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1516 Part XI: Malignant Lymphoid Diseases Chapter 91: Acute Lymphoblastic Leukemia 1517

on inherited differences in drug metabolism and disposition resulting Systemic treatment including high-dose methotrexate, intensive
from genetic polymorphisms in drug-metabolizing enzymes and in asparaginase, and dexamethasone, as well as optimal intrathecal therapy,
drug transporters, receptors, and targets. 1,179,180 Ultimately, therapy can is important to control CNS leukemia. 80,192 Triple intrathecal therapy with
be designed according to the genetic constitution of both the host and methotrexate, cytarabine, and hydrocortisone is more effective than intra-
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the host’s leukemia cells. thecal methotrexate in preventing CNS relapse. Because the presence of
Because thioguanine is more potent than mercaptopurine in ALL blasts in the CSF, even from traumatic lumbar puncture, is associated
model systems and leads to higher concentrations of thioguanine nucle- with an increased risk of CNS relapse and poor EFS, 80,81 intrathecal ther-
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otides in cells and cytotoxic concentrations in CSF, randomized trials apy should be intensified in patients with this feature. With CNS prophy-
have been performed in children to compare the effectiveness of these laxis and high-dose systemic therapy most adults with ALL remain free of
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two drugs. Thioguanine, given at a daily dose of 40 mg/m or more, CNS disease. CNS disease at the time of leukemia relapse in adults occurs
produced superior antileukemic responses to mercaptopurine, but in approximately 10 percent of cases. The frequency of CNS recurrence is
was associated with profound thrombocytopenia, an increased risk of about the same whether CNS radiation therapy (12 to 24 Gy) is used or
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death, and unacceptable rate of hepatic venoocclusive disease. Conse- whether only intrathecal cytotoxic therapy is used. Systemic high-dose
quently, mercaptopurine, remains the drug of choice for ALL, although methotrexate and cytarabine add to the CNS therapy. The outcome after
thioguanine is still used in short-term courses during the intensification CNS relapse is poor. Survival after CNS relapse is usually less than 1 year
phase of therapy. in adults. Treatment of CNS relapse requires cranial irradiation, intrath-
Intermittent pulses of vincristine and a glucocorticoid improved ecal chemotherapy, typically via an Ommaya shunt, plus reinduction and
the efficacy of antimetabolite-based continuation regimens and have reconsolidation systemic therapy.
been widely adopted for both childhood and adult ALL. 165,183 In older Stem Cell Transplantation Hematopoietic stem cell transplan-
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children and adults, prolonged glucocorticoid therapy may lead to tation during first remission remains controversial. In adult ALL,
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increased risk of osteonecrosis. Another integral component of many long-term disease-free survival rates range from 35 to 50 percent with
protocols is reinduction therapy introduced relatively soon after the first chemotherapy alone and from 45 to 60 percent with allogeneic trans-
remission. This treatment, which relies on the same drugs used during plantation. 195,196 However, interpretation of these results is difficult
the initial phase of induction therapy, has improved outcomes for chil- because of the lack of true randomization. Even so, results from both
dren and adults with ALL. 67,106–108 A second reinduction phase during adult and pediatric studies suggest allogeneic transplantation benefits
continuation treatment may further improve the outcome of patients some high-risk patients. 194,196,197 Because of their unfavorable progno-
with standard- or high-risk ALL. 142,185 The benefit of such a dou- sis, patients with the Philadelphia chromosome–positive ALL and
ble-delayed intensification may result from either the increased dose those with a poor initial response to induction therapy have been rec-
intensity of other agents such as asparaginase or anthracycline or the ommended to undergo allogeneic stem cell transplantation during the
timing or scheduling of the intensification regimen. first remission. 194–196,198 However, the advent of improved chemotherapy
Therapy of the Central Nervous System The CNS is a common has diminished the survival advantage from transplantation in children
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sanctuary for leukemic cells and requires prophylactic or presymp- with Philadelphia chromosome–positive ALL. The use of a tyrosine
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tomatic therapy. In the 1970s, the cornerstone of ALL therapy was kinase inhibitor has further improved the early treatment results,
cranial irradiation (2400 cGy) plus methotrexate administered intra- casting doubt on the benefit from transplantation in first remission in
thecally after complete remission was induced. Concerns that cranial childhood cases. Allogeneic transplantation appears to improve the
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irradiation could cause second cancer, late neurocognitive deficits, and outcome of adults with the t(4;11), but not that of children or infants
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endocrinopathy stimulated efforts to replace cranial irradiation with with the same genotype. 202
early intensification by intrathecal and systemic chemotherapy. Two Allogeneic transplantation has not been compared to chemother-
early clinical trials tested the feasibility of complete omission of pro- apy alone in a true randomized trial, and thus the results of compara-
phylactic cranial irradiation in the treatment of childhood ALL. 186–188 tive studies are biased by availability of appropriate donors and other
Although the cumulative risk of an isolated CNS relapse was relatively factors. 194,203–205 The more potent antileukemia activity of allogeneic
low (3 to 4 percent), the EFS rates in the two studies were only 68.4 transplantation is balanced against the considerable nonrelapse mor-
percent and 60.7 percent. 186–188 In another study, prophylactic cranial tality and long-term consequences of graft-versus-host disease. A
irradiation appeared to improve outcome in T-cell ALL with leuko- meta-analysis involving 3157 patients supports matched sibling donor
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cyte counts >100 × 10 /L. Thus, until recently, virtually all childhood allogeneic transplantation as the optimal postremission therapy for
study groups continued to rely on prophylactic cranial irradiation for adults with ALL with a significant reduction in relapses and a significant
80
up to 20 percent of patients. A radiation dose of 1200 cGy appeared increase in treatment related mortality. Results may differ depending
to provide adequate protection against CNS relapse, even in high- upon stem cell source, that is, related or unrelated donors or umbili-
risk patients (e.g., those with T-cell ALL and leukocyte counts >100 × cal cord stem cells. A retrospective study of 421 adults who underwent
10 /L). More recently, a study at St. Jude Children’s Research Hospi- allogeneic cord blood transplantation reported 2-year leukemia-free
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tal again tested the feasibility of total omission of prophylactic cranial survival of 39 percent for patients in first complete remission and 31
irradiation in the context of risk-adapted intrathecal and systemic che- percent for second remission. In multivariate analysis, factors associ-
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motherapy. The 5-year survival rate for the 498 patients enrolled was ated with poor outcomes were age older than 35 years, myeloablative
93.5 percent and the cumulative risk of an isolated CNS relapse rate conditioning, and more advanced disease. Reduced intensity-condi-
was only 2.7 percent, a promising result, suggesting that prophylactic tioning allografting has yielded lower nonrelapse mortality and higher
cranial irradiation can be safely omitted in the context of the effective relapse rates than myeloablative conditioning with no significant dif-
intrathecal and systemic chemotherapy. Another study by the Dutch ferences in leukemia-free survival. 206,207 The indications for allogeneic
Childhood Oncology Group also showed that prophylactic cranial transplantation in first remission should be reevaluated as chemother-
irradiation can be safely omitted from children with ALL. Prelimi- apy and transplantation continue to improve. Autologous transplanta-
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nary data from additional trials also indicate that prophylactic cranial tion failed to improve outcome in adult ALL overall, mainly because of
irradiation is not necessary. a high rate of relapse. Several small studies indicate that autologous
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