Blood Disorders in the Elderly - part 8 pps

338 Youssef Gamal, Samuel Kerr, Thomas P. Loughran generalized patch and/or plaque (T2) mycosis fun- goides. Arch Dermatol 1999; 135: 26–32. 162. Kashani-Sabet M, McMillan A, Zackheim HS. A modi- fi ed staging classifi cation for cutaneous T-cell lym- phoma. J Am Acad Dermatol 2001; 45: 700–6. 163. Sausville EA, Eddy JL, Makuch RW, et al. Histo- pathologic staging at initial diagnosis of mycosis fun- goides and the Sezary syndrome: defi nition of three distinctive prognostic groups. Ann Intern Med 1988; 109: 372–82. 164. Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 2002; 46: 95–106. 165. Kim YH, Jensen RA, Watanabe GL, Varghese A, Hoppe RT. Clinical stage IA (limited patch and plaque) mycosis fungoides: a long-term outcome analysis. Arch Dermatol 1996; 132: 1309–13. 166. Kim YH, Bishop K, Varghese A, Hoppe RT. 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Spencer J, Cerf-Bensussan N, Jarry A, et al. Enteropathy- associated T cell lymphoma (malignant histiocytosis of the intestine) is recognized by a monoclonal anti- body (HML-1) that defi nes a membrane molecule on human mucosal lymphocytes. Am J Pathol 1988; 132: 1–5. 244. Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteropathy-type intestinal T-cell lym- phoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol 2000; 18: 795–803. 245. Gonzalez CL, Medeiros LJ, Braziel RM, Jaffe ES. T-cell lymphoma involving subcutaneous tissue. A clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg Pathol 1991; 15: 17–27. 246. Go RS, Wester SM. Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic anal- ysis of 156 patients reported in the literature. Cancer 2004; 101: 1404–13. 247. Salhany KE, Macon WR, Choi JK, et al. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/ beta and gamma/delta subtypes. Am J Surg Pathol 1998; 22: 881–93. 248. Toro JR, Liewehr DJ, Pabby N, et al. Gamma-delta T-cell phenotype is associated with signifi cantly decreased survival in cutaneous T-cell lymphoma. Blood 2003; 101: 3407–12. Introduction Defi nitions Chronic lymphocytic leukemia (CLL) is a hemato- logic neoplasm of unknown etiology with a clinical course that is measured in years rather than in the weeks that used to characterize the clinical course of the acute leukemias. This distinction was made in the era before any effective therapy was available for the acute leukemias and rapid death was the usual outcome. As a result, the chronic leukemias were considered to be “favorable” diseases because of their longer prognosis. In young patients, advances in the treatment of the acute leukemias have been dra- matic, frequently resulting in cure, and as a result the chronic leukemias are no longer considered so “favo- rable.” In older patients, progress in treating the acute leukemias has been much more modest, and as a rule the prognosis of the chronic leukemias, particularly that of CLL, remains relatively favorable. The broad categories of the chronic leukemias that are encoun- tered in the older person are listed in Table 24.1. The older person is not so readily defi ned, because the concept of age is to many people, including physicians, highly subjective. A wry defi nition of “elderly” is “anyone signifi cantly older than the observer,” and psychologically there is much truth in this. From the viewpoint of the hematologist who treats leukemia by conventional means, the age of 70 years may be taken as the beginning of the older person’s estate. A physician who treats by bone- marrow transplantation might draw the boundary at 60, or even 55, years. Chronic lymphocytic leukemia in the elderly Alexander S. D. Spiers Signifi cance of older age in managing CLL Older age has a signifi cant impact on the manage- ment of most hematologic malignancies [1]. Its most obvious effect in the clinical situation is its strong association with the presence of multiple medical problems. Although disease should never be considered as an inevitable consequence of older age, the fact remains that as years accumulate, so do metabolic, degenerative, and neoplastic disorders, all of which may have a profound infl uence on the care of the patient when CLL must be managed. The most important medical conditions that affect the hematologist’s approach to the older person with CLL are listed in Table 24.2. Of almost equal importance is a physiologic change that inevitably accompanies aging: a reduced functional reserve capacity that affects all organ Table 24.1. Chronic leukemias that are encountered in the older person. Chronic lymphoid leukemias B-cell chronic lymphocytic leukemia (B-CLL) B-cell prolymphocytic leukemia (B-PLL) B-cell hairy-cell leukemia (B-HCL) B-cell lymphomas with blood involvement T-cell variants of the above