References

Dighiero G, Travade P, Chevret S et al The French Cooperative Group on CLL. B-cell chronic lymphocytic leukemia Present status and future directions. Blood 78 1901-1914, 1991. 2. O'Brien S, delGiglio A, Keating M Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 85 307-318, 1995. 3. Rozman C, Montserrat E Chronic lymphocytic leukemia. N Engl J Med 333 1052-1057, 1995. 4. Hoyer JD, Ross CW, Li C-Y et al True T-cell chronic lymphocytic leukemia A morphologic and...

Morphologic Subtypes Refractory Anemia RA

Anemia is the main manifestation (hemoglobin below 11 g dl with a low reticulocyte count) with variable dyserythropoiesis alone or accompanied by DysG and DysM (Table 14-7). However, the first hematological manifestation could be thrombocy-topenia alone or more rarely neutropenia alone. Therefore, this type might be more appropriately termed refractory cytopenias (RC). Granulocytopenia or thrombocytopenia or both may be minimal or absent. Blast cells are not present in the peripheral blood...

Acute Management of Essential Thrombocythemia

Patients presenting with ET-related hemorrhage may paradoxically need platelet transfusion to increase the number of normally functioning platelets. Platelet apheresis to reduce the platelet count rapidly while the response to hydroxyurea is awaited has sometimes been used for both persisting hemorrhage and evolving thrombosis. Early use of aspirin (300 mg) in ischemic or thrombotic situations is recommended, and anticoagulation with heparin or warfarin can be considered. Some bleeding patients...

Management of PV in Pregnancy

To decrease the thrombohemorrhagic complications the Hct should be maintained below 0.45, by phlebotomy if possible. Close monitoring of the Hct and platelet count should be performed on a monthly basis. Low-dose aspirin (75 mg) appears to improve the outcome for pregnant patients with ET133,134 and should also be given in PV. Cytoreductive agents should be avoided if possible, especially in the first trimester, but if cytore-duction is essential interferon-alpha is the drug of choice. Around...

Pregnancy and Fertility

The natural physiological changes in pregnancy, such as hemodilution and a mild thrombocytopenia may help to ameliorate the thrombotic diathesis that is present in patients with PV.123 Pregnancy itself, however, is a physiological hypercoagu-lable state, with an increase in procoagulant clotting factors (e.g. factor VII, factor VIII, and fibrinogen) and a decrease in natural anticoagulants (e.g., free protein S), occurring from about the third month of pregnancy.124

Clinical Manifestations

About 25 percent of patients present with fatigue, 25 percent with repeated infections, and 25 percent with splenomegaly, which in a minority of patients may be massive, or with cytope-nias41 (Table 8-1). In 102 newly diagnosed HCL patients, 86 had anemia, 84 thrombocytopenia, and 78 neutropenia.42 Splenomegaly was present in 93 patients. Hepatomegaly is present in 20 percent of patients. Although peripheral adenopathy is rarely found clinically, less than 10 percent of patients have peripheral...

Philadelphia Chromosomenegative

In 5 to 10 percent of patients with the clinical picture of CML, no Ph can be demonstrated by cytogenetic analysis.162 However, one-third of these patients have rearrangements of BCR-ABL that can be detected by molecular studies such as Southern blotting, FISH, or PCR. Patients with Ph-negative, BCR-ABL-posi-tive CML have similar characteristics, clinical course, and outcome compared with Ph-positive patients.163 The remaining two-thirds of Ph-negative cases have no detectable BCR-ABL...

Essential Thrombocythemia

Essential thrombocythemia (ET) is a clonal disorder19 characterized by panmyelosis of the bone marrow with a predominance of megakaryocytes resulting in marked thrombocyto-sis.112-114 Megakaryocyte progenitors may be hypersensitive to thrombopoietin. The platelet count usually exceeds 106 l. Mild leukocytosis (20 to 30,000 l) is often present, but the red cell mass is normal (unless iron deficiency occurs due to bleeding) and must be so to distinguish this entity from polycythemia vera. Bone...

Chronic Myelocytic Leukemia

CML is a myeloproliferative disorder in which the crucial pathophysiological event is the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9.14 The molecular biological details and cell biological consequences of this rearrangement are discussed in Chapter 20. The diagnosis of CML is confirmed when bone marrow or peripheral blood cells are determined to have a Philadelphia chromosome (i.e., a translocation between the long arm of chromosome 9 and the short arm of...

