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NCI CANCERLIT® Search: Chronic Lymphocytic Leukemia - September 2001
Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 21319821
AU - Robak T
TI - Cladribine in the treatment of chronic lymphocytic leukemia.
SO - Leuk Lymphoma 2001 Feb;40(5-6):551-64
AD - Department of Hematology, Medical University of Lodz, Copernicus Hospital, Poland. robaktad@psk2.am.lodz.pl
Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a nucleoside analog with substituted halogen atom at position 2 in its purine ring that makes it resistant to deamination by adenosine deaminase (ADA). 2-CdA is the drug of choice in the treatment of hairy cell leukemia, but it is also highly active in other low grade lymphoid malignancies including chronic lymphocytic leukemia (CLL). The results of the studies presented so far have shown that 2-CdA gives similar complete response (CR) rate and overall response (OR) rate to fludarabine but the influence of both agents on survival times of the patients with CLL is still uncertain. CR rate induced with 2-CdA is significantly higher than in the patients treated with conventional chemotherapy. In refractory or relapsed patients 2-CdA induces 31 to 68% of overall responses including CR in 4 to 31%. In previously untreated patients overall remission rates of about 56-82% have been achieved with 2-CdA alone. When 2-CdA was used as primary therapy the CR rate was also significantly higher and ranged from 10% to 47%. Patients who received 2-CdA as their initial therapy and experienced a response lasting at least a year may be successfully treated subsequently with the same agent. A second response has been achieved in 35 to 100% patients treated with this agent for the second time. Despite the fact that 2-CdA gives higher CR and OR rates than conventional chemotherapy, it has not been established whether it has any influence on survival time. However, cross resistance between 2-CdA and FAMP in CLL patients is evident in the majority of studies. Bone marrow suppression with anemia neutropenia and thrombocytopenia are the dose limiting factors for 2-CdA use. These side effects are pronounced in heavily pretreated patients and after multiple courses of therapy. Treatment with this agent also leads to the decrease of the CD4+/CD8+ ratio for an extensive period of time exceeding 12, even up to 24 months. In consequence, infections including opportunistic type, are frequently observed. We suggest, that in patients with CLL, 2-CdA should be used as second line treatment rather than the first line therapy until the final results of ongoing randomized clinical trials are available.

2
UI - 21261637
AU - Amiel A; Elis A; Sherker S; Gaber E; Manor Y; Fejgin MD
TI - The influence of cytogenetic aberrations on gene replication in chronic lymphocytic leukemia patients.
SO - Cancer Genet Cytogenet 2001 Mar;125(2):81-6
AD - Genetic Institute and the Department of Medicine, Meir Hospital and Sackler Faculty of Medicine, Tel Aviv University, Kfar-Saba 44281, Tel Aviv, Israel.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in humans, with the major cytogenetic aberrations of trisomy 12 and deletion of 13q14. This study examined the influence of these aberrations on general gene replication. The study group included three subgroups: (1) 15 CLL patients, (2) 4 CLL patients with trisomy 12, (3) 3 CLL patients with deletions in 13q14. Five healthy individuals served as a control group. Monocolor fluorescence in situ hybridization (FISH) with probes for c-myc, HER-2/neu, and p53 was applied to lymphocyte nuclei for the evaluation of replication timing. Asynchronous replication (SD) rate was significantly higher in all CLL patients (P < 0.01) when compared to the control group and was even higher in the group of CLL patients with trisomy 12 and 13q14 deletion (P < 0.01). The asynchrony rate was significantly higher in cells with trisomy 12 for all three probes analyzed, compared to "healthy" cells in the same patients (P < 0.001). To conclude, in CLL patients with a chromosomal aberration such as trisomy 12 and 13q14 deletion we were able to demonstrate a high rate of asynchrony of replication. The high correlation between cells with trisomy 12 and SD pattern could reflect direct influence of the aberration on gene replication and cell cycle control.