disorders (uncommon) Chronic myeloid leukemias Chronic granulocytic leukemia (CGL) Atypical myeloproliferative syndrome Chronic myelomonocytic leukemia (CMML) Rarer subvarieties of chronic myeloid neoplasia 342 24 Blood Disorders in the Elderly, ed. Lodovico Balducci, William Ershler, Giovanni de Gaetano. Published by Cambridge University Press. © Cambridge University Press 2008. Chronic lymphocytic leukemia 343 systems. As a result of this natural and universal phe- nomenon, the healthy 80-year-old who looks twenty years younger is, in fact, much more frail than a gen- uine 60-year-old, and when subjected to stress may develop failure of one, and then multiple, organs in a fashion that would not occur in a younger per- son. Because of this major, though clinically occult, impairment in the elderly, certain types of therapy are fraught with risk (e.g., intensive chemotherapy) or may even be precluded (e.g., allogeneic bone- marrow transplantation). In the older person with signifi cant other disease, the prognosis of CLL may exceed the life expectancy of the patient, and thus be of small importance, whereas a healthy 50-year-old with CLL will die from the disease unless it is cured, for example by bone- marrow transplantation. By contrast, in an elderly patient with severe coronary artery disease, the discovery of low-stage CLL has virtually no impact on life expectancy and there is no necessity to even treat the disease, let alone cure it. The reduced life expectancy that is an inevitable accompaniment of aging should not however be exaggerated. For exam- ple, a healthy woman of 75 has a life expectancy of 12 years; the diagnosis at age 75 of stage II CLL, with a prognosis of approximately seven years, therefore is not an unimportant event. There are numerous subvarieties of chronic lym- phoid leukemia and also several related disorders (Table 24.3), but the T-cell varieties are all so uncom- mon as to be of lesser importance clinically. Of the B-cell leukemias, chronic lymphocytic leukemia (B-CLL or simply CLL) is by far the most frequent and the most important. For many years a relatively neglected disease, CLL has in the last decade been the focus of much impor- tant research that has increased our understanding of its biology and signifi cantly improved its manage- ment, to the benefi t of many older patients. Terminology and classifi cation The terminology outlined in Table 24.3 is widely accepted, although some variations are encountered. Table 24.2. Concurrent medical problems that affect the management of chronic leukemia in the older person. Problem Consequences Intellectual Problems with adherence to impairment treatment Chronic lung Mortality from intercurrent disease infection; problems with some cytotoxic drugs Hypertension Cerebral hemorrhage when thrombocytopenic Angina Poor tolerance of anemia Cardiac failure Poor tolerance of transfusion, and of some drugs – e.g., anthracyclines Atherosclerosis Poor tolerance of anemia and leukocytosis Arthritis Medications promote GI hemorrhage Diabetes mellitus Exacerbations with corticosteroid therapy Liver disease Altered drug metabolism Diverticulosis Infection, perforation, sepsis Renal impairment Poor tolerance of hyperuricemia; problems with antibiotic therapy Uterine prolapse Urinary tract infections Prostatomegaly Urinary tract infections Incontinence Decubitus ulcers Other primary Multiple problems, depending cancers on site This list is not exhaustive. Consideration must also be given to the psychological, social, environmental, and often pressing economic problems that have a profound impact on the practice of geriatric oncology. Table 24.3. Chronic lymphoid leukemias and related disorders. B-cell chronic lymphocytic leukemia (B-CLL) B-cell prolymphocytic leukemia (B-PLL) B-cell hairy-cell leukemia (B-HCL) B-cell non-Hodgkin lymphomas with blood involvement Small cleaved cell Lymphoplasmacytic T-cell variants of the above disorders (uncommon) Unique T-cell disorders Sézary syndrome Adult T-cell leukemia/lymphoma (ATLL) Large granular lymphocytic (LGL) leukemia 344 Alexander S. D. Spiers The nomenclature of the chronic lymphoid leuke- mias was until recently based mainly on morpho- logic considerations; descriptions of cells as “mature” or “differentiated” were based on their appearance. The ability to characterize cells by surface mark- ers, antigenic determinants that are located on the cell membrane, led to major conceptual changes, the fi rst and most fundamental of which was the recognition of T and B cells. With the advent of automated fl ow cytometry and the ability to study the surface markers of thousands of cells in every patient, subtle differences that are undetectable by morphologic methods alone are continually emerg- ing. For