The Life Cycle And Molecular Biology Of Htlv1 And Htlv2

HTLV-1 and HTLV-2 are genomically and structurally typical of type C oncornaviruses (Figures 12-4 and 12-6). The integrated proviral DNA contains redundant long terminal repeat (LTR) sequences that contain enhancer and promoter elements for viral RNA transcription, the RNA transcriptional start and polyadenylation sites, and, at the 3' end of the transcribed RNA, a stem-loop structure termed the Rex Response Element (RRE). Like all retroviruses the HTLV contain genes, termed gag, pol, and env,...

Prolymphocyte Leukemia

Prolymphocytic leukemia (PLL), once thought to be a variant of CLL,198 is now a well-characterized clinicopathological entity characterized by specific morphological, immunophenotypic, and histological criteria.199,200 The relative frequency of PLL among patients with chronic lymphoproliferative disorders at one large center was 10 percent compared with 80 percent for CLL and 10 percent for hairy cell leukemia.201 B-cell PLL accounts for approximately 80 percent of cases with the more...

The Bcrabl Rearrangement

The Ph reciprocal translocation between the long arms of chromosomes 9 and 22 transposes the large 3' segment of ABL from chromosome 9q34 to the 5' part of BCR on chromosome 22q11 in a head-to-tail fashion, thus generating a hybrid BCR-ABL gene that is then transcribed into a chimeric BCR-ABL mRNA (Figure 4-2).20 The ABL (Abelson leukemia virus) gene is the protoonco-gene homologue of the viral transforming V-ABL gene that causes nonthymic pre-B-cell lymphomas in mice infected with the Abelson...

Full Blood Count

A raised neutrophil and platelet count supports a diagnosis of PV, although it should be remembered that smokers have higher neutrophil counts than nonsmokers do. The red cell indices may be suggestive of iron deficiency, which is common in PV. An eosinophilia and or basophilia are occasionally found in PV but are only supportive of this diagnosis. Common Causes of Secondary Polycythemia

Hairy Cell Leukemia

Formerly called leukemic reticuloendotheliosis,210-215 hairy cell leukemia is a well-characterized clinico-pathologic entity for which several successful treatment strategies exist. This disorder was first recognized by Rosenthal and colleagues212 as well as Bouroncle and co-workers210 in the 1950s, but was first characterized as hairy cell leukemia after Schrek and Donnelly213 described the hairy villous cytoplasmic projections of the leukemic cells viewed under phase microscopy in 1966. Hairy...

The Signaling Pathways of BCRABL

Fak Src Pathway

The transforming capacity of BCR-ABL is largely based on its ability to associate and interact with numerous proteins that connect it to various pathways of intracellular signaling. To understand the structural characteristics of BCR-ABL that facilitate these types of interactions, it is first necessary to dissect the functional sequences of the ABL and BCR proteins, respectively, and then to analyze their contribution to the transformed phe-notype in the chimeric protein. ABL encodes a 145-kd...

Methods Of Describing Antigen Expression

Antigen expression can be characterized according to antigen density, which is described by terms such as bright versus dim staining of antibodies or low versus high antigen expression. These descriptions relate to the intensity with which a fluorescence-conjugated antibody stains a given cell. Fluorescence intensity can be helpful diagnostically when the same antigen is expressed on contaminating normal and leukemic cells with differential density and gating procedures are inefficient in...

Second Malignancies Following Systemic Treatment of Hairy Cell Leukemia

One study has now documented an unexpected high incidence of second neoplasms in patients after treatment of HCL with alpha-2b interferon.110 Of 69 patients followed for a median of 91 months, 13 patients (19 percent) developed a second neoplasm, of which 6 were of hematopoietic origin and 7 were ade-nocarcinomas. The median survival after diagnosis of the second neoplasm was only 8.8 months. Saven et al. reported on 358 HCL patients treated with 2-CdA of whom 27 (23 males) developed second...

Info

Seiki M, Hattori S, Hirayami Y et al Human adult T-cell leukemia virus Complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci USA 80 3618,1983. 8. Posner LE, Robert-Guroff M, Kalyanaraman VS, Poiesz BJ, Ruscetti FW, Fossieck B et al Natural antibodies to the human T-cell lymphoma virus in patients with cutaneous T-cell lymphomas. J Exp Med 154 333, 1981. 9. Yoshida M, Miyoski I, Hinuma Y Isolation and characterization of retrovirus (ATLV) from...

