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Infection and Immunity in Chronic Lymphocytic Leukemia

      Patients having chronic lymphocytic leukemia (CLL) are at increased risk for infectious morbidity and mortality. The predisposition to infections in CLL patients has many components, including both immunodeficiency related to the leukemia itself (humoral and cellular immune dysfunction) and the results of cumulative immunosuppression related to CLL treatment. The risk of infectious complications increases with the duration of CLL, reflecting the natural history of the disease and the cumulative immunosuppression related to its treatment. Hence, in early, untreated CLL, the infectious risk is mainly related to hypogammaglobulinemia, and infections by encapsulated bacteria are common. However, in patients having advanced CLL, par­ticularly those who receive the newer purine analogues, neutropenia and defects in cell-mediated immunity appear to be the major predisposing factors. An expanded spectrum of pathogens, including opportunistic fungi, Pneumo­cystis carinii, Listeria monocytogenes, mycobacteria, and herpesviruses, are seen in that setting. The changing spec­trum of infections in this latter group of patients mandates a newer approach to prophylaxis and therapy.
      ADA (adenosine deaminase), BMT (bone marrow transplanta­tion), 2-CdA (2-chlorodeoxyadenosine), CLL (chronic lymphocytic leukemia), HSV (herpes simplex virus), IL-2 (interleukin 2), IVIG (Intravenous immunoglobulin), NK (natural killer), PCP (Pneumocystis carinii pneumonia), SCID (severe combined immunodeficiency), VZV (varicella zoster virus)
      Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, accounting for 30% of all leukemias.
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      It is a malignant clonal disorder predominantly of B lymphocytes; T-cell CLL accounts for only 5% of cases. The abnormal clone replaces or inhibits growth and maturation of normal B cells (B-cell CLL), depressing immunoglobulin levels. The CLL staging systems have been proposed on the basis that the major prognostic factors are the number of involved nodal areas, the extent of hepatosplenomegaly, the pattern of marrow replacement, and the degree of anemia and thrombocytopenia. In addition, the median survival duration is more than 15 years in low-risk patients but is 2 years in high-risk patients.
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      Until the early 1990s, the standard therapy consisted of alkylating agents with or without corticosteroids.
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      • Keating MJ
      Chronic lymphocylic leukemia.
      • Cheson BD
      Recent advances in the treatment of B-cell chronic lymphocytic leukemia.
      The introduction of new purine analogue compounds, such as fludarabine phosphate, pentostatin, and cladribine; monoclonal antibody-based strategies; and the early experience with bone marrow transplantation (BMT) (autologous, allogeneic, “mini-transplant”) in selected CLL patients have resulted in a resurgence of interest in clinical trials to treat this disease.
      • Keating MJ
      Chronic lymphocylic leukemia.
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      Fludarabine in particular has emerged as a very potent agent in patients having CLL refractory to alkylating agents.
      • Keating MJ
      Chronic lymphocylic leukemia.
      • Cheson BD
      Recent advances in the treatment of B-cell chronic lymphocytic leukemia.
      More recently, the combination of purine analogues with alkylating agents (eg, the fludarabine-cyclophosphamide regimen) has also emerged as a promising approach.
      • Keating MJ
      Chronic lymphocylic leukemia.
      Infection in CLL patients has long been recognized as a common cause of morbidity and mortality.
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      Uncertainty about the pathogenesis of the increased risk of infection in these patients raises controversy regarding the management of infections. Furthermore, the encouraging new therapeutic developments have often come at the cost of serious opportunistic infections. The goal of this review is to describe the clinical characteristics and risk factors of infections in CLL as well as the abnormal host defenses in this disease. In addition, we focus on the evolving pattern of infectious complications in association with newer forms of therapy and discuss approaches to prophylaxis and treatment.