example, the cells of B-CLL, despite their mature appearance, turn out to be more primitive than previously suspected. With the widespread application of fl ow cytometry, more accurate diag- noses of lymphoid neoplasms are now made, and ongoing revisions of current terminology can be anticipated. It remains to be seen to what extent these fi ne distinctions will be clinically important in selecting the most appropriate management for each patient. Features of CLL CLL is characterized by an absolute lymphocytosis in the bone marrow and peripheral blood. Cell pro- liferation is usually slow, but there is a remorselessly progressive accumulation of monoclonal, long- lived, mature-appearing B lymphocytes that are immunoincompetent and indeed produce immu- nosuppression. Whereas many other clinical fea- tures are regularly encountered in CLL, for example lymphadenopathy, splenomegaly, hepatomegaly, hematopoietic failure, hypogammaglobulinemia, and autoimmune phenomena, none is constant or essential to the diagnosis. Epidemiology CLL is the leukemia par excellence of the older person. It is rarely seen in patients aged less than 40 years, and its incidence increases steadily with advancing age, apparently without limit as it con- tinues to rise in the ninth and tenth decades of life. The incidence of CLL increases 350-fold when ages 25 to 29 are compared with ages 80 to 84 [2]. A high incidence of CLL (approximately one-third of all new cases of leukemia) combines with a lengthy survival to produce a high prevalence of the condi- tion: CLL comprises approximately half of all cases of leukemia in Western populations. It is safe to say that almost every geriatric practice or long-term care facility will have one or more patients with CLL, and physicians in every medical specialty will regu- larly encounter patients with this important disease. There is a male predominance that appears to have decreased with time; early in the twentieth century the male-to-female ratios for CLL in Western coun- tries ranged from 2.5 to 3.0, whereas in more recent studies they are between 1.6 and 1.9. There are rare families that show clustering of cases of CLL, some- times in association with cases of lymphoma or of immunologic diseases. Geographic and ethnic vari- ation in incidence is greater for CLL than for any other type of leukemia [3]. The highest incidences of CLL are observed in whites in North America and in Europe. Lower rates are reported from South America and the Caribbean, and exceptionally low rates are found in India, Japan, China, and other areas of Asia, where B-CLL is a truly rare disease. This fi nding persists when adjustment is made for the lower average age of the population in some Asian countries. The reason for these fascinating variations that are peculiar to CLL is unknown. The geriatric oncologist who practices in North America or Europe is in an area where the incidence of CLL is already very high, and continues to increase as the average age of the population increases. Symptoms More than any other leukemia, CLL is apt to be diagnosed when it is still asymptomatic. A common scenario is the senior citizen who requires a surgical procedure for one of the conditions that are frequent in older age, for example inguinal hernia, uterine prolapse, or prostatomegaly. A routine preoperative Chronic lymphocytic leukemia 345 blood count shows a marked absolute lymphocyto- sis, a follow-up bone-marrow examination shows infi ltration with mature-appearing lymphocytes, and fl ow cytometry shows the circulating lymphocytes to be positive for surface membrane immunoglobulin (sIg) and the CD5 and CD21 antigens, fi ndings typi- cal for B-CLL. At one time, establishing the diagnosis of CLL would have led to the immediate cancella- tion of surgery, which might have been appropriate if acute leukemia had been diagnosed, but would be quite unnecessary for most patients with asympto- matic CLL. It is now widely recognized that the diag- nosis of uncomplicated CLL does not preclude the provision of necessary surgery or other treatment, and indeed may not alter the patient’s lifestyle or longevity in any way. Even open heart surgery can be successfully performed in elderly patients with CLL, although special attention must be paid to the high risk of serious infections [4]. Because routine physical examinations and blood tests in the absence of symptoms are becoming a reg- ular feature of modern health care, increasing num- bers of patients are being diagnosed with early CLL. Furthermore, fl ow cytometry has conferred the abil- ity to diagnose CLL at a particularly early stage, when an absolute lymphocytosis has not become estab- lished, but a monoclonal lymphocytosis is unequivo- cally demonstrable. As a result of these