3
UI - 21320256
AU - Rivollier C; Vaillant L; Machet MC; Martin L; Jan V; Huttenberger B; Joly P; Lorette G
TI - [Paraneoplastic pemphigus: a pustular form during chronic lymphoid leukemia]
SO - Ann Dermatol Venereol 2001 May;128(5):644-8
AD - Service de Dermatologie, CHU Trousseau, 37044 Tours Cedex.
BACKGROUND: Paraneoplastic pemphigus is an autoimmune disease of the skin and mucosa described in 1990. The condition is generally associated with lymphoma or chronic lymphoid leukemia. Lesions are often misleading, masquerading as polymorphous erythema or lichen. We report a case of paraneoplastic pemphigus with pustulous skin lesions. CASE REPORT: A 52-year-old man developed over a few weeks time erosive lesions of the oral cavity and lips associated with papulous skin lesions. Secondarily, large-sized pustules, sometimes a hypopion, were observed associated with bullae. The diagnosis of paraneoplastic pemphigus was confirmed by direct immunofluorescence that evidenced IgG deposits within the keratinocytes and along the basal membrane and by indirect immunofluorescence on rat bladder that evidenced circulating antibodies. This paraneoplastic pemphigus was the inaugural sign of chronic lymphoid leukemia. DISCUSSION: Skin lesions described in paraneoplastic pemphigus include: erosion, vesicles, bullae, and psoriasiform, lichen-like, plate-like or vegetative formations. To our knowledge, this is the first report of a pustulous form; clinically similar to Hallopeau pustulous pemphigus.

4
UI - 21347117
AU - Marzano AV; Grammatica A; Cozzani E; Terracina M; Berti E
TI - Paraneoplastic pemphigus. A report of two cases associated with chronic B-cell lymphocytic leukaemia.
SO - Br J Dermatol 2001 Jul;145(1):127-31
AD - Institute of Dermatological Sciences, University of Milan, IRCCS Ospedale Maggiore of Milan, Via Pace 9, 20122 Milan, Italy.
Paraneoplastic pemphigus (PNP) is an autoimmune blistering and erosive mucocutaneous disease associated with neoplasia. Clinical manifestations are polymorphous, and include erythema, bullae, erythema multiforme-like lesions and severe mucous membrane involvement. PNP manifesting as lichenoid dermatitis has recently been observed. We describe two Italian men with fatal PNP featuring typical PNP autoantigens associated with chronic B-cell lymphocytic leukaemia. The first patient presented with an extensive blistering eruption, several erythema multiforme-like lesions and severe mucosal involvement. The second patient presented with a lichenoid dermatitis, then developed bullae, and died with an erythrodermic and exfoliative dermatosis resembling pemphigus foliaceus. Our patients represent two Italian cases of well-documented PNP. In patient 2, the sequence of clinical presentations was unique, and strongly supports the hypothesis of epitope spreading through chronic lichenoid inflammation of the dermo-epidermal junction exposing new self antigens, leading to the humoral response characteristic of PNP.

5
UI - 21396211
AU - Morrison VA; Rai KR; Peterson BL; Kolitz JE; Elias L; Appelbaum FR; Hines JD; Shepherd L; Martell RE; Larson RA; Schiffer CA
TI - Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.
SO - J Clin Oncol 2001 Aug 15;19(16):3611-21
AD - Section of Hematology/Oncology and Infectious Disease, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. morri002@tc.umn.edu
PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.

6
UI - 21406912
AU - van Besien K; Keralavarma B; Devine S; Stock W
TI - Allogeneic and autologous transplantation for chronic lymphocytic leukemia.
SO - Leukemia 2001 Sep;15(9):1317-25
AD - University of Illinois at Chicago, USA.
Autologous and allogeneic transplantation are increasingly used in the management of patients with chronic lymphocytic leukemia. Many questions regarding patient selection, efficacy and outcome are unresolved, hence a review of the literature through Medline search. Autologous transplantation for CLL has been used mainly in selected patients under the age of 60. Conditioning typically involves total body irradiation (TBI). Bone marrow and more recently peripheral blood stem cells are used. Treatment-related mortality in most series is less than 10%. Molecular remissions after autologous transplantation are common, and clinical remissions can be prolonged in some patients. Randomized studies are needed to establish whether autologous transplantation confers a survival benefit over standard chemotherapy approaches. Allogeneic transplantation has a considerable treatment-related mortality, but durable remissions sometimes occur in patients with advanced disease. The use of non-myeloablative 'mini-transplants' has been investigated as a method to reduce treatment-related mortality, but prolonged follow-up will be required to establish the cure rate obtained with this procedure. Autologous and allogeneic transplantation are promising treatment modalities. Further refinements of transplant techniques and properly designed prospective studies are necessary to establish the role of stem cell transplantation in the overall management of CLL.