      INFECTIONS IN CLL TREATED WITH STANDARD CYTOTOXIC CHEMOTHERAPY

      Many studies have emphasized the important role of infections complicating conventional chemotherapy based on alkylating agents in the morbidity and mortality associated with CLL.
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      • Osgood EE
      • Seaman AJ
      Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.
      • Scott RB
      Leukaemia.
      • Pisciotta AV
      • Hirschboeck JS
      Therapeutic considerations in chronic lymphocytic leukemia.
      • Ultmann JE
      • Fish W
      • Osserman E
      • Gellhorn A
      The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.
      • Shaw RK
      • Szwed C
      • Boggs DR
      • et al.
      Infection and immunity in chronic lymphocytic leukemia.
      • Hudson RP
      • Wilson SJ
      Hypogammaglobulinemia and chronic lymphatic leukemia.
      • Shaw RK
      • Boggs DR
      • Silberman HR
      • Frei III, E
      A study of prednisone therapy in chronic lymphocytic leukemia.
      • Aroesty JM
      • Furth FW
      Infection and chronic lymphocytic leukemia: a review of 61 cases.
      • Boggs DR
      • Soffcrman SA
      • Wintrobe MM
      • Cartwright GE
      Factors influencing the duration of survival of patients with chronic lymphocylic leukemia.
      • Zippin C
      • Cutler SJ
      • Reeves Jr, WJ
      • Lum D
      Survival in chronic lymphocytic leukemia.
      • Hansen MM
      Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.
      • Revol L
      • Creyssel R
      • Bryon PA
      • Coeur P
      • Gentilhomme O
      • Montserral-Costa E
      • Matutes E
      • Rozman C
      • et al.
      Infections in chronic lymphocytic leukaemia [in Spanish].
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      • Itala M
      • Helenius H
      • Nikoskelainen J
      • Renies K
      Infections and serum IgG levels in patients with chronic lymphocytic leukemia.
      • Lee JS
      • Dixon DO
      • Kantarjian HM
      • Keating MJ
      • Talpaz M
      Prognosis of chronic lymphocytic leukemia: a multivariate regression analysis of 325 untreated patients.
      • Catovsky D
      • Fooks J
      • Richards S
      • MRC Working Party on Leukaemia in Adults
      Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival: a report from the MRC CLL I trial.
      In fact, the incidence of moderate to severe infections in CLL patients was estimated to be 0.47 per patient-year in a large study.
      • Itala M
      • Helenius H
      • Nikoskelainen J
      • Renies K
      Infections and serum IgG levels in patients with chronic lymphocytic leukemia.
      However, most of these retrospective studies used different diagnostic criteria for infection and cause of death and focused on the analysis of leukemia status rather than on the infectious complications of leukemia. Moreover, these studies examined a select patient population, such as those having advanced refractory CLL, typically seen in tertiary care centers, and many of these efforts did not consider the stage of the underlying leukemia, neutrophil count, immunoglobulin level, or prior treatment using cytotoxic agents, which are all important factors for the type and severity of infections in CLL. Despite these limitations, several conclusions can be derived: (1) The incidence of infection in CLL patients was higher than that in an age-matched control group
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      and not associated with the increased median age of the CLL patient population. (2) The incidence and severity of infections paralleled the stage and progression of CLL. Hence, patients having advanced refractory CLL usually die of infection.
      • Kempin S
      • Lee III, BJ
      • Thaler HT
      • et al.
      Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristinc, BCNU, cyclophosphamide, melphalan, and prednisone).
      (3) Infection may be the feature at presentation that leads to the diagnosis of CLL.
      • Hansen MM
      Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.
      (4) Fever in CLL patients usually signifies infection.
      • Boggs DR
      • Soffcrman SA
      • Wintrobe MM
      • Cartwright GE
      Factors influencing the duration of survival of patients with chronic lymphocylic leukemia.
      • Hansen MM
      Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.
      (5) Finally, a subset of patients suffer from recurrent infections (mostly upper respiratory tract or soft tissue infections) usually associated with hypogammaglobulinemia.
      • Osgood EE
      • Seaman AJ
      Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.
      • Revol L
      • Creyssel R
      • Bryon PA
      • Coeur P
      • Gentilhomme O
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      • Itala M
      • Helenius H
      • Nikoskelainen J
      • Renies K
      Infections and serum IgG levels in patients with chronic lymphocytic leukemia.
      Regarding the sites of involvement of severe infection, both pneumonia and bacteremia are common, especially in patients having profound neutropenia.
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      • Osgood EE
      • Seaman AJ
      Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.
      • Ultmann JE
      • Fish W
      • Osserman E
      • Gellhorn A
      The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.
      • Shaw RK
      • Szwed C
      • Boggs DR
      • et al.
      Infection and immunity in chronic lymphocytic leukemia.
      • Hudson RP
      • Wilson SJ
      Hypogammaglobulinemia and chronic lymphatic leukemia.
      • Shaw RK
      • Boggs DR
      • Silberman HR
      • Frei III, E
      A study of prednisone therapy in chronic lymphocytic leukemia.
      • Aroesty JM
      • Furth FW
      Infection and chronic lymphocytic leukemia: a review of 61 cases.
      • Revol L
      • Creyssel R
      • Bryon PA
      • Coeur P
      • Gentilhomme O
      • Montserral-Costa E
      • Matutes E
      • Rozman C
      • et al.
      Infections in chronic lymphocytic leukaemia [in Spanish].
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      Also, the rate of nosocomial bloodstream infections was 9.4% in CLL patients in a prospective surveillance study in which 50% of the patients had profound neutropenia (polymorphonuclear neutrophil leukocyte count at the time of bacteremia onset <0.01 × 109/L).
      • Mayo JW
      • Wenzel RP
      Rates of hospital-acquired bloodstream infections in patients with specific malignancy.
      Of interest is that older series
      • Osgood EE
      • Seaman AJ
      Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.
      • Scott RB
      Leukaemia.
      • Pisciotta AV
      • Hirschboeck JS
      Therapeutic considerations in chronic lymphocytic leukemia.
      • Ultmann JE
      • Fish W
      • Osserman E
      • Gellhorn A
      The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.
      • Shaw RK
      • Szwed C
      • Boggs DR
      • et al.
      Infection and immunity in chronic lymphocytic leukemia.
      • Hudson RP
      • Wilson SJ
      Hypogammaglobulinemia and chronic lymphatic leukemia.
      • Shaw RK
      • Boggs DR
      • Silberman HR
      • Frei III, E
      A study of prednisone therapy in chronic lymphocytic leukemia.
      • Aroesty JM
      • Furth FW
      Infection and chronic lymphocytic leukemia: a review of 61 cases.
      • Boggs DR
      • Soffcrman SA
      • Wintrobe MM
      • Cartwright GE
      Factors influencing the duration of survival of patients with chronic lymphocylic leukemia.
      • Zippin C
      • Cutler SJ
      • Reeves Jr, WJ
      • Lum D
      Survival in chronic lymphocytic leukemia.
      • Hansen MM
      Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.
      • Revol L
      • Creyssel R
      • Bryon PA
      • Coeur P
      • Gentilhomme O
      • Montserral-Costa E
      • Matutes E
      • Rozman C
      • et al.
      Infections in chronic lymphocytic leukaemia [in Spanish].
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      • Itala M
      • Helenius H
      • Nikoskelainen J
      • Renies K
      Infections and serum IgG levels in patients with chronic lymphocytic leukemia.
      noted infections of the genitourinary tract, most likely due to obstruction by enlarged retroperitoneal nodes in advanced CLL.
      Pathogens seen frequently in CLL patients undergoing different therapeutic regimens are listed in Table 1. Bacterial infections caused by encapsulated organisms such as Streptococcus pneumoniae are common, especially in older series of patients.
      • Pisciotta AV
      • Hirschboeck JS
      Therapeutic considerations in chronic lymphocytic leukemia.
      • Shaw RK
      • Boggs DR
      • Silberman HR
      • Frei III, E
      A study of prednisone therapy in chronic lymphocytic leukemia.
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      • Itala M
      • Helenius H
      • Nikoskelainen J
      • Renies K
      Infections and serum IgG levels in patients with chronic lymphocytic leukemia.
      • Wintrobe MM
      • Hasenbush LL
      Chronic leukemia: early phase of chronic leukemia, results of treatment and effects of complicating infections: study of 86 adults.
      • Miller DG
      • Karnofsky DA
      Immunologic factors and resistance to infection in chronic lymphatic leukemia.
      • Salonen J
      • Nikoskelainen J
      Lethal infections in patients with hemalological malignancies.
      • Bernard C
      • Mombelli G
      • Klastersky J
      Pneumococcal bacteremia in patients with neoplastic diseases.
      • Chou MY
      • Brown AE
      • Blevins A
      • Armstrong D
      Severe pneumococcal infection in patients with neoplastic disease.
      • Armstrong D
      • Young LS
      • Meyer RD
      • Blevins AH
      Infectious complications of neoplastic disease.
      Staphylococcus aureus infections were also prominent in other series.
      • Shaw RK
      • Boggs DR
      • Silberman HR
      • Frei III, E
      A study of prednisone therapy in chronic lymphocytic leukemia.
      • Kempin S
      • Lee III, BJ
      • Thaler HT
      • et al.
      Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristinc, BCNU, cyclophosphamide, melphalan, and prednisone).
      In contrast, an increase in gram-negative bacillary infections, particu­larly bacteremias, has been noted in recent studies.
      • Montserral-Costa E
      • Matutes E
      • Rozman C
      • et al.
      Infections in chronic lymphocytic leukaemia [in Spanish].
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      • Itala M
      • Helenius H
      • Nikoskelainen J
      • Renies K
      Infections and serum IgG levels in patients with chronic lymphocytic leukemia.
      • Salonen J
      • Nikoskelainen J
      Lethal infections in patients with hemalological malignancies.
      This increase may reflect more advanced disease and profound myelosuppression in the patients studied. In fact, cytotoxic chemotherapy for advanced refractory CLL results in infectious morbidity and mortality analogous to that seen inacute leukemia. In particular, frequent fatal bacteremias or pneumonias caused by Pseudomonas aeruginosa have been reported in that setting.
      • Armstrong D
      • Young LS
      • Meyer RD
      • Blevins AH
      Infectious complications of neoplastic disease.
      Other frequently reported pathogens include Haemophilus influenzae.
      • Aroesty JM
      • Furth FW
      Infection and chronic lymphocytic leukemia: a review of 61 cases.
      Legionella Spp,
      • Kirby BD
      • Snyder KM
      • Meyer RD
      • Finegold SM
      Legionnaires' disease: report of sixty-five nosocomially acquired cases of review of the literature.
      • Schlossberg D
      • Bonoan J
      Legionella and immunosuppression.
      • Jaeger TM
      • Atkinson PP
      • Adams BA
      • Wright AJ
      • Hurt RD
      Legionella bozemanii pneumonia in an immunocompromised patient.
      and Salmonella Spp.
      • Wolfe MS
      • Louria DB
      • Armstrong D
      • Blevins A
      Salmonellosis in patients with neoplastic disease: a review of 100 episodes at Memorial Cancer Center over a 13-year period.
      However, infections caused by Liste­ria monocytogenes, Nocardia spp, and Neisseria meningitidis are relatively infrequent in CLL patients who receive cytotoxic chemotherapy.
      • Armstrong D
      • Young LS
      • Meyer RD
      • Blevins AH
      Infectious complications of neoplastic disease.
      Table 1Frequent Pathogens in Patients Having Chronic Lymphocytic Leukemia and Receiving Different Therapeutic Regimens
      CMV = cytomegalovirus; HSV = herpes simplex virus; PCP = P carinii pneumonia; VZV = varicella zoster virus.
      PathogenAlkylaling agents/sic roidsPurine analogues
      FludarabineCladribincPcntostatin
      BacieriaS pneumoniaeL monocytogenesfL monocytogenesS pneumoniae
      S aureusSlaphylococcus sppPseudomonas spp
      P aerug'mosaStreptococcus spp
      H influenzaeE coli
      Legionella sppKlebsiella spp
      Salmonella sppEnterobacter spp
      Acinetobacier spp
      N meningilidis
      C difficile
      FungiC neoformansCandida sppCandida sppCandida spp
      H capsulatumAspergiltus sppAspergitlus sppAspergillus spp
      Candida spp
      Aspergitlus spp
      VirusesHSVvzvHSVHSV
      AdenovirusCMVVZVVZV
      CMV
      OtherPCP
      Especially with coilicosteroids.
      PCPPCP
      Mycobacteria
      * CMV = cytomegalovirus; HSV = herpes simplex virus; PCP = P carinii pneumonia; VZV = varicella zoster virus.
      Especially with coilicosteroids.
      Fungal infections, particularly the endemic mycoses, have also been associated with CLL.
      • Kaplan MH
      • Rosen PP
      • Armstrong D
      Cryptococcosis in a cancer hospital: clinical and pathological correlates in forty-six patients.
      • Kauffman CA
      • Israel KS
      • Smith JW
      • White AC
      • Schwarz J
      • Brooks GF
      Histoplasmosis in immunosuppressed patients.
      For example, CLL was reported to be the most common underlying malignancy in patients having infections caused by Cryptococ­cus neoformans
      • Kaplan MH
      • Rosen PP
      • Armstrong D
      Cryptococcosis in a cancer hospital: clinical and pathological correlates in forty-six patients.
      and the underlying malignancy in 30% of patients having infections caused by Histoplasma capsulatum from an endemic area.
      • Kauffman CA
      • Israel KS
      • Smith JW
      • White AC
      • Schwarz J
      • Brooks GF
      Histoplasmosis in immunosuppressed patients.
      On the other hand, infections from Coccidioides immitis or Paracoccidioides spp are not commonly reported in association with CLL.
      • Deresinski SC
      • Stevens DA
      Coccidioidomycosis in compromised hosts: experience at Stanford University Hospital.
      • Melo CR
      • Melo IS
      • Cerski CT
      lxukaemic infiltration, para-coccidioidomycosis and nodular hyperplasia of the prostate.
      However, an increasing incidence of opportunistic mycoses such as candidiasis or aspergillosis in patients having advanced refractory CLL has been noted.
      • Kontoyiannis DP
      • Anaissie EJ
      • Bodey GP
      Infection in chronic lymphocytic leukemia: a reappraisal.
      • Terreni AA
      • DiSalvo AF
      • Baker Jr, AS
      • Crymes WB
      • Morris PR
      • Dowda Jr, H
      Disseminated Dactylaria gallopava infection in a diabetic patient with chronic lymphocytic leukemia of the T-cell type.
      These mycoses are typically associated with prolonged and profound neutropenia, administration of multiple broad-spectrum antibiotics, and prior corticosteroid use, and they have emerged as a notable cause of death in patients having advanced refractory CLL.
      • Kontoyiannis DP
      • Anaissie EJ
      • Bodey GP
      Infection in chronic lymphocytic leukemia: a reappraisal.
      Viral infections, particularly herpesvirus infections, occur frequently in CLL patients.
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      • Ultmann JE
      • Fish W
      • Osserman E
      • Gellhorn A
      The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.
      • Montserral-Costa E
      • Matutes E
      • Rozman C
      • et al.
      Infections in chronic lymphocytic leukaemia [in Spanish].
      • Hirsch MS
      Herpes group virus infections in the compromised host.
      Herpesvirus infections are usually localized, although disseminated disease occurs in patients having advanced disease and severe cell-mediated immune dysfunction.
      • Wile UJ
      • Holman HH
      Generalized herpes zoster associated with leukemia.
      • Barton RL
      • O'Leary PA
      Herpes zoster generalisatus, associated with chronic lymphatic leukemia.
      Herpes simplex virus (HSV) mucositis may follow a more chronic, indolent course in some CLL patients in contrast to the more aggressive, recurrent nature of this infection in patients having acute leukemia.
      • Barrett AP
      Chronic indolent orofacial herpes simplex virus infection in chronic leukemia: a report of three cases.
      Occasionally, severe infections caused by other viruses, such as adenovirus type 1, have been reported.
      • Ljungman P
      • Ehrnst A
      • Bjorkstrand B
      • et al.
      Lethal disseminated adenovirus type 1 infection in a patient with chronic lymphocytic leukemia.
      On a historical note, vaccinia gangrenosa and generalized vaccinia have been reported in CLL patients after smallpox vaccination.
      • Ultmann JE
      Generalized vaccinia in a patient with chronic lymphocytic leukemia and hypogammaglobulinemia.
      However, viral infections, even though they may be associated with substantial morbidity, do not seem to cause notable mortality.
      Finally, other pathogens, such as mycobacteria, infrequently cause infections.
      • Kaplan MH
      • Armstrong D
      • Rosen P
      Tuberculosis complicating neoplastic disease: a review of 201 cases.
      Similarly, Pneumocystis carinii infections are rare in patients who receive conventional cytotoxic chemotherapy.
      • Reed AE
      • Body BA
      • Austin MB
      • Frierson Jr, HF
      Cunninghamella bertholletiae and Pneumocystis carinii pneumonia as a fatal complication of chronic lymphocytic leukemia.

