Page 1540 - Williams Hematology ( PDFDrive )

1514 Part XI: Malignant Lymphoid Diseases Chapter 91: Acute Lymphoblastic Leukemia 1515

121
septicemia or disseminated fungal infection that is responding poorly to therapy. CNS-directed therapy, which overlaps other treatments, is
antimicrobial treatment alone. All blood products should be irradiated started early and is given for different lengths of time, depending on
to prevent transfusion-related graft-versus-host disease. the patient’s risk of relapse and the intensity of the primary systemic
regimen.
ANTILEUKEMIC THERAPY Remission Induction The first goal of therapy is inducing a com-
Because ALL is a heterogeneous disease with many distinct subtypes, plete remission and restoring normal hematopoiesis. The induction
there is no uniform approach to therapy. Increasingly, treatment is regimen typically includes a glucocorticoid (prednisone, prednisolone,
targeted to biologically distinct subgroups. The best results have been or dexamethasone), vincristine, and l-asparaginase for children or an
17,67,106–108
reported from experienced treatment centers using well-designed and anthracycline for adults. Children with high- or very-high-risk
rigorously applied protocols. 106–109 No consensus exists on the risk cri- ALL, and nearly all young adults with ALL, receive four or more drugs
teria and the terminology for defining prognostic subgroups. Usually, (daunorubicin, vincristine, glucocorticoid, and l-asparaginase) during
childhood ALL cases are divided into standard-risk, high- (intermedi- remission induction in contemporary clinical trials. Improvements in
ate- or average-) risk, and very-high-risk groups, although the United chemotherapy and supportive care have resulted in complete remission
States’ Children’s Oncology Group advocates four categories, including rates of approximately 98 percent for children and 85 to 90 percent for
low risk, to accommodate patients with a very low risk of relapse. Adult adults. When a complete clinical remission is induced, patients have var-
122
cases are generally divided into two risk groups. Often infant and elderly ious degrees of residual leukemia. Because the extent of residual dis-
83,123–129
ALL are considered special subgroups of ALL that require different ease is well correlated with long-term outcome, the concept of a
treatment, primarily related to intolerance. One study showed improved “molecular” or “immunologic” remission, defined as leukemia less than
122
outcome for infant ALL, using a hybrid treatment protocol with ele- 0.01 percent of nucleated marrow cells, is beginning to supplant the tra-
ments to treat both ALL and acute myeloid leukemia, and reducing dose ditional perception of remission, which is based solely on microscopic
129
intensity in the very young infants. Few studies have been performed criteria. Prospective trials are needed to demonstrate that outcomes
110
in those older than 60 years of age and their management remains a will improve when interventions to change therapy are based on mea-
therapeutic challenge. 111,112 Some successes have been achieved with the surements of residual disease.
use of dose-reduced regimens and the addition of imatinib or dasatinib Attempts have been made to intensify induction therapy based on
for patients with Philadelphia chromosome–positive ALL. 113,114 Because the premise that more rapid and complete reduction of the leukemia cell
cure is not common in patients older than age 70 years, maintenance of burden forestalls the development of drug resistance. However, several
a good quality of life is a major goal for this age group. studies have suggested intensive induction therapy is unnecessary for
children with standard-risk ALL, provided patients receive postinduc-
107
Mature B-Cell Acute Lymphoblastic Leukemia (Burkitt-Type) tion intensification therapy. Intensive induction can lead to increased
The most effective contemporary treatment regimens for mature B-cell early morbidity and mortality. More intensive induction regimens with
(Burkitt-type) ALL are drug combinations that include cyclophos- additional cyclophosphamide, high-dose cytarabine, or high-dose
phamide and/or ifosfamide given over a relatively short time (3 to anthracycline also have been tested in adults with ALL and have yielded
6 months). The first major breakthrough in this disease was reported no clear benefit, partly because of the low tolerance of adults to drug
by French investigators, who achieved a 68 percent EFS rate in their toxicity. 130,131 However, in one study, the use of high-dose dexametha-
2
2
LMB84 study featuring high-dose cyclophosphamide, high-dose sone (10 mg/m per day) instead of prednisone (60 mg/m per day) dur-
methotrexate, vincristine, doxorubicin, and conventional doses of cyta- ing remission induction significantly improved treatment outcome for
rabine. In the LMB89 study, the same group reported a cure rate of children with ALL, especially those with T-cell ALL and good predni-
87 percent, which was achieved by using increased doses of methotrex- sone response, despite a higher induction death rate. 121,132 Conceivably,
ate (to 8 g/m per dose) and cytarabine (3 g/m per dose) and by adding intensified remission induction with other relatively nonmyelosuppres-
2
2
etoposide for patients with a large leukemia cell burden. This excel- sive drugs can also improve treatment outcome. Dexamethasone pro-
115
lent result has been confirmed in a randomized international study. vided better control of systemic and CNS disease than did prednisone
116
Successful treatments also have been developed by the Berlin-Frank- in two randomized studies of childhood ALL. 133,134
furt-Münster consortium, which uses a multiagent regimen that incor- The pharmacodynamics of asparaginase differ by formulation
porates cyclophosphamide, high-dose methotrexate (1 g/m per dose), and three forms are available: one derived from Erwinia chrysanthemi,
2
etoposide, ifosfamide, doxorubicin, dexamethasone, and cytarabine another prepared from Escherichia coli, and a third made of a polyeth-
(3 g/m per dose). These intensive pediatric protocols have been ylene glycol form of the E. coli product (pegaspargase). 135,136 In terms of
117
2
translated into adult treatment regimens that are completed in as little as leukemic control, the dose intensity and duration of asparaginase treat-
18 weeks. 118–120 Because of its demonstrated efficacy in B-cell lymphoma, ment (i.e., the amount of asparagine depletion) are far more important
rituximab (anti-CD20) has been incorporated in frontline clinical trials than the type of asparaginase used. The dosages of the three preparations
for adults with B-cell ALL. 118,120 Maintenance or continuation therapy are based on their half-lives. Pegaspargase, which has the longest half-life,
2
is not needed. The remission rate is very high, and most remissions are usually is administered at 2500 IU/m every other week for one to two
durable. B-cell ALL rarely, if ever, reoccur after the first year. doses in cases of newly diagnosed ALL. By contrast, the Erwinia prepa-
2
Effective CNS therapy is an essential component of successful ration, which has the shortest half-life, is administered at 20,000 IU/m
regimens for B-cell ALL and generally consists of methotrexate and three times per week for 6 to 12 doses. The doses of E. coli l-asparagi-
2
cytarabine administered both systematically and intrathecally. Cranial nase range from 5000 to 10,000 IU/m , administered two to three times
irradiation does not appear to be necessary even for patients presenting per week for 6 to 12 doses. Because of lower immunogenicity, improved
with CNS leukemia. 116,120 efficacy, and less-frequent administration, pegaspargase has replaced the
native product as the first-line treatment for children and adults in the
Precursor B-Cell and T-Cell Acute Lymphoblastic Leukemia United States, and is also increasingly used in other ALL trials around the
Treatment for leukemias affecting the precursor B-cell and T-cell lin- world. 137–140 None of the various anthracyclines (daunorubicin, doxoru-
eages consists of three standard phases: remission induction, intensi- bicin, idarubicin, and mitoxantrone) given to adults with ALL has proven
fication (consolidation), and prolonged continuation (maintenance) superior to any other; daunorubicin is used most commonly.

Kaushansky_chapter 91_p1505-1526.indd 1515 9/21/15 12:20 PM