7
UI - 21406920
AU - Almond JB; Snowden RT; Hunter A; Dinsdale D; Cain K; Cohen GM
TI - Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex.
SO - Leukemia 2001 Sep;15(9):1388-97
AD - MRC Toxicology Unit, University of Leicester, UK.
Proteasome inhibitors, including lactacystin and MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal), potently induce apoptosis in leukaemic B cells from patients with B cell chronic lymphocytic leukaemia (B-CLL). This pro-apoptotic effect occurs in cells from patients at all stages of the disease, including those resistant to conventional chemotherapy, suggesting that proteasome inhibitors may be useful for treatment of B-CLL. Following initial inhibition of proteasomal activity, these agents induce mitochondrial cytochrome c release and caspase-dependent apoptosis, involving cleavage/activation of caspases -2, -3, -7, -8 and -9. Pre-treatment with the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe)fluoromethyl ketone (Z-VAD.fmk), did not prevent the release of cytochrome c or partial processing of caspase-9 but prevented activation of effector caspases and the induction of apoptosis. These results suggest that the release of cytochrome c is caspase independent and that caspase-9 is the initiator caspase in proteasome inhibitor-induced apoptosis of B-CLL cells. Activation of B-CLL lysates with dATP results in the formation of an approximately 700 kDa caspase-activating apoptosome complex containing Apaf-1. We describe for the first time the formation of a similar approximately 700 kDa caspase-activating apoptosome complex in B-CLL cells induced to undergo apoptosis by proteasome inhibitors.

8
UI - 21411567
AU - Yagci M; Sucak GT; Ogur G; Haznedar R
TI - Therapy-related refractory anemia with ringed sideroblasts in chronic lymphocytic leukemia. involvement of 3q21 region.
SO - Cancer Genet Cytogenet 2001 Aug;129(1):43-6
AD - Department of Hematology, Gazi University Medical School, Oyak sitesi 21, Cankaya Ankara, Turkey. erhem@med.gazi.edu.tr
Therapy-related myelodysplastic syndrome/acute myelogenous leukemia (t-MDS/AML) is extremely rare in chronic lymphocytic leukemia (CLL) despite extensive use of alkylating agents. We present a case of heavily treated CLL with resultant therapy-related refractory anemia with ringed sideroblasts (RARS). A complex cytogenetic abnormality including involvement of 3q21 was detected and to our knowledge, is the first report of a RARS case with a 3q21 abnormality.

9
UI - 21265637
AU - Wendtner CM; Schmitt B; Bergmann M; Rohnisch T; Buhmann R; Hallek M
TI - New aspects on the pathogenesis, diagnostic procedures, and therapeutic management of chronic lymphocytic leukemia.
SO - Int J Hematol 2001 Jan;73(1):32-8
AD - Medizinische Klinik III, Ludwig-Maximilians-University of Munich, Germany.
Chronic lymphocytic leukemia of the B-cell type (B-CLL) is the most frequently occurring leukemia in the Western hemisphere. Until 10 years ago, the basic medical approach to this disease was expectative and palliative. Chemotherapy with alkylating agents such as chlorambucil used to be the main therapeutic option, and only patients at advanced stages of B-CLL were treated. With the advent of new treatments such as purine analogs, high-dose therapy followed by hematopoietic progenitor support, monoclonal antibodies, and further immunotherapies, this paradigm is about to change. By using these combinations, younger patients with active disease are now treated with the goal of a long-lasting remission. More sophisticated techniques allow characterization of some of the underlying molecular genetic aberrations and (together with new serum parameters) more accurate prediction of individual prognoses than with the clinical staging systems. With the help of these developments, patients with B-CLL will be managed according to their individual risk with a watch-and-wait strategy in patients with the most indolent form of the disease, conventional chemotherapy with alkylating agents and/or purine analogs in patients at intermediate risk, and aggressive high-dose chemotherapy (followed by immunotherapy) in patients with the most aggressive form of the disease.