      PATHOGENESIS OF INFECTIONS ASSOCIATED WITH CLL TREATED WITH STANDARD CYTOTOXIC CHEMOTHERAPY

      The pathogenesis of infection in CLL is complex and mul­tifactorial.
      • Kontoyiannis DP
      • Anaissie EJ
      • Bodey GP
      Infection in chronic lymphocytic leukemia: a reappraisal.
      • Molica S
      Infections in chronic lymphocylic leukemia: risk factors, and impact on survival, and treatment.
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      The associated humoral dysfunction has traditionally been considered the most important immune defect.
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      However, antineoplastic therapy has blurred the classic associations between CLL, hypogammaglobulinemia, and recurrent infection, which were apparent in the past when “unmodified” patients having untreated CLL were studied, by producing broader, less specific immune dysregulation (Table 2).
      • Kontoyiannis DP
      • Anaissie EJ
      • Bodey GP
      Infection in chronic lymphocytic leukemia: a reappraisal.
      Table 2Predominant Immune Defects Noted in Different Stages of Chronic Lymphocytic Leukemia
      ADA = adenosine deaminase; CLL = chronic lymphocytic leukemia; LAK = lymphokine-activated killer.; NK = natural killer.
      Late stage CLL
      Immune defectEarly-stage untreated CLLTreated using cytotoxic agentsTreated using purine analogues
      Fludarabine and pentostatin.
      HypogammaglobulinemiaIgG class and subclasses (IgG3, IgG4); low mucosal IgM/IgA; low serum IgA; qualitative loss of immunoglobulin functionMore severe than in early-stage CLLMore severe than in early-stage CLL
      Neutropenia and phagocytic-celi defectsNeutropenia; lysozyme and myeloperoxidase deficiencies; monocytopenia; defects in granulocyte chemotaxis and chemiluminescenceOften more severe than in late-stage CLL with cytotoxic agent therapy
      Cell-mediated immunityFunctional T-cell defects; NK defects; LAK defects; CD4/CD8 inversionSame as early-stage CLL but secondary effects of therapy pronounced; effect of cortico steroids on lymphocytes and on monocyte-macrophage axisSame as early-stage CLL but secondary effects of therapy pronounced; inhibition of STATI, differential effect apoptosis between B and T cells, rapid reduction of CD4 cell count by fludarabine; effects on CD4/CD8 lymphocytes and on monocytes by cladribine; inhibition of ADA and effects on lymphocytes, monocytes, macrophages, and NK cells by pentostatin
      Low complementPrimary vs secondary; low Cl andC4;Cl esterase inhibitor deficiency; autoimmune featuresSame as early-stage CLLSame as early-stage CLL
      * ADA = adenosine deaminase; CLL = chronic lymphocytic leukemia; LAK = lymphokine-activated killer.; NK = natural killer.
      Fludarabine and pentostatin.

      Hypogammaglobulinemia

      Hypogammaglobulinemia is 1 of the 2 routinely measured immune defects associated with CLL (the other being neutropenia), and its association with infection in CLL patients is well known.
      • Molica S
      Infections in chronic lymphocylic leukemia: risk factors, and impact on survival, and treatment.
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      • Rozman C
      • Montscrral E
      Chronic lymphocytic leukemia.
      • Dighiero G
      Hypogammaglobulinemia and disordered immunity in CLL.
      • Chapel HM
      Hypogammaglobulinemia and chronic lymphocylic leukaemia.
      • Miller DG
      • Budinger JM
      • Karnofsky DA
      A clinical and pathological study of resistance to infection in chronic lymphatic leukemia.
      • Rai KR
      • Montserrat E
      Prognostic factors in chronic lymphocytic leukemia.
      • Griffiths H
      • Lea J
      • Bunch C
      • Lee M
      • Chapel H
      Predictors of infection in chronic lymphocylic leukaemia (CLL).
      • Foa R
      Pathogenesis of the immunodeficiency in chronic lymphocytic leukemia.
      The pathogenesis of hypogammaglobulinemia probably reflects the dysfunction of nonclonal CD5 B cells in CLL
      • Dighiero G
      Hypogammaglobulinemia and disordered immunity in CLL.
      and carries a poor prognosis.
      • Chapel HM
      Hypogammaglobulinemia and chronic lymphocylic leukaemia.
      • Miller DG
      • Budinger JM
      • Karnofsky DA
      A clinical and pathological study of resistance to infection in chronic lymphatic leukemia.
      Additionally, the incidence of hypogammaglobulinemia depends on the duration of CLL.
      • Rai KR
      • Montserrat E
      Prognostic factors in chronic lymphocytic leukemia.
      During the course of their illness, most CLL patients will ultimately have severe, permanent hypogammaglobulinemia
      • Ultmann JE
      • Fish W
      • Osserman E
      • Gellhorn A
      The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.
      • Miller DG
      • Karnofsky DA
      Immunologic factors and resistance to infection in chronic lymphatic leukemia.
      • Griffiths H
      • Lea J
      • Bunch C
      • Lee M
      • Chapel H
      Predictors of infection in chronic lymphocylic leukaemia (CLL).
      • Foa R
      Pathogenesis of the immunodeficiency in chronic lymphocytic leukemia.
      that cannot be reversed using antileukemic therapy, even if a complete remission is achieved.
      • Ultmann JE
      • Fish W
      • Osserman E
      • Gellhorn A
      The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.
      • Miller DG
      • Karnofsky DA
      Immunologic factors and resistance to infection in chronic lymphatic leukemia.
      However, patients having chemotherapy-responsive CLL generally have fewer and milder infections despite having persistently depressed immunoglobulin levels.
      • Aroesty JM
      • Furth FW
      Infection and chronic lymphocytic leukemia: a review of 61 cases.
      • Miller DG
      • Budinger JM
      • Karnofsky DA
      A clinical and pathological study of resistance to infection in chronic lymphatic leukemia.
      • Rai KR
      • Montserrat E
      Prognostic factors in chronic lymphocytic leukemia.
      In addition, CLL patients having hypogammaglobulinemia, especially that of the IgG class, seem to have a higher risk of bacterial infections, particularly recurrent ones, than do those not having hypogammaglobulinemia.
      • Pisciotta AV
      • Hirschboeck JS
      Therapeutic considerations in chronic lymphocytic leukemia.
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      • Chapel HM
      Hypogammaglobulinemia and chronic lymphocylic leukaemia.
      • Griffiths H
      • Lea J
      • Bunch C
      • Lee M
      • Chapel H
      Predictors of infection in chronic lymphocylic leukaemia (CLL).
      Bac­teria classically associated with this setting include encapsulated organisms.
      • Travade P
      • Dusatt JD
      • Cavaroc M
      • Beytout J
      • Rey M
      Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].
      • Mayo JW
      • Wenzel RP
      Rates of hospital-acquired bloodstream infections in patients with specific malignancy.
      Not all studies, however, have been able to confirm this association.
      Questions have been raised about the relative importance of each immunoglobulin class and the immunoglobulin level below which the risk of infection greatly increases. Specifically, selective deficiencies of IgG3 and IgG4 were found in a small case-control study of patients having B-cell CLL.
      • Copson ER
      • Ellis BA
      • Westwood NB
      • Majumdar G
      IgG subclass levels in patients with B cell chronic lymphocytic leukaemia.
      This is important because IgG3 helps protect against herpesvirus,
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      a common viral infection in CLL.
      • Hirsch MS
      Herpes group virus infections in the compromised host.
      Also, an important role has been attributed recently to immunoglobulin deficiencies in mucosal surfaces.
      • Morrison VA
      The infectious complications of chronic lymphocytic leukemia.
      Much lower salivary IgM levels have been reported in CLL pa­tients compared with controls, as has a higher risk of infection in patients having a low serum IgA level.

      Morrison VA, Opstad NL, Janoff EN. Correlation of systemic and mucosal immunoglobulin (Ig) levels in patients (pts) with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) [abstract]. In: Proceedings of the 34th Annual Meeting of the Infectious Diseases Society of America; 1996; New Orleans, La. Abstract 92.

