Acute Leukemias - Republican Scientific Medical Library

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122 Chapter 8 · Diagnosis of <strong>Acute</strong> Lymphoblastic Leukemia Terminal deoxynucleotidyltransferase (TdT) expression along with CD19+ or cyCD79a and surface or cytoplasmic CD22+ are diagnostic for early precursor B-cell involvement, irrespective of CD13 and CD33 expression. The expression of CD10 (common ALL antigen, CALLA) in addition to the above markers is diagnostic for more mature (intermediate) precursor ALL. Although CD19 protein expression is diagnostic for Bcell lineage, it is detected in 80% of acute myeloid leukemia (AML) cases that carry the t(8;21) chromosomal abnormality [46]; however, these cases are MPO positive and easily distinguished from ALL. CD20 is expressed in approximately 55% of patients with precursor B-cell ALL and more frequently in Burkitt leukemia patients. In most but not all cases, precursor B-cell cells are surface IgM-negative. Blast cells that lack TdT expression are classified as Burkitt (L3) if they show L3type morphology (vacuolated, deeply basophilic cytoplasm); otherwise, they should be classified as “Burkitt-like.” Most importantly, these cells must show blast morphology (Fig. 8.1). The diagnosis of precursor T-cell ALL is based on lack of expression of B-cell markers and expression of surface CD3 (sCD3) or cytoplasmic CD3 (cyCD3) in MPO-negative/NSE-negative blasts. However, approximately 10% of precursor T-cell ALL cases are TdT negative [25] and many coexpress CD4, CD8, and CD2. Lack of CD1a expression indicates early-stage differentiation; these T-cell ALL cases appear to be especially aggressive [71]. 8.4 Atypical <strong>Acute</strong> Lymphoblastic Leukemia 8.4.1 Burkitt-Like (Atypical Burkitt) ALL Rare cases of ALL show blasts with only mature B-cell markers (TdT–, CD19+, and surface IgM+) that are morphologically similar to the L2 rather than L3 cell type (lack deep blue cytoplasm with vacuoles). These cases are classified as Burkitt-like and are treated as Burkitt leukemia [24, 25]. 8.4.2 ALL with Eosinophilia Some cases of ALL demonstrate significant eosinophilia, which appears to be stimulated by the secretion of IL-5 and IL-3. The eosinophils have normal morphology and are reactive, not leukemic. In some of these patients, the IL-3 gene on chromosome 5q31 is translocated to the IgH gene locus on chromosome 14 (translocation t(5;14) (q31;q32) [9, 71, 83]. Rarely, patients may present with eosinophilia without evidence of ALL, raising the question of hypereosinophilic syndrome, which converts to ALL within weeks to months. The eosinophilia disappears with remission and may come back as an early sign of relapse [9, 71, 83]. 8.4.3 Aplastic and Hypoplastic ALL Rarely, young patients with ALL may present with hypoplastic or aplastic bone marrow. In the early stage, leukemic blasts may not be conspicuous and overt leukemia may manifest within weeks to months after marrow recovery. This manifestation is frequently interpreted as myelodysplastic syndrome or aplastic anemia, but the lack of dysplastic changes should help rule out myelodysplastic syndrome. This phenomenon may be due to an unusual immune response attempting to suppress the leukemic hematopoietic cells, which coincidentally suppresses normal hematopoietic cells. The other possibility is that the leukemic cells produce inhibiting factors that suppress normal hematopoiesis [71, 55]. 8.4.4 Granular ALL Rare cases of ALL show significant numbers of blasts with large (0.25-micron) basophilic granules. These granules are believed to be either abnormal mitochondria or cytoplasmic organelles, but their clinical significance is not known. Although the granules are MPO negative, they are more common in ALL cases that coexpress myeloid markers [37, 42, 71]. The blasts should not be confused with those of acute basophilic leukemia, which is more frequently seen in patients with acutephase CML. 8.4.5 Hand Mirror ALL Blasts in some cases of leukemia show uropod (handle) morphology with elongated cytoplasm, which may represent an attachment or endocytotic process. This morphology can be seen in reactive lymphoid and monocytoid cells as well as blasts. Once thought to be specific for ALL or mixed-lineage leukemia, this morphology can also be seen in AML [81].