10
UI - 21265627
AU - Miyata A; Kojima K; Yoshino T; Fujii S; Shinagawa K; Ichimura K
TI - Concurrent Hodgkin's disease (mixed cellularity type) and T-cell chronic lymphocytic leukemia/prolymphocytic leukemia.
SO - Int J Hematol 2001 Feb;73(2):230-5
AD - Department of Internal Medicine, Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers, Hiroshima, Japan. myatak@mint.ocn.ne.jp
We describe a patient with leukopenic T-cell chronic lymphocytic leukemia/prolymphocytic leukemia (T-CLL/PLL), according to the Revised European-American Classification of Lymphoid Neoplasms. This patient simultaneously developed classic Hodgkin's disease (HD), a combination previously unreported. The leukemic cells were small and mature, did not have cytoplasmic granulation, and appeared similar to B-cell chronic lymphocytic leukemia. Immunophenotyping of the bone marrow-infiltrating cells revealed a postthymic suppressor/cytotoxic phenotype of CD2+, CD3+, CD4, CD5+, CD8+, CD25-, TCR-alpha beta. A lymph node biopsy showed the histological features of HD (mixed cellularity) with infiltrating CD8+ lymphocytes, and immunohistochemical examination revealed the following phenotype of Reed-Sternberg cells: LeuM1/CD15+, BerH2/CD30+, L26/PanB-, UCHL-1/CD45RO-, cyCD3-, CD4, CD8-, CD20-, CD79a-, EMA-, EBER-1+, LMP-1+. Southern blot analysis of the bone marrow and lymph node revealed the same rearrangement of bands of T-cell-receptor genes. Although the HD was treated with chemotherapy that resulted in complete remission, the T-PLL/CLL took an indolent course. This case may suggest the existence of a subtype of T-CLL/PLL with leukopenia and an indolent clinical course. Both diseases were believed to be independent and not a transformation of one to the other.

11
UI - 21361183
AU - Pettitt AR; Sherrington PD; Stewart G; Cawley JC; Taylor AM; Stankovic T
TI - p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation.
SO - Blood 2001 Aug 1;98(3):814-22
AD - Department of Haematology, University of Liverpool, Liverpool L69 3GA, United Kingdom. andrew.pettitt@rlbuh-tr.nwest.nhs.uk
The well-established association between TP53 mutations and adverse clinical outcome in a range of human cancers reflects the importance of p53 protein in regulating tumor-cell growth and survival. Although it is theoretically possible for p53 dysfunction to arise through mechanisms that do not involve TP53 mutation, such a phenomenon has not previously been demonstrated in a sporadic tumor. Here, we show that p53 dysfunction in B-cell chronic lymphocytic leukemia (CLL) can occur in the absence of TP53 mutation and that such dysfunction is associated with mutation of the gene encoding ATM, a kinase implicated in p53 activation. Forty-three patients with CLL were examined for p53 dysfunction, as detected by impaired up-regulation of p53 and of the p53-dependent protein p21(CIP1/WAF1) after exposure to ionizing radiation (IR). Thirty (70%) patients had normal p53 responses and underwent progressive IR-induced apoptosis. In 13 (30%) patients, p21 up-regulation was markedly impaired, indicating p53 dysfunction. Six (14%) of these patients with p53 dysfunction had increased baseline levels of p53, were found to have TP53 mutations, and were completely resistant to IR-induced apoptosis. In the other 7 (16%) patients with p53 dysfunction, IR-induced p53 up-regulation and apoptosis were markedly impaired, but baseline levels of p53 were not increased, and no TP53 mutations were detected. Each of these patients was found to have at least one ATM mutation, and a variable reduction in ATM protein was detected in all 4 patients examined. This is the first study to provide a direct demonstration that p53 dysfunction can arise in a sporadic tumor by a mechanism that does not involve TP53 mutation. (Blood. 2001;98:814-822)

12
UI - 21339573
AU - Vaisban E; Zaina A; Braester A; Manaster J; Horn Y
TI - Acute tumor lysis syndrome induced by high-dose corticosteroids in a patient with chronic lymphatic leukemia.
SO - Ann Hematol 2001 May;80(5):314-5
AD - Department of Internal Medicine, A, Western Galilee Hospital, Naharyia, Israel.
Acute tumor lysis syndrome (TLS) has been reported in hematological malignancies, such as aggressive non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and rarely, in other malignancies (solid tumors) in association with the administration of cytotoxic therapy. We report a case of a patient with chronic lymphatic leukemia (CLL) who developed autoimmune hemolytic anemia treated by high dose corticosteroids and, following this treatment, developed acute tumor lysis syndrome. Only one similar case has been reported recently. Clinicians should be aware that corticosteroids alone may produce this potentially life-threatening complication.