      • Morrison VA
      • Hibbs JR
      • Janoff EN
      Systemic and mucosal immunoglobulin (IG) levels and risk of infection in patients (pts) with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) [abstract].
      • Morrison VA
      • Opstad NL
      • Janoff EN
      Mucosal immunoglobulin (Ig) levels in patients (pts) with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) [abstract].
      Addition­ally, a predominant IgA deficiency is associated with an increased frequency of upper respiratory tract infections similar to that observed in patients having a selective secretory IgA deficiency.
      • Ammann AJ
      • Hong R
      Selective IgA deficiency: presentation of 30 cases and a review of the literature.
      Finally, Rozman et a1
      • Rozman C
      • Montserrat E
      • Vinolas N
      Serum immunoglobulins in B-chronic lymphocytic leukemia: natural history and prognostic significance.
      found that a decreased IgA level had prognostic importance for survival in B-cell CLL patients. Further studies are needed to define the role of mucosal immune dysfunction in CLL patients. Finally, the prevalence of infection in CLL patients with hypergammaglobulinemia
      • Hansen MM
      Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.
      or monoclonal gammopathy
      • Dcegan MJ
      • Abraham JP
      • Sawdyk M
      • Van Slyck EJ
      High incidence of monoclonal proteins in the scrum and urine of chronic lymphocytic leukemia patients.
      has not been adequately studied.
      On the other hand, CLL patients having hypogammaglobulinemia may be free of infections in contrast with those having normal immunoglobulin levels who may suffer recurrent infections.
      • Kontoyiannis DP
      • Anaissie EJ
      • Bodey GP
      Infection in chronic lymphocytic leukemia: a reappraisal.
      It has been speculated that the inability of B cells to mount a specific humoral response against a pathogen may be more important than the hypogammaglobulinemia itself.
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      Deficiencies in secondary-antibody response to common antigens in CLL were first reported long ago.
      • Saslaw S
      • Carlisle HN
      • Bouroncle B
      Antibody response in hematologic patients.
      • Barr M
      • Fairley GH
      Circulating antibodies in reticuloses.
      • Cone L
      • Uhr W, J
      Immunological deficiency disorders associated with chronic lymphocytic leukemi a and multiple myeloma.
      • Heath RB
      • Fairley GH
      • Malpas JS
      Production of antibodies against viruses in leukaemia and related diseases.
      Deficiencies of specific antibodies against common pathogens, such as low IgG titers to Escherichia coli and S pneumoniae associated with recurrent infections caused by these pathogens, were subsequently found.
      • Chapel HM
      Hypogammaglobulinemia and chronic lymphocylic leukaemia.
      In other studies, the response to immunization against S pneumoniae
      • Jacobson DR
      • Ballard HS
      • Silber R
      • Ripps CS
      • Smith JA
      • Schiffman GS
      Antibody response to pneumococcal immunization in patients with chronic lymphocytic leukemia [abstract].
      • Shapiro ED
      • Berg AT
      • Austrian R
      • et al.
      The protective efficacy of polyvalent pneumococcal polysaccharide vaccine.
      and influenza
      • Gribabis DA
      • Panayiotidis P
      • Boussiotis VA
      • Hannoun C
      • Pangalis GA
      Influenza virus vaccine in B-cell chronic lymphocytic leukaemia patients.
      was shown to be defective in CLL patients. A qualitative loss of im­munoglobulin function in CLL patients having recurrent infections is supported by several other observations: (1) the immunoglobulin threshold below which the risk of infection increases is much higher in CLL (and other acquired hypogammaglobulinemic states) than in congenital hypogammaglobulinemic states
      • Janeway CA
      • Gitlin D
      The gamma globulins.
      ; and (2) patients having multiple myeloma, another clonal disease marked by B-cell dysregulation, frequently have severe recurrent infections with the same spectrum of pathogens as CLL patients do despite having normal immunoglobulin levels.
      • Lawson HA
      • Stuart CA
      • Pauli AM
      • Phillips AM
      • Phillips RW
      Observations on the antibody content of the blood in patients with multiple myeloma.
      Unfortunately, no reliable method of qualitative assessment of immunoglobulin function exists to determine whether loss of such function is important in the pathogenesis of infection in CLL. It can only be speculated that this is a reflection of the heterogeneity in the levels of specific IgG subclasses recently found in CLL.
      • Copson ER
      • Ellis BA
      • Westwood NB
      • Majumdar G
      IgG subclass levels in patients with B cell chronic lymphocytic leukaemia.
      • Lacombe C
      • Gombert J
      • Dreyfus B
      • Brizard A
      • Preud' Homme JL
      Heterogeneity of scrum IgG subclass deficiencies in B chronic lymphocytic leukemia.

      Cell-Mediated Immunity

      Ample in vitro and in vivo evidence of impaired cell-mediated immunity in CLL does exist.
      • Freedman AS
      lmmunobiology of chronic lymphocytic leukemia.
      However, the distinction between primary impairment and impairment secondary to cytotoxic chemotherapy is not always made.
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      Effects on T-cell colony growth,
      • Foa R
      • Catovsky D
      • Lauria F
      • Galton DA
      Reduced T-colony forming capacity by T-lymphocytes from B-chronic lymphocyte leukaemia.
      increases in T-suppressor activity,
      • Kay NE
      Abnormal T-cell subpopulation function in CLL: excessive suppressor (T gamma) and deficient helper (T mu) activity with respect to B-cell proliferation.
      decreases in T-helper activity,
      • Kay NE
      Abnormal T-cell subpopulation function in CLL: excessive suppressor (T gamma) and deficient helper (T mu) activity with respect to B-cell proliferation.
      • Foa R
      • Catovsky D
      • Brozovic M
      • et al.
      Clinical staging and immunological findings in chronic lymphocytic leukemia.
      reversal of the CD4/CD8 ratio,
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      • Platsoucas CD
      • Galinski M
      • Kcmpin S
      • Reich L
      • Clarkson B
      • Good RA
      Abnormal T lymphocyte subpopulations in patients with B cell chronic lymphocytic leukemia: an analysis by monoclonal antibodies.
      increases in soluble interleukin 2 (IL-2) receptors,
      • Kay NE
      • Perri RT
      Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regutale B-cell immunoglobulin synthesis [published correction appears in Blood. 1989;73:2232).
      defects in large granular lymphocytes,
      • Kay NE
      • Perri RT
      Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regutale B-cell immunoglobulin synthesis [published correction appears in Blood. 1989;73:2232).
      lymphokine-activated killer cells,
      • Foa R
      • Fierro MT
      • Raspadori D
      • et al.
      Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors.
      or natural killer (NK) cells,
      • Ziegler HW
      • Kay NE
      • Zarling JM
      Deficiency of natural killer cell activity in patients with chronic lymphocytic leukemia.
      and increases in CD4+CD45+ cells, a subset of T cells believed to be functionally naive in terms of antigen exposure,
      • Briggs PC
      • Kraft N
      • Atkins RC
      T cells and CD45 R expression in B-chronic lymphocytic leukemia.
      have all been reported. These complex functional abnormalities of T-cell subsets may play a role in the pathogenesis of hypogammaglobulinemia in B-cell CLL.
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      • Foa R
      Pathogenesis of the immunodeficiency in chronic lymphocytic leukemia.
      • Hersey P
      • Wotherspoon J
      • Reid G
      • Gun FW
      Hypogammaglobulinaemia associated with abnormalities of both B and T lymphocytes in patients with chronic lymphatic leukaemia.
      • Apostolopoulos A
      • Symeonidis A
      • Zoumbos N
      Prognostic significance of immune function parameters in patients with chronic lymphocytic leukaemia.
      In addition, the defect in NK-cell activity could promote hypogammaglobulinemia as CD16+ B-cell CLL NK cells inhibit mitogen-induced immunoglobulin secretion by normal B cells.
      • Zaknoen SL
      • Kay NE
      Immunoregulatory cell dysfunction in chronic B-cell teukemias.
      Recent evidence offers new insight into the profound alterations in the T-cell repertoire of CLL patients and the role of clonal T-cell populations in the pathogenesis of this disease. Analysis of the CD4+ and CD8+ cell repertoire has shown that oligoclonality is much more common in both of these T-cell populations in CLL patients than in age-matched controls and that oligoclonal expansions are predominantly found in the CD57+ subset of both populations.
      • Serrano D
      • Monteiro J
      • Allen SL
      • et al.
      Clonal expansion within the CD4+-CD57+ and CD8+CD57+ T cell subsets in chronic lymphocytic leukemia.
      • Alatrakchi N
      • Faracc F
      • Frau E
      • Carde P
      • Munck JN
      • Triebel F
      T-cell clonal expansion in patients with B-cell lymphoproliferative disorders.
      Also, an elevated frequency of CD4+CD57+ cells has been correlated with more advanced disease, and the most extreme oligoclonal expansions of CD4+CD57+ cells have occurred in patients having an advanced stage of CLL. It seems that a systemic antigen-specific immune reaction involving few T-cell receptor clonotypes is a hall-mark of B-cell malignancies.
      • Alatrakchi N
      • Faracc F
      • Frau E
      • Carde P
      • Munck JN
      • Triebel F
      T-cell clonal expansion in patients with B-cell lymphoproliferative disorders.
      It is unclear whether the T-cell dysfunction seen in CLL is reversible. Some of these functional defects may be improved with use of interferon therapy
      • Platsoucas CD
      • Fernandes G
      • Gupta SL
      • et al.
      Defective spontaneous and antibody-dependent cytoloxicity mediated by E-rosette-positive and E-rosctte-negative cells in untreated patients with chronic lymphocytic leukemia: augmentation by in vitro treatment with interferon.
      • Villamor N
      • Rcverter JC
      • Montscrrat E
      • Urbano-Ispizua A
      • Vives-Corrons JL
      • Rozman C
      Recombinant alpha 2b-interferon may restore natural-killer activity in patients with B-chronic lymphocytic leukemia.
      or splenic irra­diation.
      • McCann SR
      • Whelan CA
      • Breslin B
      Temperley IJ. Lymphocyte sub-populations following splenic irradiation in patients with chronic lymphocytic leukaemia.
      Also, decreased reactivity of CLL patients to skin tests has been reported with use of recall antigens.
      • Rozman C
      • Montscrral E
      Chronic lymphocytic leukemia.
      • Serrano D
      • Monteiro J
      • Allen SL
      • et al.
      Clonal expansion within the CD4+-CD57+ and CD8+CD57+ T cell subsets in chronic lymphocytic leukemia.
      • Miller DG
      Patterns of immunological deficiency in lymphomas and leukemias.
      • Miller DG
      • Lizardo JG
      • Snyderman RK
      Homologous and heterolagous skin transplantation in patients with lymphomatous disease.
      • Block JB
      • Haynes HA
      • Thompson WL
      • Neiman PE
      Delayed hypersensitivity in chronic lymphocytic leukemia.
      • Bouroncle BA
      • Clausen KP
      • Aschenbrand JF
      Studies of the delayed response of phytohemagglutinin (PHA) stimulated lymphocytes in 25 chronic lymphatic leukemia patients before and during therapy.
      This could be explained by the poor antigenic T-cell responses to the antigens.
      • Linsley PS
      • Ledbetter JA
      The role of the CD28 receptor during T cell responses to antigen.
      For example, when compared with normal T cells, a lower percentage of CD4+ and CD8+ cells in CLL express CD28, an important accessory molecule in creating antigenic T-cell responses.
      • Linsley PS
      • Ledbetter JA
      The role of the CD28 receptor during T cell responses to antigen.
      • Rossi E
      • Matutes E
      • Morilla R
      • Owusu-Ankomah K
      • Heffernan AM
      • Catovsky D
      Zeta chain and CD28 are poorly expressed on T lymphocytes from chronic lymphocytic leukemia.