Fbc

B12 and folate Urea and creatinine Liver function tests Uric acid Chest x-ray Abdominal ultrasound Bone marrow aspirate trephine Bone marrow karyotype BFU-E Abbreviations FBC, full blood count BFU-E, burst forming unit erythroid. a Stage 1 investigations are more general, inexpensive tests aimed at picking up secondary causes. Stage 2 investigations are more specific tests either specifically aimed at proving or disproving a diagnosis of PV, or * may be suggested by the results of stage 1 tests...

Clinical Features And Natural History

Thrombosis is the major cause of morbidity and mortality in untreated PV. The increased risk of thrombosis relates to the hemorheological effects of the erythrocytosis and may be further exacerbated by accompanying thrombocythemia and possibly by abnormal platelet function. In a large retrospective study of over 1000 patients, 20 percent of patients presented with a thrombotic complication, with arterial and venous events comprising two-thirds and one-third of these thromboses, respectively.14...

John T Reilly Maria Messinezy and Thomas C Pearson

The Diagnostic Criteria of Essential Thrombocythemia 1. Platelet count above 600 x 109 L (trial) above 400 x 109 L (clinical) 2. No cause of a secondary reactive thrombocytosis 3. Normal red cell mass if hematocrit above 51 percent in males, above 47 percent in females, and in those with high normal hematocrit and demonstrable splenomegaly 4. Stainable iron in marrow or normal serum ferritin or normal red cell mean corpuscular volume (if measurement suggests iron deficiency,...

Renal and Liver Function Tests and Serum Uric Acid

Any renal impairment may suggest renal causes of secondary erythrocytosis. Cirrhosis and excessive alcohol consumption causing impaired liver function may result in an absolute ery-throcytosis due to associated hypoxemia, diminished Epo Table 9-3. Proposed Modified Criteria for the Diagnosis of Polycythemia Veraa A1 Raised red cell mass (> 25 above normal predicted value) A2 Absence of cause of secondary polycythemia A3 Palpable splenomegaly B1 Thrombocytosis (platelet count > 400 x 109 L)...

CD117positive Acute Lymphocytic Leukemia

Although CD117 has a higher specificity in the recognition of AML than have CD33 and CD13, its expression is not exclusively seen on myeloid leukemic cells. Approximately 2 percent of adult ALL expressed CD117 on 100 percent of lymphoblasts in ECOG study E2993 (Paietta E, unpublished observation). These ALLs were of very immature T-cell phenotype, expressing intracytoplasmic, but not membrane CD3, TdT, CD2, and CD7 in the absence of CD5 and usually without CD4 or CD8. Other recent, acceptably...

Nukhet N Tuzuner and John M Bennett

Commonly associated with acute megakaryoblastic leukemia. The second example is hypocellullar (hypoplastic) acute leukemia in which bone marrow aspirations from several sites and biopsy from one site are necessary for diagnosis.3 The third example is that of an uncommon localized extramedullary mass of cells of the granulocytic-monocytic series (granulocytic sarcomas).4 These tumors can be seen in an established diagnosis of acute myeloblastic leukemia (AML), either at presentation or as the...

Chronic Lymphocytic Leukemia

CLL represents a monoclonal proliferation of mature-appearing B lymphocytes, although approximately 5 percent of patients have a T-cell variant.152-155 Patients with B-cell CLL present with generalized lymphadenopathy, splenomegaly, and or slowly progressive lymphocytosis. Although lymphocyte counts in patients with CLL may exceed 200,000 p.l, in contrast to the sticky myeloblasts in AML, leukostatic syndromes (cerebral or lung involvement) are rare.156 An absolute lymphocyte count of greater...

Diagnosis

Definition, Diagnostic Criteria, and Differential Diagnosis CML is a clonal myeloproliferative expansion of transformed primitive hematopoietic progenitor cells involving myeloid, monocytic, erythroid, megakaryocytic, B-lymphoid, and occasionally T-lymphoid lineages.1 Since the 1960s when Nowell and Hungerford2 described the specific karyotypic abnormality the Philadelphia (Ph) chromosome there has been rapid progress in our understanding of pathogenesis, providing us with the means to easily...