13
UI - 21340672
AU - Jarosova M; Jedlickova K; Holzerova M; Urbanova R; Papajik T; Raida L; Pikalova Z; Lakoma I; Prekopova I; Kropackova J; Indrak K
TI - Contribution of comparative genomic hybridization and fluorescence in situ hybridization to the detection of chromosomal abnormalities in B-cell chronic lymphocytic leukemia.
SO - Onkologie 2001 Feb;24(1):60-5
AD - Department of Hematology/Oncology, Palacky University Hospital, Olomouc (Czech Republic). marie.jarosova@fnol.cz
BACKGROUND: B-chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in Western Europe and the United States, is characterized by clonal chromosomal abnormalities detected in almost half of the studied patients. The precise determination of chromosomal changes helps to indicate the prognosis and to understand the pathogenesis of CLL. METHODS AND PATIENTS: We applied conventional cytogenetics (CC), FISH and comparative genomic hybridization (CGH) to the investigation of clonal abnormalities in 88 B-CLL patients at the time of diagnosis. RESULTS: By using CC of bone marrow cells without any stimulation, non-random chromosomal changes were found in 17 (19%) of 88 patients.The employment of FISH and CGH revealed chromosomal changes in additional 33 patients, thus increasing the detection rate of chromosomal abnormalities to 57%. The most common abnormalities detected in our patients included deletions of 13q in 16 cases (18%), followed by trisomy of chromosome 12 in 12 patients (13%), deletions of 11q in 10 patients (11%) and deletions of 17p in 10 patients (11%). A statistically significant correlation between higher disease activity and the presence of deletions 11q and 17p was observed. CONCLUSION: The addition of FISH and CGH to CC in 88 B-CLL patients improved the detection of clonal chromosomal changes from 19 to 57%. The most frequent chromosomal change was deletion of 13q14 (18%). Deletions of 11q23 and 17p13 were found in patients with higher clinical disease activity. Our results underline the importance of employing FISH and CGH techniques in CLL patients. CC without any stimulation has a low detection rate and is not suggested for detection of chromosomal changes in CLL. Copyright 2001 S. Karger GmbH, Freiburg

14
UI - 21362936
AU - Genevieve F; Delisle V; Gardembas M; Foussard C; Gardais J; Zandecki M
TI - [Chronic lymphoid hemopathies in adults: chronic lymphocytic leukaemia and the phase of dissemination of small cell lymphomas]
SO - Ann Biol Clin (Paris) 2001 Jul-Aug;59(4):403-15
AD - Laboratoire d'hematologie, Centre hospitalier universitaire d'Angers, 4, rue Larrey, 49033 Angers cedex 01.
Chronic lymphocytic leukaemia is the most frequent haematological cancer in adult patients, and its incidence raises with aging. Diagnosis needs several clinical and biological data, but hemogram together with the morphological and immunophenotypic analysis of the lymphoid cells take the major place. If the diagnosis is performed easily in about 65% of the patients, various clinicobiological entities were reported in the past few years that must be identified, at least because some are of adverse prognosis. Moreover, the other chronic lymphoid neoplasms, corresponding to the various low and intermediate grade non-Hodgkin's lymphomas (mainly of follicular type, marginal zone, mantle cell zone), may disseminate within the blood and the bone marrow. Those circulating lymphoma cells must be identified at diagnosis in order to perform the accurate diagnosis and to avoid an erroneous diagnosis of atypical chronic lymphocytic leukaemia. Up to 90% of lymphoid malignancies are B cell disorders, contrasting with only a few cases of T cell origin: some of those latter cases cannot be neglected however, as they may be observed in Western countries. Most recent classifications (REAL and WHO) defined all hematological malignancies: each entity referred to clinical, morphological, immunological, cytogenetic, and molecular findings. The basis of these classifications is pathophysiological, trying in each disorder to define a normal counterpart to the pathological clone. Reviewing main steps of the immune response in the normal patient, corresponding to those involving B cells, it is possible indeed to localize and demonstrate a function for many of the cells that expand in lymphoid malignancies.