      Neutropenia and Phagocytic Cell Defects

      The association of neutropenia with infection-related morbidity and mortality in CLL patients was reported as early as 1938
      • Wintrobe MM
      • Hasenbush LL
      Chronic leukemia: early phase of chronic leukemia, results of treatment and effects of complicating infections: study of 86 adults.
      ; several later studies have supported this association;
      • Shaw RK
      • Boggs DR
      • Silberman HR
      • Frei III, E
      A study of prednisone therapy in chronic lymphocytic leukemia.
      • Hansen MM
      Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.
      • Montserral-Costa E
      • Matutes E
      • Rozman C
      • et al.
      Infections in chronic lymphocytic leukaemia [in Spanish].
      • Arnold C
      • McPhedran P
      Leukemia, myeloproliferative disorders-natural history: prognostic significance of neutrophil counts, gamma globulin levels, and symptoms in chronic lymphocytic leukemia [abstract].
      but others have not.
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      • Miller DG
      Patterns of immunological deficiency in lymphomas and leukemias.
      Monocytopenia may be an additional risk factor for infection.
      • De Rossi G
      • Maura FR
      • Ialongo P
      • Coluzzi S
      • Pizzo F
      Monocytopenia and infections in chronic lymphocytic leukemia [letter].
      The neutrophil function in CLL patients has been reported to be normal,
      • Boggs DR
      The cellular composition of inflammatory exudates in human leukemias.
      but other reports have indicated notable deficiencies of enzymes (in particular, lysozyme and myeloperoxidase), mainly in monocytes but also in neutrophils.
      • Zeya HI
      • Keku E
      • Richards F II
      • Spurr CL
      Monocyte and granulocyte defect in chronic lymphocytic leukemia.
      These enzyme deficiencies were not associated with impaired transformation of monocytes to macrophages and were reversed when complete hematologic remission was achieved. Severe impairments of most granulocyte functions have been reported in CLL patients having a history of infections compared with those not having infections or with healthy controls
      • Zeya HI
      • Keku E
      • Richards F II
      • Spurr CL
      Monocyte and granulocyte defect in chronic lymphocytic leukemia.
      ; defective granulocyte chemotaxis represents an important predictor of infections in these patients.
      • Itala M
      • Vainio O
      • Rcmes K
      Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia.
      As the use of combination cytotoxic chemotherapy for advanced-stage CLL increases, it is likely that neutropenia and qualitative phagocytic cell defects associated with CLL will contribute more to the risk of infection in CLL patients.

      Complement

      Several studies have shown that the complement activity in CLL is abnormal and associated with shortened survival, severe infections, and increased incidence of autoimmune features.
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      • Shvidel L
      • Vorst E
      • Berrebi A
      Complement values in B chronic lymphocytic leukemia: prognostic significance and correlation with cell maturation stage [letter].
      • Varga L
      • Czink E
      • Miszlai Z
      • et al.
      Low activity of the classical complement pathway predicts short survival of patients with chronic lymphocytic leukaemia.
      • Heath ME
      • Cheson BD
      Defective complement activity in chronic lymphocytic leukemia.
      • Dicato M
      • Schmit JC
      • Mahon G
      • Ries F
      Chronic activation of complement in chronic lymphatic leukemia [abstract].
      • Schlesinger M
      • Broman I
      • Lugassy G
      The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives.
      • Fust G
      • Czink E
      • Minh D
      • Miszlay Z
      • Varga L
      • Hollan SR
      Depressed classical complement pathway activities in chronic lymphocytic leukaemia.
      In 1 study, poor bacterial opsonization (particularly of S pneumoniae, S aureus, and H influenzae) was associated with defective complement activation and decreased levels of C3b in CLL patients who had received corticosteroids.
      • Heath ME
      • Cheson BD
      Defective complement activity in chronic lymphocytic leukemia.
      Hypogammaglobulinemia, which was common in these patients, was not sufficient to explain this defect because it was not corrected by adding specific antibacterial antibodies. Whether this complement deficiency represents a primary or secondary (chemotherapy-related) defect is unknown. In contrast, an association between hypogammaglobulinemia, chronic activation of the complement pathway, and major bacterial infections was reported by Dicato et al.
      • Dicato M
      • Schmit JC
      • Mahon G
      • Ries F
      Chronic activation of complement in chronic lymphatic leukemia [abstract].
      Finally, an acquired deficiency of C1 esterase inhibitor associated with low levels of C1 and C4 was reported to result in serious infections in CLL patients.
      • Fust G
      • Czink E
      • Minh D
      • Miszlay Z
      • Varga L
      • Hollan SR
      Depressed classical complement pathway activities in chronic lymphocytic leukaemia.

      Splenectomy

      Splenectomy, which is now infrequently performed in CLL patients,
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      • Stein RS
      • Weikcrt D
      • Reynolds V
      • Greer JP
      • Flexner JM
      Splencctomy for end-stage chronic lymphocytic leukemia.
      could have accounted for some of the CLL-related encapsulated bacterial infections seen in old series.
      • Holt JM
      • Witts LJ
      Splenectomy in leukaemia and the reliculoses.
      Because autoimmune phenomena associated with CLL have been shown to respond to splenectomy
      • Diehl LF
      • Ketchum LH
      Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia.
      and recent studies have shown a good hematologic response and potential survival benefit following this procedure, its role may be upgraded in the future.
      • Cusack Jr, JC
      • Seymour JF
      • Lerner S
      • Keating MJ
      • Pollock RE
      Role of splenectomy in chronic lymphocytic leukemia.
      • Seymour JF
      • Cusack JD
      • Lerner SA
      • Pollock RE
      • Keating MJ
      Case/control study of the role of splenectomy in chronic lymphocytic leukemia.

      Age

      Chronic lymphocytic leukemia is typically seen in older people (94% of CLL patients are older than 50 years).
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      Whether the immune system decline associated with the aging process
      • Ginaldi L
      • De Martinis M
      • D'Ostilio A
      • et al.
      The immune system in the elderly, II: specific cellular immunity.
      adds to the immune dysfunction associated with the disease is unknown. Both cellular and humoral immune responses are modified in the elderly, although changes in T-cell responses and function are more prominent.
      • Pawelec G
      • Effros RB
      • Caruso C
      • Remarque E
      • Bamett Y
      • Solana R
      T cells and aging (update February 1999).
      The observed functional changes may be responsible for the association between advanced age and an increased susceptibility to infection.

      Effects of Treatment

      The effects of conventional cytotoxic chemotherapy on infectious complications in CLL, a disease having inherent immunodeficiency, are difficult to dissect. Alkylating agents, with or without corticosteroids, are typically given to patients who have advanced CLL and multiple concomitant risk factors for infection.
      • Foon KA
      • Rai KR
      • Gale RP
      Chronic lymphocytic leukemia: new insights inlü biology and therapy.
      • Montserrat E
      • Alcala A
      • Parody R
      • et al.
      Treatment of chronic lymphocytic leukemia in advanced stages: a randomized trial comparing chlorambucil plus prednisone versus cyclophospha-mide, vincristine, and prednisone.
      • Faguet GB
      Chronic lymphocytic leukemia: an updated review.
      • Keating MJ
      • Scouros M
      • Murphy S
      • et al.
      Multiple agent chemotherapy (POACH) in previously treated and untreated patients with chronic lymphocytic leukemia.
      • Sawitsky A
      • Rai KR
      • Glidewell O
      • Silver RT
      Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia.
      Response to chemotherapy may result in a lower incidence of infection
      • Shaw RK
      • Szwed C
      • Boggs DR
      • et al.
      Infection and immunity in chronic lymphocytic leukemia.
      • Miller DG
      • Karnofsky DA
      Immunologic factors and resistance to infection in chronic lymphatic leukemia.
      ;on the other hand, combination chemotherapy and its associated neutropenia and T-cell dysfunction may further impair an already dysfunctioning immune system. In fact, most patients having advanced refractory CLL who receive combination cytotoxic chemotherapy experience serious infectious complications.
      • Kempin S
      • Lee III, BJ
      • Thaler HT
      • et al.
      Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristinc, BCNU, cyclophosphamide, melphalan, and prednisone).
      • Keating MJ
      • Scouros M
      • Murphy S
      • et al.
      Multiple agent chemotherapy (POACH) in previously treated and untreated patients with chronic lymphocytic leukemia.
      The impact of adrenal corticosteroids on the risk of infection in CLL patients has also been investigated. Shaw et al
      • Shaw RK
      • Boggs DR
      • Silberman HR
      • Frei III, E
      A study of prednisone therapy in chronic lymphocytic leukemia.
      randomly assigned half of their patients to a regimen of 1 mg/kg of prednisone for 3 months followed by a 3-month washout period; this sequence was reversed for the other half of the patients. More frequent and severe infections, especially those caused by S aureus, were noted in connection with prednisone therapy. Prior conventional cytotoxic chemotherapy and corticosteroid therapy has also been an important risk factor for the increased incidence and severity of opportunistic infections in patients having alkylating agentrefractory CLL treated using fludarabine.
      • Anaissic EJ
      • Kontoyiannis DP
      • O'Brien S
      • et al.
      Infections in patients with chronic lymphocytic leukemia treated with fludarabine.
      Furthermore, a broad spectrum of pathogens, including gram-negative rods, opportunistic fungi, P carinii, Legionella spp, mycobacteria, and reactivated herpesviruses, was the major cause of early death in 147 patients having fludarabine-refractory CLL treated at the University of Texas M. D. Anderson Cancer Center (D.P.K. and M.J.K., unpublished data). These findings underscore the additive effects of immunosuppression of the advanced stage of disease and the immunodeficiency of alkylators, corticosteroids, and purine analogues on the incidence of infection in CLL patients.