Agnogenic Myeloid Metaplasiamyelofibrosis

Agnogenic myeloid metaplasia-myelofibrosis has been described by at least 37 different names, such as idiopathic myelofibrosis with myeloid metaplasia.124,125 Patients with this entity generally present with anemia, massive splenomegaly, and nucleated and tear-drop red cell forms in the peripheral blood. Basophilia and an elevation of the white count with a left shift are not uncommon although as the disease progresses, leukopenia may supervene.126 Early in the disease (before marrow fibrosis...

Red Cell Mass Demonstration of an Absolute Erythrocytosis

A diagnosis of an absolute erythrocytosis can only be made when an individual's RCM measurement is more than 25 percent above their mean predicted value. The RCM result and predicted values should be expressed in terms of the patient's surface area rather than body weight. As fat is relatively avascular, results expressed in terms of total body weight lack precision in the obese patient. Using surface area to calculate the predicted RCM, 98 percent of males and 99 percent of females fell within...

John M Goldman and Myrtle Y Gordon

Although chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) can be grouped together for some purposes, they differ in many ways, CML being a disease with well-defined progressive stages (chronic phase acceleration transformation) occurring in middle life, whereas CLL is a relatively indolent disease involving mainly the elderly. Whereas CML has well characterized molecular features, which can reasonably be assumed to be related to its pathogenesis, the cause of CLL is...

Immunophenotyping Versus Morphology

There is a strong tendency to divide diseases into subtypes that share clinical, biological, and hopefully, prognostic features that can predict success if a uniform treatment approach is taken. In the acute leukemias, the first comprehensive classification scheme was based on the site of origin, that is, myeloblastic leukemia was considered to be that which arises from the bone marrow whereas the lymphoblastic leukemias were considered to originate in lymphoid tissue.7 Relatively precise...

Variants of CML

There are several disease entities that resemble CML but lack the Philadelphia chromosome or molecular evidence for bcr-abl translocation. Patients who are Philadelphia chromosome negative, but bcr-abl translocation positive appear to have a similar natural history to those who are Philadelphia chromosome positive.102 The term chronic neutrophilic leukemia, sometimes characterized as Philadelphia-negative CML, has been used to describe those with an elevated white count with a majority of...

Sezary Syndrome

Sezary syndrome is one of several closely related clinicopatho-logical entities referred to as cutaneous T-cell lymphoma (CTCL).238-242 The most commonly occurring entity, mycosis fungoides, is characterized by chronic, slowly progressive cutaneous lesions (plaques and nodules) with eventual adenopathy, bone marrow involvement, and systemic disease.243,244 These disorders are caused by the proliferation of mature T cells (CD4 or helper cell phenotype positive) that have a high affinity for the...

Cytoreductive Agents

The value of platelet count reduction in ET depends on the estimated risk of major thrombotic or hemorrhagic complications in the untreated patient. The parameters that separate patients into different risk categories are still somewhat uncertain, but there is widespread agreement that older patients with higher platelet counts (rather arbitrary values of 60 years and above 1,000 or 1,500 X 109 L may be taken), or other thrombotic risk factors as above (particularly a previous ischemic event or...

Molecular Biology and Cytogenetics of Chronic Lymphocytic Leukemia

Cytogenetics Translocation

Early cytogenetic studies in chronic lymphocytic leukemia (CLL), performed in the 1960s and 1970s, failed to detect clonal cytogenetic abnormalities. This inauspicious start to the investigation of genetic abnormalities in CLL was the consequence of the low spontaneous mitotic rate in CLL and the use of the T-cell mitogen phytohemaglutinin to obtain analyzable metaphases. With the discovery of polyclonal B-cell mitogens, the first cytogenetic abnormality in CLL, trisomy 12, was discovered in...

Hydroxyurea

Hydroxyurea (HU) is a potent inhibitor of the enzyme ribonucleotide diphosphate reductase and prevents DNA synthesis. This drug was first used in the PVSG-08 trial, initiated in 1977, to find a safer agent to prevent the early thrombosis associated with phlebotomy alone. Fifty-one patients were enrolled into this study, all receiving HU and its efficacy and safety were compared retrospectively to the 194 patients previously enrolled into the PVSG-01 phlebotomy arm.21 Following the first 7 years...

