Current Management of Acute Lymphoblastic Leukemia in Adults
Current Management of Acute Lymphoblastic Leukemia in Adults
Acute lymphoblastic leukemia (ALL) accounts for 20% of all acute
leukemias seen in patients over 20 years of age, and affects approximately
2 persons per 100,000 in the United States annually. Despite its
relative rarity, ALL continues to generate considerable interest
because of its high mortality when untreated, and because of the
biologic and therapeutic lessons learned from studying this disease.
The success of therapy in childhood ALL has also fueled a quest
for similar cure rates in adults, using intensive remission induction
chemotherapy and the concepts of post-remission consolidation
and maintenance therapies. So far, treatment for adult ALL has
yielded inferior, but increasingly promising, complete remission
rates of 75% to 90% and 3-year survival rates of 25% to 50%.1
Moreover, recent studies have contributed to an understanding
of the biology of ALL and its prognostic factors [2-4]. Importantly,
specific therapies directed at relatively homogeneous subgroups
of ALL are now emerging. Parallel improvements in supportive care,
such as antibiotic prophylaxis, the appropriate use of bone marrow
transplantation, and perhaps the use of hematopoietic growth factors
have also contributed to better survival rates.
The diagnosis of ALL continues to rely on morphology and cytochemistry.
However, with the increasing availability of immunophenotyping
by flow cytometry, this technique has become an important part
of the diagnostic evaluation (Table 1). Thus, in the initial assessment
of the acute leukemia patient, a relatively limited panel of monoclonal
antibodies will allow patients to be divided into those with ALL
derived from either B lymphocytes (B-lineage) or T lymphocytes
(T-lineage) and those with acute myeloid leukemia (AML). The distinction
between ALL and AML is the critical first step in the selection
of therapy, and when this division is not correctly made, poor
results are common.
Other diseases may be confused with ALL, the most common of which
are listed in Table 2. Minimally differentiated AML (MO by the
French-American-British Cooperative Group [FAB] criteria) and
acute undifferentiated leukemia lack lymphoid surface markers,
and are rarely cured with typical ALL treatment.
The diagnosis of AML-MO is often difficult to make, as it relies
on morphology, cytochemistry, and immunophenotyping. These cells
usually have FAB-L2 morphology and are negative for myeloperoxidase
or Sudan Black B reactivity. Thus, patients with AML-MO are often
mistakenly entered into ALL clinical trials, where their outcome
has been poor. However, these cases, by definition, do not express
lymphoid-specific markers. They may be positive for terminal deoxynucleotidyl
transferase (TdT) reactivity and CD7 expression, but these markers
are not specific for lymphoblasts. In contrast, AML-MO cells are
positive for CD13, CD33, or other myeloid markers, suggesting
a minimal level of differentiation along the granulocytic pathway.
Occasional patients may have hybrid acute leukemia, wherein the
blast cells express both myeloid and lymphoid surface markers.
They may be either bilineal, when such features are seen in separate
cell populations, or biphenotypic, when they are seen on the same
cell. In the former case, therapy is usually based on the dominant
In approximately 20% of cases of typical ALL in adults, the individual
lymphoblasts express both myeloid and lymphoid antigens. These
cases are more commonly B-lineage than T-lineage in origin. The
myeloid antigen-positive ALL immunophenotype does not appear to
be associated with a poor outcome in children, but the data are
less clear in adults . However, recent improvements in treatment
may have overcome the poor prognosis formerly associated with
myeloid antigen expression in adult ALL [4,6].
Together, the use of morphology, cytochemical stains, immunophenotyping,
and electron microscopy can reliably differentiate between AML
and ALL in more than 95% of patients. Most cases of ALL are strongly
positive for terminal deoxynucleotidyl transferase. Lymphoblasts
that are negative for terminal deoxynucleotidyl transferase often
have FAB-L3 morphology, and correspond to mature B-cell ALL. Such
cases are sometimes called Burkitt cell ALL, because of their
similarities with Burkitt's lymphoma. The lymphoblasts of these
patients generally express surface membrane immunoglobulins, and
the 8;14 translocation or one of its variants [t(2;8) or t(8;22)]
is usually present.
Cytogenetic evaluation has become a critical part of the pretreatment
evaluation of patients with ALL . Indeed, the most predictable
clinical outcomes occur when patients are classified according
to recurring cytogenetic abnormal- ities.4 The most common of
these involves the Philadelphia chromosome . Originally described
in chronic myelogenous leukemia, this rearrangement involves the
translocation of the ABL proto-oncogene from chromosome 9 to the
breakpoint cluster region (BCR) gene on chromosome 22: t(9;22)(q34;q11).
In chronic myelogenous leukemia, this results in the production
of the hybrid protein p210, but in Philadelphia-positive ALL,
either a p210 or a smaller p190 protein results.
The importance of recognizing this subgroup lies in the considerably
shorter survival observed in both childhood and adult Phildelphia-positive
ALL cases. Although fewer than 5% of childhood ALL cases are positive
for this chromosome, the frequency of positivity increases steadily
with age, and approximately 30% of adults with ALL have Philadelphia-positive
disease [3,8]. Indeed, the poorer prognosis of adult ALL overall
may be due, in part, to the proportionately higher number of Philadelphia-positive
cases seen among adults.
Other karyotypes that occur in ALL and have important prognostic
significance include t(8;14), t(4;11), and t(1;19). The poorer
prognosis associated with certain karyotypes has dictated that
different approaches be taken with these patients, as discussed
Table 3 lists the adverse prognostic factors that have a major
influence on complete remission rates, remission duration, and
survival in patients with ALL [1,4]. In multivariate analyses,
patients presenting with white blood cell counts > 30,000/µL
have had a significantly shorter duration of remission than patients
with lower leukocyte counts. However, among patients with T-cell
ALL, extreme leukocytosis does not negatively affect outcome .
Older age (> 60 years) is another adverse characteristic. Remission
duration and overall survival have decreased in almost every adult
ALL trial as the ages of the patient groups have increased. Minor
prognostic factors, or those that have had some significance with
certain treatment regimens, are the percentage of circulating
blast cells; the degree of bone marrow involvement; the presence
of hepatomegaly, splenomegaly, or lymphadenopathy; lactate dehydrogenase
levels; central nervous system (CNS) involvement at presentation;
and the time required to achieve complete remission (eg, >
4 to 6 weeks).