      INFECTIONS IN CLL PATIENTS FOLLOWING NEWER THERAPIES

      The introduction of new purine analogues during the past decade has renewed clinical interest in the treatment of CLL.
      • Keating MJ
      Chronic lymphocylic leukemia.
      Treatment using these agents appears to provide better results compared with conventional therapeutic schemes.
      • Keating MJ
      Chronic lymphocylic leukemia.
      The most interesting of these agents are fludarabine phosphate, pentostatin, and cladribine (Table 1).
      • Keating MJ
      Chronic lymphocylic leukemia.
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      However, their clinical use has been accompanied by an apparent increase in opportunistic infections caused by uncommon pathogens such as P carinii, L monocytogenes, herpes zoster virus, and fungi.
      • Anaissic EJ
      • Kontoyiannis DP
      • O'Brien S
      • et al.
      Infections in patients with chronic lymphocytic leukemia treated with fludarabine.
      • Cheson BD
      Infectious and immunosuppressive complications of purine analog therapy.

      Fludarabine

      Fludarabine is a fluorinated nucleotide analogue of the antiviral agent vidarabine.
      • Ross SR
      • McTavish D
      • Faulds D
      Fludarabine: a review of its pharmacological properties and therapeutic potential in malignancy.
      which has been extensively investigated at M. D. Anderson Cancer Center.
      • Keating MJ
      Fludarabine phosphate in the treatment of chronic lymphocytic leukemia.
      • Keating MJ
      • Kantarjian H
      • Talpaz M
      • et al.
      Fludarabine: a new agent with major activity against chronic lymphocytic leukemia.
      En­couraging data from several recent clinical trials support the use of fludarabine as a first-line therapeutic agent against symptomatic CLL.
      • Keating MJ
      Chronic lymphocylic leukemia.
      • Twomey JJ
      Infections complicating multiple myeloma and chronic lymphocytic leukemia.
      Although well tolerated, fludarabine therapy has been associated with serious opportunistic infections, such as P carinii pneumonia (PCP), varicella zoster virus (VZV), and L monocytogenes, in CLL patients.
      • Anaissic EJ
      • Kontoyiannis DP
      • O'Brien S
      • et al.
      Infections in patients with chronic lymphocytic leukemia treated with fludarabine.
      • Cheson BD
      Infectious and immunosuppressive complications of purine analog therapy.
      To evaluate risk factors for infection following fludarabine therapy, 402 patients who had received fludarabine with or without prednisone in monthly 5-day courses at M. D. Anderson were studied.
      • Anaissic EJ
      • Kontoyiannis DP
      • O'Brien S
      • et al.
      Infections in patients with chronic lymphocytic leukemia treated with fludarabine.
      One third of the patients were previously untreated, about half had Rai stage III or IV disease, and one third had hypogammaglobulinemia. Risk factors for major infections were an advanced Rai stage, previous cytotoxic chemotherapy, a low serum albumin level, an elevated creatinine or β2-microglobulin level, a poor performance status, and a poor response to therapy. Listeria monocytogenes infec­tion or PCP developed in 11 patients, all of whom had received prednisone and 10 of whom had been heavily pretreated. Also, patients having a CD4 cell count less than 0.05 × 109/L frequently had herpes zoster virus. Other researchers have observed a similar pattern of severe opportunistic infections in case reports and small series
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      • Terreni AA
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      Herpes group virus infections in the compromised host.
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      Generalized herpes zoster associated with leukemia.
      • Barton RL
      • O'Leary PA
      Herpes zoster generalisatus, associated with chronic lymphatic leukemia.
      • Barrett AP
      Chronic indolent orofacial herpes simplex virus infection in chronic leukemia: a report of three cases.
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      • et al.
      Lethal disseminated adenovirus type 1 infection in a patient with chronic lymphocytic leukemia.
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      Generalized vaccinia in a patient with chronic lymphocytic leukemia and hypogammaglobulinemia.
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      • Rosen P
      Tuberculosis complicating neoplastic disease: a review of 201 cases.
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      • Body BA
      • Austin MB
      • Frierson Jr, HF
      Cunninghamella bertholletiae and Pneumocystis carinii pneumonia as a fatal complication of chronic lymphocytic leukemia.
      • Molica S
      Infections in chronic lymphocylic leukemia: risk factors, and impact on survival, and treatment.
      • Chapel HM
      • Bunch C
      Mechanisms of infection in chronic lymphocytic leukemia.
      • Rozman C
      • Montscrral E
      Chronic lymphocytic leukemia.
      • Dighiero G
      Hypogammaglobulinemia and disordered immunity in CLL.
      • Chapel HM
      Hypogammaglobulinemia and chronic lymphocylic leukaemia.
      • Miller DG
      • Budinger JM
      • Karnofsky DA
      A clinical and pathological study of resistance to infection in chronic lymphatic leukemia.
      • Rai KR
      • Montserrat E
      Prognostic factors in chronic lymphocytic leukemia.
      • Griffiths H
      • Lea J
      • Bunch C
      • Lee M
      • Chapel H
      Predictors of infection in chronic lymphocylic leukaemia (CLL).
      • Foa R
      Pathogenesis of the immunodeficiency in chronic lymphocytic leukemia.
      • Copson ER
      • Ellis BA
      • Westwood NB
      • Majumdar G
      IgG subclass levels in patients with B cell chronic lymphocytic leukaemia.
      • Morrison VA
      The infectious complications of chronic lymphocytic leukemia.

      Morrison VA, Opstad NL, Janoff EN. Correlation of systemic and mucosal immunoglobulin (Ig) levels in patients (pts) with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) [abstract]. In: Proceedings of the 34th Annual Meeting of the Infectious Diseases Society of America; 1996; New Orleans, La. Abstract 92.