a 8.5 · Cytogenetic and Molecular Abnormalities 123 8.4.6 Natural Killer ALL (Blastic NK) Rare cases of ALL have been reported in which the blasts lack myeloid and lymphoid markers (CD3 and CD19) but express CD56. These cases are classified as ALL of the natural killer cell phenotype. Blastic NK cells may show cytoplasmic CD3 and, occasionally, other Tcell markers (CD4 or CD7), and can be positive or negative for TdT. They lack evidence of T-cell receptor gene rearrangement. These cases should be distinguished from myeloid leukemia that expresses myeloid markers in addition to CD56. Expression of CD56 can also be seen in some cases that are typically lymphoblastic, with clear T-cell surface markers. Such cases should be considered precursor T-cell ALL with CD56 expression [52, 61, 71]. 8.4.7 Biphenotypic and Bilineage ALL In biphenotypic leukemia, markers specific for lymphoid as well as myeloid lineages can coexist in the same blast population. When two distinct cell populations coexist, one with lymphoid and the other with myeloid markers, the term “bilineage” applies. Biphenotypic and bilineage ALL are lumped together with other undifferentiated subtypes in the WHO classification of “acute leukemia of ambiguous lineage.” Despite significant confusion over the terminology, there is agreement that cells of ALL can express CD13 or CD33 or both, especially when they are positive for Philadelphia chromosome. These cases should be called “ALL with myeloid markers” rather than “biphenotypic ALL.” Biphenotypic ALL is characterized by the expression of lymphoid markers (CD19 with TdT or CD3 with TdT) along with myeloid markers (MPO with CD13, or MPO with CD33). Several scoring systems can be used for the diagnosis of biphenotypic ALL; the Immunologic Classification of Leukemia is the most widely accepted [4, 75]. The importance of classification is to decide whether a patient should be treated for lymphoblastic leukemia or for myeloid leukemia. For practical purposes, MD Anderson Cancer Center uses a simplified approach for classifying these cases with ambiguous lineage or minimal differentiation. This approach is based on blasts being negative for MPO and NSE and positive for TdT (Fig. 8.3). If these blasts express one of the major lymphoid markers (CD10, CD19, CD3) or two of the other lymphoid markers, the case Fig. 8.3. Schematic approach for a clinically useful diagnosis of leukemia of ambiguous lineage (minimally differentiated) as used by MD Anderson Cancer Center. is classified as lymphoblastic leukemia, irrespective of whether myeloid markers are expressed [4, 14, 31, 49, 71]. Patients who have one myeloid marker but fewer than two lymphoid markers (other than CD19, CD3, or CD10) are classified as having ALL with minimal differentiation. 8.4.8 MPO-Positive ALL This term should be reserved for rare cases of ALL that demonstrate typical lymphoid markers without myeloid markers, except for strong positivity (20–30%) for MPO. Most of these cases show lymphoblasts with deep basophilic cytoplasm [82]. These cases should be distinguished from Burkitt cases as well as AML. 8.5 Cytogenetic and Molecular Abnormalities Approximately 45% of ALL cases demonstrate recurrent ALL-specific cytogenetic abnormalities on conventional karyotyping studies, establishing cytogenetic study as a valuable diagnostic and prognostic tool for evaluating patients with ALL. In addition, most of these abnormalities can be detected using fluorescence in-situ hybridization (FISH), Southern blotting of genomic DNA, and reverse transcription-polymerase chain reaction (RT- PCR) of mRNA. FISH and RT-PCR are used to detect minimal residual disease and to monitor patients after therapy; real-time RT-PCR allows the quantitative monitoring of residual disease. The most common cytogenetic abnormalities are listed in Table 8.1 and discussed below.
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E.H. Estey · S.H. Faderl · H. M.
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E. H. Estey Department of Leukemia
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VI Table of Contents 14 Philadelphi
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VIII Contributors S. H. Faderl Depa
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X Contributors D. Wartenberg Depart
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Therapy of AML Elihu Estey Contents
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a 1.2 · Standard Therapy 3 Table 1
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a 1.2 · Standard Therapy 5 Table 1
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a 1.2 · Standard Therapy 7 tween G
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a 1.2 · Standard Therapy 9 Fig. 1.
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a 1.2 · Standard Therapy 11 of tre
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a 1.2 · Standard Therapy 13 Table
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a 1.2 · Standard Therapy 15 permit
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a References 17 19. Care RS, Valk P
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a References 19 6-thioguanine in th
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Acute Myeloid Leukemia: Epidemiolog
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a 3.1 · Epidemiology 49 3.1.4 Gend
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a 3.2 · Etiology 51 part of the in
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a 3.2 · Etiology 53 for the develo
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a References 55 38. Crane MM, Stom
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Relapsed and Refractory Acute Myelo
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a 4.2 · Prognostic Factors in Pati
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a 12.3 · Subset-Specific Approache
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Treatment of Adult ALL According to
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a 13.2 · Therapy for Younger (15-6
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a 13.3 · Therapy of Ph/BCR-ABL-Pos
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a 13.5 · Prognostic Factors 173 13
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a References 175 Only patients with
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Philadelphia Chromosome-Positive Ac
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a 14.2 · Molecular Biology of the
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a 14.3 · Treatment of Ph+ ALL 181
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a 14.4 · Hematopoietic Stem Cell T
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a References 185 2. Kurzrock R, Sht
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a References 187 56. Mori T, Manabe
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a References 189 acute lymphoblasti
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192 Chapter 15 · Burkitt’s Acute
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204 Chapter 16 · Treatment of Lymp
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216 Chapter 17 · The Role of Allog
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230 Chapter 18 · The Role of Autol
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238 Chapter 19 · Novel Therapies i
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248 Chapter 20 · Minimal Residual
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276 Chapter 22 · Relapsed Acute Ly
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278 Chapter 22 · Relapsed Acute Ly
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Emergencies in Acute Lymphoblastic
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a 23.5 · Hyperleukocytosis 283 LA
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a 23.9 · Neurological Complication
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a References 287 29. Hingorani AD,
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Subject Index A aberrant methylatio
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a Subject Index 291 CREB, see enhan
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a Subject Index 293 MUD, see matche
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