advances, the survival of patients with CLL is likely to increase sig- nifi cantly, but it should be remembered that much of this “improvement” will be factitious and due to the statistical phenomenon of lead time bias – i.e. longer survival that is due solely to earlier diagnosis. Some patients with CLL present with symptoms that are frequently associated with malignancy and with immunodefi ciency disorders: malaise, weakness, night sweats, fever without apparent infection, and weight loss. Such constitutional symptoms are less frequent in CLL than they are in Hodgkin disease. Other patients with CLL may present with symp- toms of anemia: loss of energy, fatigue, dyspnea, anorexia, weight loss, and pallor. In the older person with cardiac disease or peripheral vascular disease, the symptoms of anemia may be angina, cardiac failure, or intermittent claudication. In an elderly patient with CLL, the anemia may be exacerbated by – or be entirely due to – intercurrent unrelated problems, for example gastrointestinal bleeding or a defi ciency of vitamin B 12 or folate. Such problems should be excluded before anemia is attributed to the leukemia itself, otherwise the disease may be erroneously upstaged. A less frequent presentation of CLL is with symp- toms attributable to thrombocytopenia: bruising, purpura, or hemorrhage. Presentation with infec- tion is more common; patients with CLL are prone to infection by reason of hypogammaglobulinemia, decreased T-cell function, neutropenia, or combi- nations of these defects. Respiratory tract infection, particularly bronchitis and bronchopneumonia, may be the precipitating problem that leads to the diagnosis of CLL. Some patients present with the symptoms of one of the autoimmune disorders that are frequent in patients with CLL: immune throm- bocytopenic purpura, autoimmune hemolytic ane- mia, or connective tissue disease. Some patients with CLL initially present with sym- ptoms that are due to organomegaly. Lymphadeno- pathy in the neck, axilla, or groin may become quite severe before it is symptomatic. In CLL, splenomegaly is less frequent and usually much less marked than it is in chronic granulocytic leukemia, and sympto- matic enlargement of the spleen is rarely a cause of initial presentation. Similarly, splenic infarction is rare in CLL. Although leukocytosis greater than 200 ϫ 10 9 /L is not rare in untreated CLL, it is almost never sympto- matic. Hyperviscosity of the blood and leukostatic lesions in the lungs and brain, frequent in acute myeloid leukemia (AML) with a high blast cell count, have been reported in CLL [5] but are very rare, even when the leukocyte count exceeds one million per microliter. This is because the lymphocyte of CLL, unlike the myeloblast, is small, readily deformable, relatively nonadherent, and does not invade blood vessel walls. Thus emergency treatment for hyper- leukocytosis is rarely required in CLL, and the height of the leukocyte count per se is seldom an indication for treatment. Most patients, and not a few physi- cians, are diffi cult to convince that this is so. 346 Alexander S. D. Spiers Physical signs The patient with CLL may not only be asymptomatic but also may have no physical signs that are referable to the disease. When abnormal fi ndings are present, pallor and lymphadenopathy are the most frequent. Lymphadenopathy may be found in a single area or in multiple lymph-node fi elds. The nodes are typically soft, mobile, non-tender, and not matted together, and generally they are small, in the 1–2 cm range. Massive lymphadenopathy, with a bull neck or a severely distorted axilla, occurs but is uncom- mon. Lymphedema is rarely associated with the lym- phadenopathy of CLL. Clinically, the enlarged lymph nodes of CLL are quite different from the hard, adherent nodes that characterize involvement by carcinoma. Splenomegaly is frequently absent, and when present is rarely massive; splenic enlargement that extends below the umbilicus or across the midline is more suggestive of chronic granulocytic leukemia, prolymphocytic leukemia (PLL), or hairy- cell leukemia. Hepatomegaly, if present at diagnosis, is usually mild. Bruises and purpura are not frequent features of newly diagnosed CLL, but both conditions may be observed in the older person in the absence of any hematologic disease, as a consequence of decreased elasticity of the skin. Cutaneous infi ltrates may occur in B-CLL but are more frequent in the rare T-cell variant of the disease. Lesions of herpes zoster are not uncommon in CLL and are sometimes a presenting feature. Presentation with meningeal involvement [6] or with neurologic problems sugges- tive of progressive multifocal leukoencephalopathy [7] is rare but important to bear in mind, particularly in the