Commitment to the Megakaryocytic Lineage

The most primitive megakaryocytic precursors, the burst-forming units of megakaryocytes (BFU-MK), express CD34 and CD109170 and are resistant to 5-fluorouracil treatment, in contrast to the more differentiated still CD34+HLA-DR+ megakaryocyte colony-forming units (CFU-MK).235 Mpl, the product of the gene encoding the thrombopoietic receptor, and GPIIb (CD41) are first expressed in CD34+ precursor cells together with CD9, a member of the tetraspanin superfamily,236 with GPIIb (CD41) and CD9...

Immunophenotyping of Acute Erythroid and Megakaryocyte Leukemia

There exists considerable overlap between the erythroid and megakaryocytic lineage at the gene as well as the protein level, both during normal development and in leukemic disorders.231-233'236'237'444'445 In terms of their immunophenotypic diagnosis, the lack of MPO expression by blast cells is the first indication of acute erythroid AEL or acute megakaryocytic leukemia AMegL . The majority of patients with AEL lack CD34 and HLA-DR expression.446 Despite the finding of glycophorin A as early...

Lineage ALL Subtypes

Although the nomenclature for B-lineage ALL subtypes varies among published reports, the major subtypes and their characteristic antigenic features show enough overlap and inherent heterogeneity to justify a coherent presentation Table 15-3 . The most immature subtype of B-lineage ALL termed ProB, Pre-Pre-B, CD10- Early Pre-B, Null-Cell, Early-Early-B, early B-precursor ALL, or B1 Subtype is recognized as such on the basis of cytoplasmic CD22 cCD22 and or cytoplasmic CD79a and or surface CD19...

Lineage Uncommitted Antigens

Many lineage-uncommitted antigens are stem cell antigens, which in normal hematopoiesis mark cells with self-renewal capacity and differentiation potential along more than one cell lineage. During normal hematopoiesis, their expression diminishes parallel to progressive maturation. When present on leukemic blast cells, they may suggest a less differentiated phe-notype. Although their expression in leukemia does not support a particular lineage affiliation, some of these antigens demonstrate...

Phylogeny And Epidemiology Of Htlv1 And Htlv2

Phylogenetic analyses of BLV, HTLV-1, HTLV-2 and simian T-cell lymphoma leukemia virus strains from around the world indicate that the PTLV diverged from BLV approximately 60,000 to 100,000 years ago.12 The PTLV are endemic to many, but not all, species of Old World primates including humans. It is clear that many incidences of cross-species transmissions have occurred over many thousands of years and PTLV strains are grouped more by geographic origin than by host species. The PTLV can be...

Polycythemia Vera

Polycythemia vera PCV is a well-recognized clinical and pathological entity characterized by trilineage hyperplasia of the bone marrow with increased numbers of circulating ery-throcytes, granulocytes, and platelets.140 Splenomegaly is almost always present, but hepatomegaly is less common, although both organs display EMH. PCV is an acquired monoclonal disorder of a pluripotent stem cell resulting in expansion of committed stem cell pools, most prominently the erythroid series.140,141...

Morphologic Types of Blastic Transformation

As discussed earlier, CML originates in a pluripotent hematopoi-etic stem cell. Support for this hypothesis was initially derived from the observation that blastic transformation could result in a leukemic syndrome from one of virtually any hematopoietic lineage. Immature cells in patients having undergone blast transformation have included undifferentiated blasts, myeloblasts, promyelocytes, myelomonoblasts, monoblasts, erythroblasts, megakaryoblasts, or lymphoblasts Table 3-4 .93 Although...

Blastic Transformation

Blastic transformation, also called acute blast crisis or terminal phase, occurs in virtually all nontransplanted patients with CML, either following an accelerated phase or acutely during the course of stable phase CML.32,65 Most accept the definition of blast crisis as the development of greater than or equal to 30 percent blasts in the marrow or the peripheral blood.89 In the blast crisis stage, progressive anemia and thrombocytopenia occur with death usually due to bleeding or infection....

Contributors

Aisenberg, MD, PhD, Professor, Department of Medicine, Harvard Medical School Physician, Department of Hema-tology Oncology, Massachusetts General Hospital, Boston, Massachusetts Elias J. Anaissie, MD, Professor of Medicine, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas Claudio Anasetti, MD, Professor of Medicine, Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, Division of Oncology,...