15
UI - 21433627
AU - Molica S; Vitelli G; Levato D; Giannarelli D; Gandolfo GM
TI - Elevated serum levels of soluble CD44 can identify a subgroup of patients with early B-cell chronic lymphocytic leukemia who are at high risk of disease progression.
SO - Cancer 2001 Aug 15;92(4):713-9
AD - Divisione Ematologia e Oncologia Clinica, Azienda Ospedaliera Pugliese-Ciaccio, via Pio X, 88100 Catanzaro, Italy. smolica@libero.it
BACKGROUND: Although soluble CD44 (sCD44) is considered a reliable marker of both tumor burden and disease activity, to the authors' knowledge, its predictive and prognostic value in B-cell chronic lymphocytic leukemia (CLL) has not been addressed to date. METHODS: The authors studied 94 previously untreated CD5-positive B-cell CLL patients whose sera was taken at the time of diagnosis, stored at - 70 degrees C, and analyzed for the presence of standard sCD44 (sCD44(std)) using a commercial enzyme-linked-immunoadsorbent-assay. The impact of the sCD44 level on the clinical outcome of the disease was assessed in 74 patients with early CLL (61 Binet Stage A patients and 13 asymptomatic Stage B patients). Because the time to disease progression appears to predict the survival time of patients with CLL, it was used as a surrogate endpoint in the current study. RESULTS: Patients with higher than median sCD44 levels (i.e., 642 ng/mL) had a more advanced clinical disease stage (P = 0.04), higher peripheral blood lymphocytosis (P = 0.006), and increased circulating levels of either lactate dehydrogenase (P = 0.01) or beta(2)-microglobulin (P < 0.0001). In univariate analysis, seven of the nine parameters investigated predicted progression-free survival (PFS). In a stepwise multiple regression analysis, only 2 parameters provided independent prognostic information regarding PFS: Rai substages (0 vs. I-II) (P = 0.002) and serum sCD44 levels > 642 ng/mL (P = 0.01). When added to the classification of smoldering CLL versus nonsmoldering CLL, the sCD44 level distinguished two groups within the group of nonsmoldering Stage A patients; patients with a sCD44 level > 642 ng/mL had a median PFS of 36 months, whereas patients with a sCD44 level < 642 ng/mL experienced a longer PFS (median had not been reached at 8 years of follow-up). Furthermore, serum levels of sCD44 defined two different patterns of PFS within the group of patients with Rai disease Stages I-II (P = 0.01). CONCLUSIONS: An increased serum level of sCD44 can be considered to be a promising parameter for predicting the risk of disease progression in patients with early CLL. Furthermore, sCD44 helps to refine the prognostic stratification of patients with either nonsmoldering CLL or Rai Stage I-II disease, thus enabling the identification of different prognostic subgroups in patients with early CLL. Copyright 2001 American Cancer Society.

16
UI - 21260581
AU - Hamblin TJ
TI - Achieving optimal outcomes in chronic lymphocytic leukaemia.
SO - Drugs 2001;61(5):593-611
AD - Department of Haematology, Royal Bournemouth Hospital, England. terjoha@aol.com
Chronic lymphocytic leukaemia (CLL) is a disease of late middle age and older. The majority of patients are diagnosed because of a lymphocytosis of at least 5 x 10(9)/L on an incidental blood count. It needs to be distinguished from mantle cell lymphoma and splenic marginal zone lymphoma by lymphocyte markers. The immunophenotype of CLL is sparse surface immunoglobulin, CD5+, CD19+, CD23+, CD79b-, and FMC7-. The disease is staged according to the presence of lymphadenopathy and/or splenomegaly and the features of bone marrow suppression. Most patients have an early stage of disease when diagnosed and perhaps 50% will never progress. This group of patients have a normal life expectancy and do not require treatment beyond reassurance. Progression involves an increasing white cell count, enlarging lymph nodes and spleen, anaemia and thrombocytopenia. Complications of progression include autoimmune haemolytic anaemia and thrombocytopenia, immunodeficiency, and the development of a more aggressive lymphoma. A range of prognostic factors is available to predict progression, but most haematologists rely on close observation of the patient. Intermittent chlorambucil remains the first choice treatment for the majority of patients. Combination chemotherapy offers no advantage. Intravenous fludarabine is probably more effective than chlorambucil, but no trial has yet shown a survival advantage for using it first rather than as a salvage treatment in patients not responding to chlorambucil. It is at least 40 times as expensive as chlorambucil. Cladribine may be as effective as fludarabine, although it has been used less and is even more expensive. Patients who relapse after chlorambucil should be offered retreatment with the same agent and if refractory should be switched to fludarabine, which may also be offered for retreatment on relapse. For patients refractory to both drugs, a variety of options are available. High dose corticosteroids, high dose chlorambucil, CHOP (cyclophosphamide, prednisolone, vincristine and doxorubicin), anti-CD52, anti-CD20 and a range of experimental drugs which are being evaluated in clinical trials. Younger patients should be offered the chance of treatment with curative intent, preferably in the context of a clinical trial. Autologous stem cell transplantation after achieving a remission with fludarabine has relative safety and may produce molecular complete remissions. Only time will tell whether some of these patients are cured but it seems unlikely. Standard allogeneic bone marrow transplant is probably too hazardous for most patients, but non-myeloablative regimens hold out the hope of invoking a graft-versus-leukaemia effect without a high tumour-related mortality. Trials of immunotherapy are exciting options for a few patients in specialised centres.

