Leukemia: A Transition From Basic Science to Clinical Practice
The hematologic malignancies, broadly defined as the "leukemias," are cancers
that cross socioeconomic and gender lines and affect persons of every age group. Nearly
22,000 individuals in the United States will die of these malignancies each year, and the
associated personal and economic loss is great.
The term "leukemia" actually refers to a family of blood cancers, each having
a distinct pattern of symptoms and cytology and each differing in age of onset, prognosis,
and therapeutic options. The acute leukemias -- acute myelogenous leukemia (AML) and acute
lymphoblastic leukemia (ALL) -- have been recognized for their rapid clinical progression
when untreated and are diagnosed by the identification of primitive, poorly differentiated
hematopoietic precursors (blasts) in the blood and bone marrow. The chronic leukemias are
more heterogeneous and also include myeloid and lymphoid disorders. Chronic myelogenous
leukemia (CML), a relatively indolent disorder that is most common in young adults, is
characterized by a proliferation of mature and immature myeloid precursors. CML gives rise
to high peripheral blood white counts and splenomegaly. The chronic lymphoid leukemias, of
which chronic lymphocytic leukemia (CLL) and hairy cell leukemia are the most common, are
generally disorders of mid to late adulthood. They are usually indolent but, in many
cases, may not be curable with conventional therapy. Patients will have variable numbers
of circulating malignant lymphoid cells. The degree of splenomegaly, lymphadenopathy, and
bone marrow involvement will depend on the subtype of leukemia diagnosed.
While the myelodysplastic syndromes are often not considered under the heading of
"leukemia," they share many of the same cytogenetic and molecular abnormalities
as AML. Approximately half of patients with myelodysplasia will develop AML within a few
years of diagnosis, and hence this disorder has been referred to as
"preleukemia" in the past. Myelodysplasia is a syndrome of bone marrow failure,
with morphologically and functionally abnormal myeloid precursors showing failure to
mature appropriately. In many instances, the distinction between AML and myelodysplasia is
blurred, further supporting the close association between these entities.
Of all the malignancies, the leukemias have perhaps been the object of the most intense
and extensive basic science investigations. It has been suggested that this was a natural
evolution, since malignant cells in single-cell suspensions could be readily retrieved
without invasive surgical procedures. These cell suspensions could be purified and grown
in vitro, allowing for relatively pure populations of tumor cells and the establishment of
cultured cell lines. The identification of hematopoietic growth factors, first in cultured
supernatants and later in purified form, has allowed the systematic evaluation of cell
growth kinetics and differentiation and has opened the door for tumor biologists and
geneticists.
With the recognition that many subtypes of leukemia are characterized by reproducible
karyotypic abnormalities, a tremendous growth in the field of cytogenetics has been
realized. In this issue of Cancer Control, Peter Papenhausen, PhD, and his
colleagues explore the rapidly expanding area of cytogenetic and molecular abnormalities
that are currently recognized as diagnostic or prognostic variables in acute and chronic
leukemia and myelodysplasia. While classical karyotypic analysis remains the mainstay of
cytogenetics, new techniques that utilize concomitant molecular probes (FISH and
comparative genomic hybridization) are proving to be powerful adjuncts to basic biologic
and clinical investigations.
The chromosomal abnormalities that were identified by classical cytogenetics have
become the focus of many molecular biologists. The majority of genes that have been cloned
from these breaksites are known to be involved in cell proliferation, cell death, or cell
differentiation. These so-called "oncogenes" are critical components in the
multifactorial pathway leading to the development of a malignancy, and correlates have
been found in nearly all animal species and human tissues. The discovery of oncogenes has
truly revolutionized cancer biology and is probably the major factor responsible for the
marked growth in the fields of molecular biology and diagnostic hematopathology. The
molecular identification of translocation breaksites, or immunologic identification of the
associated chimeric proteins, is becoming common practice in the clinical and laboratory
evaluation of patients with leukemia. More accurate subtyping and classification of the
acute and chronic leukemias has been made possible by the recognition that the leukemic
cell morphology is closely related to the molecular genotype. Cytogenetics has also proven
to be one of the most important and reproducible prognostic variables in the evaluation of
patients with both acute and chronic leukemia. Factors such as growth fraction, DNA
ploidy, immunophenotype, and multidrug resistance are closely related.