      • Morrison VA
      • Hibbs JR
      • Janoff EN
      Systemic and mucosal immunoglobulin (IG) levels and risk of infection in patients (pts) with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) [abstract].
      • Morrison VA
      • Opstad NL
      • Janoff EN
      Mucosal immunoglobulin (Ig) levels in patients (pts) with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) [abstract].
      • Ammann AJ
      • Hong R
      Selective IgA deficiency: presentation of 30 cases and a review of the literature.
      • Rozman C
      • Montserrat E
      • Vinolas N
      Serum immunoglobulins in B-chronic lymphocytic leukemia: natural history and prognostic significance.
      • Dcegan MJ
      • Abraham JP
      • Sawdyk M
      • Van Slyck EJ
      High incidence of monoclonal proteins in the scrum and urine of chronic lymphocytic leukemia patients.
      • Saslaw S
      • Carlisle HN
      • Bouroncle B
      Antibody response in hematologic patients.
      • Barr M
      • Fairley GH
      Circulating antibodies in reticuloses.
      • Cone L
      • Uhr W, J
      Immunological deficiency disorders associated with chronic lymphocytic leukemi a and multiple myeloma.
      • Heath RB
      • Fairley GH
      • Malpas JS
      Production of antibodies against viruses in leukaemia and related diseases.
      • Jacobson DR
      • Ballard HS
      • Silber R
      • Ripps CS
      • Smith JA
      • Schiffman GS
      Antibody response to pneumococcal immunization in patients with chronic lymphocytic leukemia [abstract].
      • Shapiro ED
      • Berg AT
      • Austrian R
      • et al.
      The protective efficacy of polyvalent pneumococcal polysaccharide vaccine.
      • Gribabis DA
      • Panayiotidis P
      • Boussiotis VA
      • Hannoun C
      • Pangalis GA
      Influenza virus vaccine in B-cell chronic lymphocytic leukaemia patients.
      • Janeway CA
      • Gitlin D
      The gamma globulins.
      • Lawson HA
      • Stuart CA
      • Pauli AM
      • Phillips AM
      • Phillips RW
      Observations on the antibody content of the blood in patients with multiple myeloma.
      • Lacombe C
      • Gombert J
      • Dreyfus B
      • Brizard A
      • Preud' Homme JL
      Heterogeneity of scrum IgG subclass deficiencies in B chronic lymphocytic leukemia.
      • Freedman AS
      lmmunobiology of chronic lymphocytic leukemia.
      • Foa R
      • Catovsky D
      • Lauria F
      • Galton DA
      Reduced T-colony forming capacity by T-lymphocytes from B-chronic lymphocyte leukaemia.
      • Kay NE
      Abnormal T-cell subpopulation function in CLL: excessive suppressor (T gamma) and deficient helper (T mu) activity with respect to B-cell proliferation.
      • Foa R
      • Catovsky D
      • Brozovic M
      • et al.
      Clinical staging and immunological findings in chronic lymphocytic leukemia.
      • Platsoucas CD
      • Galinski M
      • Kcmpin S
      • Reich L
      • Clarkson B
      • Good RA
      Abnormal T lymphocyte subpopulations in patients with B cell chronic lymphocytic leukemia: an analysis by monoclonal antibodies.
      • Kay NE
      • Perri RT
      Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regutale B-cell immunoglobulin synthesis [published correction appears in Blood. 1989;73:2232).
      • Foa R
      • Fierro MT
      • Raspadori D
      • et al.
      Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors.
      • Ziegler HW
      • Kay NE
      • Zarling JM
      Deficiency of natural killer cell activity in patients with chronic lymphocytic leukemia.
      • Briggs PC
      • Kraft N
      • Atkins RC
      T cells and CD45 R expression in B-chronic lymphocytic leukemia.
      • Hersey P
      • Wotherspoon J
      • Reid G
      • Gun FW
      Hypogammaglobulinaemia associated with abnormalities of both B and T lymphocytes in patients with chronic lymphatic leukaemia.
      • Apostolopoulos A
      • Symeonidis A
      • Zoumbos N
      Prognostic significance of immune function parameters in patients with chronic lymphocytic leukaemia.
      • Zaknoen SL
      • Kay NE
      Immunoregulatory cell dysfunction in chronic B-cell teukemias.
      • Serrano D
      • Monteiro J
      • Allen SL
      • et al.
      Clonal expansion within the CD4+-CD57+ and CD8+CD57+ T cell subsets in chronic lymphocytic leukemia.
      • Alatrakchi N
      • Faracc F
      • Frau E
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      • Munck JN
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      T-cell clonal expansion in patients with B-cell lymphoproliferative disorders.
      • Platsoucas CD
      • Fernandes G
      • Gupta SL
      • et al.
      Defective spontaneous and antibody-dependent cytoloxicity mediated by E-rosette-positive and E-rosctte-negative cells in untreated patients with chronic lymphocytic leukemia: augmentation by in vitro treatment with interferon.
      • Villamor N
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      • Montscrrat E
      • Urbano-Ispizua A
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      Recombinant alpha 2b-interferon may restore natural-killer activity in patients with B-chronic lymphocytic leukemia.
      • McCann SR
      • Whelan CA
      • Breslin B
      Temperley IJ. Lymphocyte sub-populations following splenic irradiation in patients with chronic lymphocytic leukaemia.
      • Miller DG
      Patterns of immunological deficiency in lymphomas and leukemias.
      • Miller DG
      • Lizardo JG
      • Snyderman RK
      Homologous and heterolagous skin transplantation in patients with lymphomatous disease.
      • Block JB
      • Haynes HA
      • Thompson WL
      • Neiman PE
      Delayed hypersensitivity in chronic lymphocytic leukemia.
      • Bouroncle BA
      • Clausen KP
      • Aschenbrand JF
      Studies of the delayed response of phytohemagglutinin (PHA) stimulated lymphocytes in 25 chronic lymphatic leukemia patients before and during therapy.
      • Linsley PS
      • Ledbetter JA
      The role of the CD28 receptor during T cell responses to antigen.
      • Rossi E
      • Matutes E
      • Morilla R
      • Owusu-Ankomah K
      • Heffernan AM
      • Catovsky D
      Zeta chain and CD28 are poorly expressed on T lymphocytes from chronic lymphocytic leukemia.
      • Arnold C
      • McPhedran P
      Leukemia, myeloproliferative disorders-natural history: prognostic significance of neutrophil counts, gamma globulin levels, and symptoms in chronic lymphocytic leukemia [abstract].
      • De Rossi G
      • Maura FR
      • Ialongo P
      • Coluzzi S
      • Pizzo F
      Monocytopenia and infections in chronic lymphocytic leukemia [letter].
      • Boggs DR
      The cellular composition of inflammatory exudates in human leukemias.
      • Zeya HI
      • Keku E
      • Richards F II
      • Spurr CL
      Monocyte and granulocyte defect in chronic lymphocytic leukemia.
      • Itala M
      • Vainio O
      • Rcmes K
      Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia.
      • Shvidel L
      • Vorst E
      • Berrebi A
      Complement values in B chronic lymphocytic leukemia: prognostic significance and correlation with cell maturation stage [letter].
      • Varga L
      • Czink E
      • Miszlai Z
      • et al.
      Low activity of the classical complement pathway predicts short survival of patients with chronic lymphocytic leukaemia.
      • Heath ME
      • Cheson BD
      Defective complement activity in chronic lymphocytic leukemia.
      • Dicato M
      • Schmit JC
      • Mahon G
      • Ries F
      Chronic activation of complement in chronic lymphatic leukemia [abstract].
      • Schlesinger M
      • Broman I
      • Lugassy G
      The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives.
      • Fust G
      • Czink E
      • Minh D
      • Miszlay Z
      • Varga L
      • Hollan SR
      Depressed classical complement pathway activities in chronic lymphocytic leukaemia.
      • Stein RS
      • Weikcrt D
      • Reynolds V
      • Greer JP
      • Flexner JM
      Splencctomy for end-stage chronic lymphocytic leukemia.
      • Holt JM
      • Witts LJ
      Splenectomy in leukaemia and the reliculoses.
      • Diehl LF
      • Ketchum LH
      Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia.
      • Cusack Jr, JC
      • Seymour JF
      • Lerner S
      • Keating MJ
      • Pollock RE
      Role of splenectomy in chronic lymphocytic leukemia.
      • Seymour JF
      • Cusack JD
      • Lerner SA
      • Pollock RE
      • Keating MJ
      Case/control study of the role of splenectomy in chronic lymphocytic leukemia.
      • Ginaldi L
      • De Martinis M
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      • et al.
      The immune system in the elderly, II: specific cellular immunity.
      • Pawelec G
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      T cells and aging (update February 1999).
      • Montserrat E
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      • Parody R
      • et al.
      Treatment of chronic lymphocytic leukemia in advanced stages: a randomized trial comparing chlorambucil plus prednisone versus cyclophospha-mide, vincristine, and prednisone.
      • Faguet GB
      Chronic lymphocytic leukemia: an updated review.
      • Keating MJ
      • Scouros M
      • Murphy S
      • et al.
      Multiple agent chemotherapy (POACH) in previously treated and untreated patients with chronic lymphocytic leukemia.
      • Sawitsky A
      • Rai KR
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      • Silver RT
      Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia.
      • Anaissic EJ
      • Kontoyiannis DP
      • O'Brien S
      • et al.
      Infections in patients with chronic lymphocytic leukemia treated with fludarabine.
      • Cheson BD
      Infectious and immunosuppressive complications of purine analog therapy.
      • Ross SR
      • McTavish D
      • Faulds D
      Fludarabine: a review of its pharmacological properties and therapeutic potential in malignancy.
      • Keating MJ
      Fludarabine phosphate in the treatment of chronic lymphocytic leukemia.
      • Keating MJ
      • Kantarjian H
      • Talpaz M
      • et al.
      Fludarabine: a new agent with major activity against chronic lymphocytic leukemia.
      • Girmenia C
      • Mauro FR
      • Rahimi S
      Late listeriosis after fludarabine plus prednisone treatment.
      • Cleveland KO
      • Gelfand MS
      Listerial brain abscess in a patient with chronic lymphocytic leukemia treated with fludarabine [tetter].
      • Bastion Y
      • Coiffier B
      • Tigaud JD
      • Espinouse D
      • Bryon PA
      Pneumocyslis pneumonia in a patient treated with fludarabine for chronic lymphocytic leukemia [letter].
      • Sanders C
      • Perez EA
      • Lawrence HJ
      Opportunistic infections in patients with chronic lymphocytic leukemia following treatment with fludarabine [letlerl.
      • Puccio CA
      • Mittelman A
      • Lichtman SM
      • et al.
      A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia.
      • Stelitano C
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      • Krapp MG
      • et al.
      Fludarabine treatment in B-cell chronic lymphocytic leukemia: response, toxicity and survival analysis in 47 cases.
      • Re D
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      • et al.
      Two cases of toxoplasmic encephalitis in patients with acute T-cell leukaemia and lymphoma.
      • Eftekhari P
      • Lassoued K
      • Oksenhendler E
      • Scieux C
      • Clauvel JP
      Severe respiratory syncytial virus pulmonary infection in a patient treated with fludarabine for chronic lymphocytic leukemia.
      of patients having advanced CLL who were receiving fludarabine monthly that occurred mostly during the first 3 cycles of therapy. Similar infections were also reported in patients receiving fludarabine for low-grade lymphoma
      • Redman JR
      • Cabanillas F
      • Velasquez WS
      • et al.
      Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma.
      or Waldenström macroglobulinemia
      • Foran JM
      • Rohatiner AZ
      • Coiffier B
      • et al.
      Multicentcr phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenstrom's macroglobulinemia, and mantle cell lymphoma.
      • Dimopoulos MA
      • O'Brien S
      • Kantarjian H
      • et al.
      Fludarabine therapy m Waldenstrom's macroglobulinemia.
      or newer combined therapeutic modalities having fludarabine and epirubicin
      • Rummel MJ
      • Kafer G
      • Pfreundschuh M
      • et al.
      Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia: a German multicenter phase II study.
      or cyclophosphamide
      • Frewin R
      • Turner D
      • Tighe M
      • Davies S
      • Rule S
      • Johnson S
      Combination therapy with fludarabine and cyclophosphamide as salvage treatment in lymphoproliferative disorders.
      for refractory CLL.