17
UI - 21324125
AU - Andres E; Vinzio S; Maloisel F; Carre S; Perrin AE; Goichot B; Schlienger JL
TI - [Autoimmune peripheral neuropathies with anti-MAG antibodies and hematological disorders. Five cases]
SO - Ann Med Interne (Paris) 2001 Apr;152(3):147-51
AD - Services de Medecine Interne et Nutrition, Clinique Medicale B, Hopital, 67091 Strasbourg Cedex, France.
OBJECTIVE: The aim of this study was to report our experience with autoimmune neuropathies associated with hematological disorders and to describe their etiological and clinical polymorphism. PATIENTS AND METHODS: A retrospective study was conducted in five patients with autoimmune peripheral neuropathies with anti-MAG (myelin-associated glycoprotein) antibodies. RESULTS: Autoimmune neuropathies were associated with Waldenstrom's macroglobulinemia (n=2), Hodgkin disease (n=1), chronic lymphocytic leukemia (n=1) and idiopathic polyclonal B lymphoproliferation (n=1). Most of the patients had a sensorial polyneuropathy, predominant in the legs, exhibiting slow progress. Our patients showed a disappointing response to chemotherapy with stabilization or short response.

18
UI - 21421106
AU - Brito-Babapulle V; Baou M; Matutes E; Morilla R; Atkinson S; Catovsky D
TI - Deletions of D13S25, D13S319 and RB-1 mapping to 13q14.3 in T-cell prolymphocytic leukaemia.
SO - Br J Haematol 2001 Aug;114(2):327-32
AD - Academic Department of Haematology and Cytogenetics/Institute of Cancer Research, London, UK. vasantha@icr.ac.uk
Deletions of 13q14.3 are well known in several malignancies and are thought to be associated with tumour suppressor function. The RB-1 gene is a tumour suppressor gene, but other loci including D13S319 and D13S25 telomeric to this within 13q14.3 are deleted in B-cell chronic lymphocytic leukaemia (B-CLL), multiple myeloma and non-Hodgkin's lymphoma, with varying clinical significance. The fluorescence in situ hybridization screening of 22 patients with T-prolymphocytic leukaemia (T-PLL) for deletions of 13q14.3 revealed loss of D13S25 in 17 cases (mean 40% range 13-98%), with 11 patients having at least a 20% deletion. Mapping the deletions for the RB-1, D13S319,and D13S25 loci revealed D13S25 as the most frequently deleted marker. However, patients with only the D13S25 deletion had low percentages of cells with the deletion (12-13%), suggesting that loss of D13S25 on its own may not provide sufficient growth advantage. The use of the YAC 954c12, which maps immediately adjacent to D13S25, defined the telomeric border of the deletion in some of the cases. Inv(14)(q11q32) and t(14;14)(q11;q32) are characteristic of T-PLL, but are also observed in premalignant T-cell clones in patients with ataxia telangiectasia. Transition to overt leukaemia may result from loss of suppressor function. Thus, 13q14.3 deletions could contribute to the development of overt leukaemia in T-PLL, but the involvement of more than one gene in the region cannot be excluded.

19
UI - 21421108
AU - Hallek M; Schmitt B; Wilhelm M; Busch R; Krober A; Fostitsch HP; Sezer O; Herold M; Knauf W; Wendtner CM; Kuse R; Freund M; Franke A; Schriever F; Nerl C; Dohner H; Thiel E; Hiddemann W; Brittinger G; Emmerich B; German Chronic Lymphocytic Leukaemia Study Group
TI - Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group.
SO - Br J Haematol 2001 Aug;114(2):342-8
AD - Klinikum der Universitat Munchen, Grosshadern, Munchen, Germany. mhallek@med3.med.uni-muenchen.de
The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B-cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m(2) in a 30-min IV infusion, d 1-3, and cyclophosphamide 250 mg/m(2) in a 30-min IV infusion on d 1-3. Cycles were repeated every 28 d. Twenty-one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute-sponsored Working Group, were recorded in 29 out of 32 assessable patients (90.6%). Twenty-four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69.4%, 16.7% and 16.7%) respectively. Other side-effects were uncommon. No treatment-related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side-effect. These results warrant further study on the FC combination in randomized trials.