As advances in molecular biology have been immediately translated into advances in
diagnosis, the impact on treatment is only beginning. One of the first examples of
"targeted leukemia therapy" occurred somewhat through serendipity. Acute
promyelocytic leukemia (APL) is characterized by a chromosomal translocation involving
chromosomes 15 and 17, at the site of the retinoic acid receptor gene. Today, the use of
all-trans-retinoic acid, which greatly improves long-term remissions of APL, has become
the standard of care for treatment of APL. Another example of a therapeutic intervention
evolving in response to basic science investigations is the development of pharmacologic
agents aimed at reversing multidrug resistance. This followed the identification and
characterization of several cytosolic and membrane proteins that could impart a
drug-resistant phenotype to tumor cells. Clinical trials in this area continue to receive
critical attention. Meanwhile, pharmacologists and tumor biologists continue to work
toward the identification of critical cell pathways in oncogenesis, so that the dream of
"oncogene-targeted drug discovery" can eventually be realized.
As new information has been generated through laboratory investigations, so too has
progress been made in the therapy of these malignancies. Myelodysplasia remains difficult
to treat. Patients are often elderly, and the abnormal bone marrow cells are frequently
resistant to conventional chemotherapy. Significant mortality and morbidity result from
persistent and recurrent infections, as well as bleeding. More accurate diagnoses,
combined with the development of better prognostic scales, have helped to select patients
most likely to require immediate intervention. Supportive care, including the use of
hematopoietic growth factors, remains the mainstay of treatment. Clinical trials that
involve multidrug resistance reversal and intensive chemotherapy are ongoing. Bone marrow
transplantation is still considered to be experimental in this disorder, with few eligible
patients in view of their advanced age at diagnosis.
Advances in chemotherapy have included refinement of the dosage and timing of cytotoxic
agents, as well as the development of less toxic regimens for high-dose therapy with stem
cell rescue (both autologous and allogeneic stem cell transplantation). In this issue,
Ruben Saez, MD, reviews the role of conventional and high-dose therapy for AML and
provides some guidelines for therapeutic decision making at the time of diagnosis and
relapse. New agents also have been investigated, and several have shown promise in
affecting the outcome, either by increasing remission induction rate or prolonging the
asymptomatic phase. Interferon has been shown to be capable of eliminating Philadelphia
chromosome-positive cells from the bone marrows of patients with CML, and it most likely
can prolong the duration of chronic phase. Cures have been realized after allogeneic bone
marrow transplantation in this disease, and posttransplant therapies are under
investigation in an attempt to ameliorate transplant-related morbidity/mortality, as well
as relapse rate. The discovery of the nucleoside analogs and the institution of trials of
fludarabine and 2-CdA in the chronic lymphoid leukemias have produced the first
documentations of complete remission in these disorders. Whether this can eventually be
translated into a durable remission or cure remains to be seen. The advent of these agents
is perhaps the most significant therapeutic advance yet seen in these lymphoid leukemias.
As diagnosis and research applications become complex and more technically advanced and
as therapy becomes more intense, it is increasingly more important to remember the patient
as an individual person. It can be easy to lose the human side of medicine in a quagmire
of technology. Quality-of-life issues are gaining increased prominence, patient tolerance
of chemotherapy is improved due to the effective use of analgesic and antiemetic
medications, and the psychosocial aspects of repeated or prolonged hospitalization are
being addressed. National and local support groups are being formed, and hospitals and
cancer centers are providing a forum to address patient and family concerns during and
after treatment. In this issue, Donna Corwin Moss, MA, CSW, describes the role of leukemia
support groups and provides an insight into the contributions of national organizations
such as the Leukemia Society of America. Other areas of ongoing investigation revolve
around the issues of posttherapy morbidity. While patients are now frequently cured of
their leukemia, postchemotherapy or radiation therapy-induced cognitive or sensory
disorders, infertility and sexual dysfunction, and growth retardation are emerging as
important issues.
We have come a long way in our understanding of hematologic cancer. Still, many
unresolved issues remain. This issue of Cancer Control can touch on only a few of
these important topics. It is our hope that advances in biology, diagnosis, treatment, and
patient satisfaction with outcome will continue into the next century.
Lynn C. Moscinski, MD
Associate Professor of Pathology
Leukemia Lymphoma Program
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Fla
Back to Cancer Control Journal Volume 4 Number 5