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1520 Part XI: Malignant Lymphoid Diseases Chapter 91: Acute Lymphoblastic Leukemia 1521

women, a low marital rate. Many children with profound deficien-
cies of growth hormone receive hormone replacement therapy, which
permits attainment of acceptable final heights without an increased
chance of relapse. 270
The most devastating complication is the development of brain
tumors and therapy-related myeloid leukemia. 271,272 Children who
undergo cranial irradiation at age 6 years or younger are most suscepti-
ble to development of brain tumors. Intensive use of antimetabolites
273
before and during cranial irradiation also increases the risk of brain
tumor. The median latency period for high-grade brain tumors
177
is 9 years; it is 20 years for low-grade tumors (e.g., meningioma). 266,273
Therapy-related myeloid leukemia has been linked to intensive
treatment with epipodophyllotoxins (teniposide and etoposide). The
risk of disease depends on treatment schedule, concomitant use of
other agents (e.g., l-asparaginase, alkylating agents, perhaps antime-
tabolites), and host pharmacogenetics. 176,274 The long-term survival rate
for patients with this complication is very low, even when the patients
undergo allogeneic stem cell transplantation. No evidence indicates an
increased incidence of cancer or birth defects among the offspring of
adult survivors of childhood ALL. 275,276
Figure 91–5. T1-weighted magnetic resonance image without con-
trast demonstrates a clot in the superior sagittal sinus (arrow) and sev-
eral frontal lobe hematomas. PROGNOSTIC FACTORS
The cornerstone of the modern therapeutic approach to childhood ALL
generally are reversible. Cerebral thrombosis can be readily distin- has been careful assessment of the risk of relapse so that only high-risk
guished from transient ischemic lesions by magnetic resonance imaging or very-high-risk patients are treated with intensive therapy. 277,278 Less-
or computed tomography (Fig. 91–5). Occasionally, cerebral thrombo- toxic treatments (usually antimetabolites) are reserved for low-risk or
sis may not be apparent by diagnostic imaging until a few days after standard-risk patients. By contrast, almost all adult patients are candi-
the onset of symptoms and signs. Thrombotic complications (especially dates for intensive therapy. Of the many variables that influence progno-
in leg veins or inferior vena cava) are also common in adults receiving sis, treatment is the most important. Some of the factors that emerged as
asparaginase. 136–140 useful prognostic indicators in the past have disappeared as treatment
Emphasis on the intensive use of vincristine, methotrexate and has improved; others have shown predictive strength in one or several
glucocorticoids has led to an increased frequency of neurotoxicity, 252,253 trials, but not in others. For example, T-cell ALL, once associated with a
and of osteonecrosis. Many long-term survivors of childhood ALL, poor prognosis, now has long-term response rates of 70 to 85 percent in
254
especially those who received high cumulative doses of glucocorticoid, children 2,17,190 and 50 to 60 percent in adults 66,67,279 as a result of effective
methotrexate, or cranial irradiation, have developed severe osteopo- intensive chemotherapy. Outcomes for mature B-cell ALL, also a poor
rosis. 254–257 Early identification of bone lesions and the introduction of prognostic subset in the past, have improved in both children and adults
therapy to prevent fractures is recommended. Treatment with anthra- and 80 percent or more are cured with short but intensive chemother-
cyclines can produce severe cardiomyopathy, especially when anthra- apy treatments. 280
cyclines are given in high cumulative and peak doses to children, and Age and leukocyte count continue to be used for risk classification
particularly young girls. 258–260 Prolonged infusion did not appear to in almost every pediatric clinical trial involving precursor B-cell ALL.
reduce late cardiotoxicity compared to bolus administration. The exis- In a workshop sponsored by the National Cancer Institute, participants
261
tence of a safe cumulative dose of anthracycline is controversial. Cardiac agreed on a presenting age of between 1 and 9 years and a leukocyte
abnormalities are persistent and progressive years after anthracycline count of less than 50 × 10 /L as the minimum criteria for low-risk ALL.
9
therapy. In one study, dexrazoxane prevented or reduced anthracy- These criteria apply only to precursor B-cell ALL and not to T-cell ALL.
262
cline-induced cardiotoxicity without interfering with antileukemic Among adults, the outcome of therapy worsens with increasing age
activity. 263,264 In current pediatric trials, limited doses of anthracyclines and leukocyte count. Age younger than 35 years and leukocyte count
are used, even for high-risk cases, to decrease the risk of subsequent less than 30 × 10 /L are considered favorable prognostic indicators
9
cardiomyopathy. Most regimens for adult ALL restrict cumulative (Table 91–7). 67,150,152 In general, age younger than 60 years is consid-
anthracycline dosage to levels associated with less than 5 percent risk of ered a practical guide for selecting candidates who might benefit from
congestive heart failure. intensive therapy, including allogeneic transplantation. Any decision to
Cranial irradiation has been implicated as the cause of numer- begin aggressive treatment in patients older than age 60 years must be
ous late sequelae in children, including second cancer, neurocogni- weighed against the risk of increased morbidity and mortality. 111,112
tive deficits, and endocrine abnormalities that can lead to obesity, Male sex has long been recognized as an adverse prognostic factor
short stature, precocious puberty, and osteoporosis. 265–269 In general, in childhood ALL but has less influence in adult ALL. Its prognostic
these complications are seen in girls more often than in boys and in significance was abolished in a number of childhood studies in which
young children more often than in older children or adults. Long- overall outcome was improved. Black race conferred a poor outcome
term followup studies of survivors of childhood ALL reveal a greater in the national clinical trials, 281,282 but in a single-institution study with
than 10 percent cumulative risk of second neoplasms after 30 years equal access to effective treatment regimens, race had no prognostic
of observation, and a higher-than-average mortality rate among significance. 283
patients who had received cranial irradiation. 266,267 Patients who Primary genetic abnormalities have important prognostic sig-
had been irradiated also had a high unemployment rate and, among nificance. Hyperdiploidy (>50 chromosomes) and ETV6-RUNX1

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