older patient in whom central nervous system disorders of divers etiology are relatively frequent. Laboratory fi ndings CLL is characterized by an absolute and sustained lymphocytosis in the peripheral blood, with pre- dominantly mature-appearing lymphocytes, although some atypical forms can be detected in most cases and in a few instances 50% or more of the cells possess atypical morphologic features (Fig. 24.1). There is an accompanying lymphocyto- sis in the bone marrow but evidence of bone- marrow failure – anemia, neutropenia, or thrombocytopenia – is frequently absent. A Working Group sponsored by the National Cancer Institute has further specifi ed typical cases of B-CLL that can be considered for protocol stud- ies [8]. Marker studies should show sIgϩ, CD19ϩ, CD20ϩ, or CD24ϩ. The cells must be CD5ϩ but negative for other pan-T markers, express either kappa or lambda light chains, and sIg must be present at low density. The minimum threshold for blood lymphocytes is 5 ϫ 10 9 /L and the blood lym- phocytosis must be sustained over a period of at least four weeks upon repeated examinations. The lymphocytes must appear mature and no more than 55% may be atypical prolymphocytes or lymphob- lasts. Patients with 11–55% prolymphocytes – thus resembling PLL – should be considered for special studies because the prognostic signifi cance of their high incidence of cellular atypia is not well defi ned (Figs. 24.2, 24.3). The bone-marrow aspirate must contain у30% lymphoid cells. The bone-marrow biopsy may show diffuse or nodular lymphocytic infi ltration and the marrow must be normocellular or hypercellular. Figure 24.1 This peripheral smear shows that there can be heterogeneity in the appearance of the abnormal lymphocytes in CLL. Kadin, M., ASH Image Bank 2003: 100690. Copyright American Society of Hematology. All rights reserved. See color plate section. Chronic lymphocytic leukemia 347 The above specifi cation is not universally accepted. Some hematologists will diagnose CLL when the lymphocytosis is less than 5 ϫ 10 9 /L if a B-cell monoclone with the appropriate surface markers is demonstrable. While such cases may indeed have CLL at an early stage, their inclusion in clinical stud- ies may affect survival data by the mechanism of lead time bias referred to earlier. Cytogenetic fi ndings in CLL This topic has been reviewed in depth [9], and only a few salient features will be considered here. Most types of chromosomal analysis require divid- ing cells that are in metaphase. Whereas this is no great problem in the acute leukemias or in chronic granulocytic leukemia (CGL), it is a major obstacle in CLL, since the tumor cells have a very low mitotic index and must be activated in vitro with mitogens that are effective for B cells (e.g., Escherichia coli lipopolysaccharide, Epstein–Barr virus). Cells from some patients with CLL do not respond to mitogens and evaluable metaphases cannot be obtained; in general it is not known if such unresponsive cells harbor any chromosomal anomalies. In some cases, fl uorescent stains for specifi c chromosomes can be applied to interphase cells and may demonstrate numerical abnormalities – e.g., trisomies. Cytogenetic techniques in CLL cells have shown two major chromosomal abnormalities with a prob- able pathogenetic role: trisomy 12 and deletions of the long arm of chromosome 13 (13q14). No rel- evant gene on chromosome 12, and no pathogenetic mechanism by which the occurrence of trisomy 12 may lead to the development of CLL, has been documented. Terminal deletions of the long arm of chromosomes 6 and 11 might also be signifi cant in CLL. Additional material on the long arm of chro- mosome 14 (14qϩ) to form a marker chromosome is a common additional abnormality that does not appear to be of prognostic signifi cance. Trisomy 12 has been associated with a poor survival, whereas 13q deletions or a normal karyotype indicate a good prognosis. Complex abnormal karyotypes in the CLL cells are more commonly found at diagnosis than developing during the course of the disease, and are adverse prognostic signs. A large Danish study of 480 unselected newly diagnosed patients has produced new cytogenetic data in CLL and correlated them with immunophe- notypic studies [10]. Of note, 25% of patients were considered to have an atypical immunophenotype. In patients with a typical CLL immunophenotype, chromosomal abnormalities were found in 22%, but Figure 24.2 This mixed-cell variant of CLL contains a dimorphic population of cells. Kadin, M., ASH Image Bank 2003: 100935. Copyright American Society of Hematology. All rights reserved. See color plate section. Figure 24.3 PLL variant of CLL: prominent nuclei characterize the prolymphocytes. Kadin, M., ASH Image Bank 2003: 100935. Copyright American Society of Hematology. All rights reserved. See color plate section. [...]