Page 1093 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 78 Lymphoid Leukemias 1057

the prognostic factors at diagnosis). Isolated extramedullary ON ThE hOriZON
relapse carries a better prognosis. Although some relapses can
be treated with chemotherapy only, most are being treated Translational Research of Acute Lymphoblastic
with SCT. The most important prognostic factor that has Leukemia (ALL)
emerged is the MRD level before transplantation. More than • Whole genomic analyses will discover all leukemia genetic abnormalities,
half the late relapses in patients with “good prognosis” ALL are enabling further personalization of treatment.
curable. The prognosis of early relapses and relapsed T-cell ALL • Novel therapies targeting specific leukemia-associated abnormalities
is grim. will be implemented.
• Immunotherapy utilizing antibodies directed against lymphoid antigens
Treatment Sequelae and conjugated either to toxins or to T-cell engaging molecules or
modified T cells will be routinely implemented in treatment of high-risk
In the 1990s, improvements in supportive care reduced the rate ALL.
of early death to <2%. However, the death rate among older
patients during remission induction therapy remains as high as
30% because of hematological, hepatic, and cardiac toxicities.
Long-term toxicity is of major concern for children cured
from ALL. Aseptic necrosis of various bones has emerged as a CHRONIC LYMPHOCYTIC LEUKEMIA
common late toxicity of glucocorticoids, especially in adolescent
girls treated with dexamethasone. The rate of long-term neuro- Chronic lymphocytic leukemia (CLL) is an often indolent
toxicity has been reduced as a result of replacement of cranial lymphoproliferative neoplasm of mature peripheral circulating
irradiation with high-dose and intrathecal methotrexate. However B cells. It is the most common leukemia in adults living in
intensive methotrexate therapy can also have late neurodegenera- countries in the Western hemisphere. CLL originates from a
tion effects. The dose of anthracyclines used in most ALL protocols clonal lymphoid evolved mature stem cell that can be identified
is unlikely to produce severe cardiomyopathy. by its distinct B-cell Ig gene rearrangement. Both clinically and
Secondary cancers are a major concern. The development of at the molecular level, it is a heterogeneous disease. Some patients
therapy-related acute myeloid leukemia (AML) has been linked have an indolent course, whereas other have a more rapid and
to the use of topoisomerase II inhibitors (teniposide and eto- aggressive disease. During its progression, CLL may be associated
poside), and the risk is apparently dependent on the treatment with significant immune deficiencies and autoimmune phenom-
schedule and the concomitant use of other agents. Children who ena that can complicate its course and treatment. These abnor-
received cranial irradiation at 6 years of age or younger are most malities may be profound and thus alter the nature of the disease.
susceptible to the development of brain tumors. They are attributed to the clonal nature of its B-cell origin. Less
Long-term follow-up studies reported from Scandinavia of than 5% of patients have T-cell CLL. Understanding the molecular
children cured of ALL confirm excellent long-term outcomes, pathways involving BCR moieties enables focusing of novel and
as judged by their socioeducational achievements and by repro- targeted chemoimmunotherapy.
ductive success resulting in healthy offspring. 18
Epidemiology
Current Controversies and Future Perspectives The extensive use of automated peripheral blood lymphocyte
The high cure rates in patients with ALL (nearly 90% of children counts has increased the rate of diagnosis of asymptomatic
and 50% of adults) attest to the steady progress that has been patients with CLL. The incidence rate of CLL increases logarithmi-
made in treating this disease. A further increase in cure rates cally from age 35 years, with a median age at the time of diagnosis
will require efforts to maximize the efficacy and minimize the of 65 years. There is a male predilection, and the disease appears
toxicity of current therapy. Currently MRD measurement can to have geographical and ethnic variations in incidence. In the
reliably identify the extremely good-risk and extremely poor-risk United States, CLL is uncommon in people of Asian descent.
patients. However, about half the patients belong to an “intermedi- Because many of these patients may never require tissue diagnosis
ate risk” group in which most of the relapses occur. Optimization or inpatient treatment, cases among them are not likely to be
of diagnosis and treatment of this group of patients is one of recorded in a tumor registry, thus making the true annual
the current major challenges. incidence of the disease higher than previously thought (6.8 per
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Advanced genomic technologies carry the promise of discover- 100 000 population). With sensitive techniques, a monoclonal
ing the full spectrum of leukemogenic pathways and the identifica- population of B lymphocytes that is indistinguishable in immu-
tion of targets for new therapies. Genomic analysis has also nophenotype from CLL cells may be found in the blood of 3.5%
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discovered marked subclonal heterogeneity. Most of the relapses of persons >40 years of age. 23
apparently arise from a minor subclone present at diagnosis. The presence of B lymphocytes <5000/µL showing clonality
The identification and specific targeting of these resistant cells is defined as monoclonal B-lymphocytosis (MBL). MBL is an
is a major future challenge. indolent disorder that may progress to frank CLL at a rate of
An exciting development is the advent of immunotherapy. 1–2% per year, and almost all patients with CLL begin with
Blinatumomab, a novel bispecific antibody engaging autologous MBL. This state is divided into low or high MBL (below or above
T cells against CD19 positive leukemic cells, has been recently 500/µL clonal lymphocytes in the peripheral blood). Low MBL
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approved for therapy. New cell therapy based on autologous is more abundant and rarely progresses to frank CLL, whereas
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T cells engineered to express anti-CD19 receptor coupled to high MBL may progress at the above-mentioned rate. Some
intracytoplasmic stimulatory molecules (CAR-T cells) have also patients with MBL will experience autoimmune phenomenon,
shown a tremendous efficacy against highly resistant B-cell as later described for CLL. However, the importance of the MBL
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precursor ALL. This is therefore an exciting period in novel clone is not fully understood and does not necessarily imply a
treatments of ALL beyond chemotherapy. future progression to CLL. 24