20
UI - 21415931
AU - Seligmann H; Levi R; Konijn AM; Prokocimer M
TI - Thiamine deficiency in patients with B-chronic lymphocytic leukaemia: a pilot study.
SO - Postgrad Med J 2001 Sep;77(911):582-5
AD - Clinical Pharmacology Unit, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel. konijn@md2.huji.ac.il
Malignancy associated primary thiamine deficiency has been documented in several experimental tumours, sporadic clinical case reports, and in a number of patients with fast growing haematological malignancies. Thiamine status was assessed prospectively in 14 untreated B-chronic lymphocytic leukaemia (CLL) patients, and in 14 age matched control patients with non-malignant disease. Patients with any known cause of absolute, relative, or functional thiamine deficiency were excluded. High (>15%) thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in five out of 14 CLL patients (35.7%) and in none of the controls (p=0.057). Mean (SD) TPPE in the thiamine deficient patients group was 21.6 (3.4)%. In all the patients, thiamine deficiency was subclinical. No correlates for the thiamine deficiency have been found save for an increment of more than 20% in the total leucocyte count over the preceding three months, which was found in all five thiamine deficient patients compared with only one of the nine non-thiamine deficient CLL patients. Thus, CLL patients may be prone to develop primary thiamine deficiency possibly promoted by the increased leucocytes span, which may increase thiamine consumption. Since even subclinical thiamine deficiency may be detrimental to the patient's clinical course, and in view of the theoretical danger of thiamine promoted tumour cell proliferation, further large scale studies are warranted to confirm this observation, and to elucidate the issue of thiamine supplementation to CLL patients.

21
UI - 21438702
AU - Kaplan D; Meyerson H; Lewandowska K
TI - High resolution immunophenotypic analysis of chronic lymphocytic leukemic cells by enzymatic amplification staining.
SO - Am J Clin Pathol 2001 Sep;116(3):429-36
AD - Dept of Pathology, Case Western Reserve University, Biomedical Research Bldg, Room 926, 2109 Adelbert Rd, Cleveland, OH 44106-4943, USA.
Immunophenotypic analysis of chronic lymphocytic leukemia (CLL) cells is essential for the diagnosis of this disorder. Unfortunately, surface immunoglobulin light chains and CD79b are expressed faintly or not at all by CLL cells from many patients. We developed an enzymatic amplification staining procedure that amplifies the fluorescent signal by 10- to 100-fold. By using this technology, we have been able to resolve immunoglobulin light chain exclusion and CD79b expression on the cells from most cases. This new capability can be used for high-resolution immunophenotypic analysis of leukemias and lymphomas.

22
UI - 21438703
AU - Huh YO; Keating MJ; Saffer HL; Jilani I; Lerner S; Albitar M
TI - Higher levels of surface CD20 expression on circulating lymphocytes compared with bone marrow and lymph nodes in B-cell chronic lymphocytic leukemia.
SO - Am J Clin Pathol 2001 Sep;116(3):437-43
AD - Departments of Hematopathology and Leukemia, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA.
Differential expression of CD20 surface antigen in B-cell neoplasms at different sites is largely unknown. The number of CD20 antibodies bound per cell (CD20 ABC) in bone marrow (BM), peripheral blood (PB), and lymph node aspirate (LNA) samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) or other B-cell disease was studied using quantitative flow cytometry. CD20 ABC differed significantly with the specimen type in B-CLL, being highest in PB (mean, 9,051) and lower in BM (mean, 4,067) and LNA (mean, 3,951). No difference in CD20 ABC between BM and PB samples was found in splenic lymphoma, mantle cell lymphoma, or follicular lymphoma. Also, we found a significant difference of CD20 ABC by type of disease: lowest in B-CLL; higher in splenic, follicular, and mantle cell lymphoma; and highest in hairy cell leukemia. The lower CD20 surface antigen levels in BM and LNA than in PB in B-CLL may have clinical relevance with regard to the efficacy of rituximab therapy.

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