Page 1091 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 78 Lymphoid Leukemias 1055

Principles of Therapy 1 TABLE 78.4 Major Prognostic Factors in
acute Lymphoblastic Leukemia (aLL)
a
Supportive therapy is given before the initiation of leukemia
specific therapy. This includes hydration, treatment, and preventive Prognostic
therapy of hyperuricemia; blood and platelet transfusion; and Factor good Prognosis Worse Prognosis
treatment of emergencies, such as respiratory insufficiency Age at Age 1 year to <10 years <1 year; >10 year
associated with mediastinal leukemia. It is highly recommended diagnosis (children) (children)
that children and adults with ALL be treated in specialized centers >60 years (adult)
as a part of clinical prospective studies. Such clinical trials have Peripheral <50 000 cells/µL >100 000 cells/µL
led to the dramatic improvement in the outcome of patients blood WBC
with ALL achieved over the last several decades. Response to Early response to therapy Slow response to
Negative MRD at the end
therapy.
therapy
Typical remission induction regimens include a glucocorticoid of induction High MRD
(prednisone, prednisolone, or dexamethasone), vincristine, Genetic Hyperdiploidy (>50 chr.); BCR/ABL MLL/AF4
l-asparaginase, and, in many protocols, anthracycline. The abnormalities TEL/AML1 (ETV6/ Hypodiploidy <45 chr.
rate of complete remission now ranges from 97% to 99% in RUNX1)
children and from 75% to 90% in adults. Intensification therapy a The most important prognostic factor is the treatment protocol. Thus the prognostic
uses either high doses of multiple agents not used during the significance of various clinical and laboratory variables may differ between protocols.
induction phase or repeats the induction regimen. Regimens Here, the significant parameters common to most studies are listed.
used for children include high-dose methotrexate with or WBC, white blood cells; MRD, minimal residual disease; chr., chromosomes.
without 6-mercaptopurine; high-dose l-asparaginase given for
an extended period; an epipodophyllotoxin plus cytarabine; or
a combination of dexamethasone, vincristine, l-asparaginase, The most significant prognostic factor is the initial response
doxorubicin, and thioguanine, with or without cyclophosphamide. to therapy. A rapid clearance of leukemic cells from blood or
Another integral component of many protocols is reinduc- bone marrow confers a favorable prognosis. More recently, the
tion therapy. This treatment employs drugs similar to those level of minimal residual disease after the induction of clinical
used during the initial phase of induction therapy and has remission has emerged as a powerful tool for gauging treatment
improved the outcomes of both children and adults with ALL. response and predicting outcome.
Maintenance therapy consist a combination of methotrexate
administered weekly and mercaptopurine administered daily. Where Immunology Meets Oncology—Minimal
Some protocols add intermittent pulses of vincristine and Residual Disease
dexamethasone. Modern treatment protocols have led to morphological complete
CNS prophylactic therapy consisting of cranial irradiation remission in the majority of patients, which is defined as <5%
plus intrathecal chemotherapy, introduced after the induction blasts in bone marrow examination. If treatment is discontinued
of complete remission, became one of the cornerstones of ALL at that stage, in most patients the disease will eventually relapse.
therapy in the 1970s. More recently, because of concerns about Indeed, all prospective clinical studies have shown that ALL
neurotoxicity and the occurrence of brain tumors, intensive should be treated for at least 2 years. These facts indicate that
intrathecal and systemic chemotherapy are used instead for most at the completion of remission induction not all clonogenic
patients. malignant lymphoblasts have been destroyed, even though most
Allogeneic stem cell transplantation (SCT) is reserved for of the patients are in clinical and morphological remission. Indeed,
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relapsed or refractory leukemia and for patients with a very- by this criterion, patients may have as many as 10 undetectable
high-risk leukemia that is likely to demonstrate a slow response neoplastic cells when in remission. Since, by definition, leukemic
to therapy. With modern therapy, including targeted therapy cells must constitute at least 1–5% of the nucleated cells in bone
with imatinib for BCR–ABL, there is almost no indication for marrow to be detected by microscopic examination, morphologi-
SCT in first remission. With improvements in the prevention cal examination is clearly inadequate for evaluation of the quality
of transplant-related toxicities, suitable marrow donors are not of remission in patients with ALL. Therefore more sensitive
only human leukocyte antigen (HLA)–identical siblings or techniques for the detection of rare leukemic cells are required.
single-antigen mismatched family members but also matched This is the rationale behind the recent incorporation of modern
unrelated donors and, in some situations, two- and three-antigen techniques of detection of minimal residual disease (MRD) into
mismatched family members. treatment protocols of childhood ALL.
During the last 2 decades, two general methodologies have
Prognostic Factors been developed for the sensitive detection of submicroscopic
Modern therapy for ALL is based on adjustment of the intensity residual leukemic cells. These methodologies could not have
of therapy to the risk assessment of the relapse hazard (Table been developed without elucidation of the scientific basis of the
78.4). The two major clinical parameters of prognostic significance developmental phenotype of immune cells (Chapters 7 and 8) and
are age at diagnosis and leukocyte count. A presenting age between of the elaborate process of Ig gene rearrangements (Chapter 4).
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1 and 9 years and a leukocyte count <50 × 10 /L are favorable The most widely studied DNA-based MRD methodology is
prognostic factors. In adults, the outcome of therapy worsens based on the identification of clonospecific rearrangements of
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with increasing age and leukocyte count. Patients >60 years of Ig genes or TCRs (Ig/TCR-PCR). This approach exploits the
9
age and/or a leukocyte counts >100 × 10 /L have a particularly physiological process of somatic rearrangement of Ig and TCR
poor response to treatment. Females fare somewhat better gene loci that occur during the early differentiation of B cells
compared with males. The prognostic significance of the major and T cells. Thus any single T or B lymphocyte carries a unique
genetic aberrations has been described above. rearrangement that is not shared by any other lymphoid cell.