... arabinosyl-2fluoroadenine [73,74] It is actively taken up by cells and phosphorylated to its 5Ј-triphosphate, F-ara-ATP , which is the active form of the drug F-ara-ATP inhibits DNA synthesis by competing with deoxy-ATP for incorporation into DNA, and also by inhibiting ribonucleotide reductase F-ara-ATP is also incorporated into RNA and is an inhibitor of DNA repair The major toxicity of fludarabine... (FLU)-Prednisone (PRED): a safe, effective combination 367 3 68 Alexander S D Spiers 82 83 84 85 86 87 88 89 90 91 92 in refractory chronic lymphocytic leukemia Proc Am Soc Clin Oncol 1 989 ; 8: 201 (abstract) Keating MJ, O’Brien S, Lerner S, et al Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy Blood 19 98; 92: 1165–71 French Cooperative Group... reappraised? Is there a place for maintenance therapy with fludarabine? Is there an optimal combination – and sequencing – for administering fludarabine and an alkylating agent as combined therapy? The National Cancer Institute has sponsored revised guidelines for diagnosis and treatment of CLL [90], and further revisions are to be expected Cladribine The purine analog cladribine (2-chlorodeoxyadenosine) has... the clinical responses were minor in degree and usually transient, so this did not appear to be an effective treatment A logical extension of MoAb therapy was to give the antibodies a warhead by conjugating them with immunotoxins before their administration Studies have been carried out with single-chain immunotoxins – usually the A chain of ricin – and with two-chain immunotoxins consisting of ricin... tyrosine kinase JAK2 [9] JAK2 is the cognate tyrosine kinase for the erythropoietin receptor, the thrombopoietin receptor, Mpl, and the granulocyte colony-stimulating factor receptor In over 90% of polycythemia vera patients and approximately 40% of idiopathic myelofibrosis and essential thrombocytosis patients, a point mutation in the autoinhibitory pseudokinase domain of the JAK2 gene (V617F) results in. .. corticosteroid therapy A suggested mechanism for AIHA in this setting is the severe suppression of T cells that is induced by fludarabine; the inhibition of autoregulatory suppressor cells that maintain tolerance may trigger autoimmune hemolysis [96– 98] Since fludarabine antagonizes adenosine deaminase, there is accumulation of deoxyadenosine in erythrocytes during treatment with fludarabine; this damages the cells... chains but with the nonspecific galactose-binding sites of ricin blocked These compounds have shown major activity against CLL cells in vitro, but clinical experience Chronic lymphocytic leukemia thus far is limited and responses have been relatively minor Clinical studies are in progress with a fusion protein that has been produced by recombinant DNA technology, in which the receptor-binding domain... treatment there was severe suppression of both CD4ϩ and CD8ϩ T lymphocytes in the blood, and recovery towards normal levels was slow, but despite this the incidence of infections was low for patients in remission Richter’s syndrome occurred in nine patients, and eight of these died These results indicate that fludarabine is a potent regimen for initial induction therapy in previously untreated CLL, and the. .. combination of the two drugs was not superior to fludarabine alone and was more toxic, leading to the closure of that arm of the study [87 ] In Germany the combination of fludarabine with epirubicin was studied in 44 patients; of the 38 patients who were evaluable for response, 25 were previously untreated [88 ] For the whole group the overall response rate was 82 %, with 32% complete remissions; for the untreated... 1 987 ; 59: 181 5– 18 71 Binet JL, Catovsky D, Dighiero G, et al Chronic lymphocytic leukemia: recommendations for diagnosis, staging and response criteria Ann Intern Med 1 989 ; 110: 236 8 72 Frederickson S Specificity of adenosine deaminase toward adenosine and 2Ј-deoxyadenosine analogues Arch Biochem Biophys 1966; 113: 383 73 Malspeis L, Grever MR, Staubus AE, et al Pharmacokinetics of 2-F-ara-A (9-beta-D-arabinofuranosyl 2- uoroadenine) . by the International Workshop on CLL [39]; they differ from the Rai sys- tem in detail but not in principle and they produce similar clinical results. In North America the Rai sys- tem is the. arabinosyl- 2- fl uoroadenine [73,74]. It is actively taken up by cells and phosphorylated to its 5 Ј -triphosphate, F-ara-ATP, which is the active form of the drug. F-ara-ATP inhib- its DNA synthesis. B-cell chronic lymphocytic leukemia (B-CLL) B-cell prolymphocytic leukemia (B-PLL) B-cell hairy-cell leukemia (B-HCL) B-cell lymphomas with blood involvement T-cell variants of the above disorders