be children. Obesity, most prevalent among female survivors of child-
irradiated in patients who are receiving immunosuppressive therapy hood ALL, may be related to metabolic syndrome caused by treatment
to prevent graft-versus-host disease. Patients should avoid foods with cranial radiation and corticosteroids. Osteopenia, fractures, and
that may be contaminated with pathogens and reduce salt intake, osteonecrosis have been observed in up to 30% of survivors of child-
which could induce hypertension and resultant seizure in patients hood ALL. Osteonecrosis, which can lead to significant pain, loss of
receiving glucocorticoids during induction. Adolescents, obese function, and total joint replacement, has been reported in approxi-
individuals, and patients with Down syndrome are at increased mately 8% of children with ALL, with the highest frequency observed
risk of hyperglycemia and other complications. Prophylactic use of in those diagnosed in adolescence. Testicular function (in boys treated
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trimethoprim-sulfamethoxazole (or pentamidine or atovaquone in with less than 6 g/m cumulative dose of cyclophosphamide) and
patients with poor tolerance to trimethoprim-sulfamethoxazole) suc- especially ovarian function are relatively unaffected by antileukemic
cessfully prevents Pneumocystis jiroveci (formerly carinii) pneumonia. therapy. Offspring of patients successfully treated for childhood ALL
Dental evaluation at diagnosis and meticulous oral hygiene during are generally expected to be as normal as the general population.
chemotherapy minimizes the oral complications of leukemia and its However, recent studies showed that about 5% of patients with ALL
treatment. It is important to distinguish between herpes simplex viral inherit major cancer predisposing genes, some of which (such as
infection and chemotherapy-induced oral mucositis. Occasionally, TP53) have important clinical implication to the immediate family
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patients have nausea and substantial pain on swallowing because members. Second malignant neoplasms, including malignant