      Cladribine

      Treatment using cladribine, similar to that using fludarabine, has frequently led to serious infectious complications.
      • Cheson BD
      Infectious and immunosuppressive complications of purine analog therapy.
      • Piro LD
      • Carrera CJ
      • Beutler E
      • Carson DA
      2-Chlorodeoxy-adenosine: an effective new agent for the treatment of chronic lymphocytic leukemia.
      • Saven A
      • Carrera CJ
      • Carson DA
      • Beutler E
      • Piro LD
      2-Chlorodeoxyadenosine treatment of refractory chronic lymphocytic leukemia.
      • Betticher DC
      • Fey MF
      • von Rohr A
      • et al.
      High incidence of infections after 2-chlorodeoxyadenosine (2-CDA) therapy in patients with malignant lymphomas and chronic and acute leukaemias.
      • Van Den Neste E
      • Delannoy A
      • Vandercam B
      • et al.
      Infectious complications after 2-chlorodeoxyadenosine therapy.
      • Juliusson G
      • Liltemark J
      Long-term survival following cladribine (2-chlorodeoxyadenosine) therapy in previously treated patients with chronic lymphocytic leukemia.
      • Robak T
      • Blonski JZ
      • Urbanska-Rys H
      • Blasinska-Morawiec M
      • Skotnicki AB
      2-Chlorodeoxyadenosine (cladribine) in the treatment of patients with chronic lymphocytic leukemia 55 years old and younger.
      • Spielbcrger RT
      • Stock W
      • Larson RA
      Listeriosis after 2-chlorodeoxyadenosine treatment [letter].
      These infections usually occurred around 2 months after the initiation of therapy. The pattern of infections after cladribine treatment was notable for an increase in episodes of fever of undetermined origin and herpetic infections. Severe pneumonias and bacteremias were common, as were upper respiratory tract infections and reactivation of herpesviruses. A broad range of common pathogens were seen, including both gram-positive (eg, Staphylococcus and Streptococcus spp) and gram-negative bacteria (eg, E coli, Klebsiella spp, Enterobacter spp, Aci­netobacter spp, N meningitidisi), L monocytogenes, PCP, herpesviruses (HSV, VZV), cytomegalovirus, adenovirus, and Candida and Aspergillus Spp.
      • Cheson BD
      Infectious and immunosuppressive complications of purine analog therapy.
      • Piro LD
      • Carrera CJ
      • Beutler E
      • Carson DA
      2-Chlorodeoxy-adenosine: an effective new agent for the treatment of chronic lymphocytic leukemia.
      • Saven A
      • Carrera CJ
      • Carson DA
      • Beutler E
      • Piro LD
      2-Chlorodeoxyadenosine treatment of refractory chronic lymphocytic leukemia.
      • Betticher DC
      • Fey MF
      • von Rohr A
      • et al.
      High incidence of infections after 2-chlorodeoxyadenosine (2-CDA) therapy in patients with malignant lymphomas and chronic and acute leukaemias.
      • Van Den Neste E
      • Delannoy A
      • Vandercam B
      • et al.
      Infectious complications after 2-chlorodeoxyadenosine therapy.
      • Juliusson G
      • Liltemark J
      Long-term survival following cladribine (2-chlorodeoxyadenosine) therapy in previously treated patients with chronic lymphocytic leukemia.
      • Robak T
      • Blonski JZ
      • Urbanska-Rys H
      • Blasinska-Morawiec M
      • Skotnicki AB
      2-Chlorodeoxyadenosine (cladribine) in the treatment of patients with chronic lymphocytic leukemia 55 years old and younger.
      • Spielbcrger RT
      • Stock W
      • Larson RA
      Listeriosis after 2-chlorodeoxyadenosine treatment [letter].
      Previous chemotherapy, advanced age, lymphopenia, and a history of infections 6 months prior to commencing cladribine therapy carried an increased risk of subsequent severe infection. Patients who previously received fludarabine had the highest rate of infection, underscoring the harmful effects of prior therapies using other purine analogues as well as the effect of progressive disease. Specifically, in a study at M. D. Anderson in which cladribine was given to patients having advanced fludarabine-refractory CLL, severe and unusual infections such as PCP were noted in a subset of patients.
      • O'Brien S
      • Kantarjian H
      • Estey E
      • et al.
      Lack of effect of 2-chlorodeoxyadenosine therapy in patients with chronic lymphocytic leukemia refractory to fludarabine therapy.
      Table 3 summarizes the risk factors for serious infections in patients having CLL treated using either fludarabine or cladribine.
      Table 3Risk Factors fur Serious Infections in Patients Having Chronic Lyntphocytic Leukemia Treated With Fludarabine or Cladribine
      • Fludarabine
        • Advanced Rai stage
        • Previous cytotoxic chemotherapy
        • Low serum albumin level
        • Elevated crcatinine
        • Elevated β,-microglobulin level
        • Poor performance status
        • Poor response to therapy
      • Cladribine
        • Advanced stage of disease
        • Previous cytotoxic chemotherapy
        • Previous fludarabine use
        • Infection during the 6 mo prior to cladribine therapy
        • Lymphopcnia

      Pentostatin

      Pentostatin therapy has been associated with the same pattern of infections as that associated with fludarabine and cladribine.
      • Cheson BD
      Infectious and immunosuppressive complications of purine analog therapy.
      • Dillman RO
      • Mick R
      • McIntyre OR
      Pentostatin in chronic lymphocytic leukemia: a phase II trial of cancer and leukemia group B.
      • Riddell S
      • Johnston JB
      • Bowman D
      • Glazer R
      • Israels LG
      2'-Deoxycoformycin (DCF) in chronic lymphatic leukemia (CLL) and Waldenstrom's macroglobulinemia (WM) [abstract].
      • Johnson SA
      • Catovsky D
      • Child JA
      • Newland AC
      • Milligan DW
      • Janmohamcd R
      Phase I/II evaluation of pentostatin (2'-deoxycoformycin) in a five day schedule for the treatment of relapsed/refractory B-cell chronic lymphocytic leukaemia.
      For example, Dillman et al
      • Dillman RO
      • Mick R
      • McIntyre OR
      Pentostatin in chronic lymphocytic leukemia: a phase II trial of cancer and leukemia group B.
      reported that severe life-threatening infections developed in 34 of 39 patients having advanced CLL who received pentostatin. These infections were usually seen during the first few weeks of therapy and were much more common in pretreated patients having advanced-stage CLL. The spectrum of infections included S pneumoniae pneumonia, fatal Pseudomonas bacteremia, HSV and VZV infections, disseminated candidiasis, and PCP.
      Even though treatment using purine analogues has resulted in serious infectious complications in CLL patients, interestingly, this has not been the case in patients who received biologic-response modifiers, such as the interferons, IL-2, and most of the available monoclonal antibodies.
      • Talpaz M
      • Rosenblum M
      • Kurzrock R
      • Reuben J
      • Kantarjian H
      • Gutterman J
      Clinical and laboratory changes induced by alpha interferon in chronic lymphocytic leukemia-a pilot study.
      • Kay NE
      • Oken MM
      • Mazza JJ
      • Bradley EC
      Evidence for tumor reduction in refractory or relapsed B-CLL patients with infusional interleukin-2.
      • Hertler AA
      • Schlossman DM
      • Borowitz MJ
      • et al.
      A phase I study of T101-ricin A chain immunotoxin in refractory chronic lymphocytic leukemia.
      However, caution is necessary when using all new forms of therapy. For example, profound lymphopenia was observed in preliminary studies of CLL patients who received an investigational anti-CD52 monoclonal antibody, alemtuzumab.
      • Osterborg A
      • Dyer MJ
      • Bunjes D
      • et al.
      European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia.
      • Rai KR
      • Hoffman M
      • Janson D
      • et al.
      Immunosuppression and opportunistic infections (OI) in patients with chronic lymphocytic leukemia (CLL) following Campalh I-H therapy [abstract].
      These patients did not receive anti-infective prophylaxis and had a high frequency of infections caused by opportunistic pathogens, including HSV, VZV, cytomegalovirus, P carinii, Cryptococcus neoformans, L monocytogenes, and opportunistic fungi. Our preliminary experience with alemtuzumab in patients having fludarabine-refractory CLL revealed a high incidence of cytomegalovirus reactivation (D.P.K. and M.J.K., unpublished data). Our patients routinely received trimethoprim-sulfamethoxasole and valacyclovir prophylaxis, which could have accounted for the lack of serious infections caused by HSV, VZV, P carinii, or L monocyto­genes. Additionally, rituximab is a genetically engineered chimeric (murine-human) monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B cells
      • Byrd JC
      • Waselenko JK
      • Maneatis TJ
      • et al.
      Rituximab therapy in hematologie malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance.
      ; its use against CLL has been limited thus far.
      • Byrd JC
      • Waselenko JK
      • Maneatis TJ
      • et al.
      Rituximab therapy in hematologie malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance.
      • Nguyen DT
      • Amess JA
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      • Hendry L
      • Diamond LW
      IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients.
      Infections with pathogens such as E coli, herpesvirus, and Candida spp were seen in 19 of 54 lymphoma patients in a multicenter trial evaluating rituximab.
      • Coiffier B
      • Haioun C
      • Ketterer N
      • et al.
      Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study.
      This rate of infection was slightly higher than that previously reported in patients having low-grade lymphoma treated using rituximab.
      • Maloney DG
      • Grillo-Lopez AJ
      • White CA
      • et al.
      IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma.
      • Maloney DG
      • Grillo-Lopez AJ
      • Bodkin DJ
      • et al.
      IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma.
      Finally, bone marrow transplantation (BMT) has also been used in the treatment of CLL, specifically to induce a prolonged period of disease-free survival in selected subsets of CLL patients.
      • Khouri IF
      • Keating MJ
      • Champlin R
      Hematopoietic stem cell transplantation for chronic lymphocytic leukemia.
      • Michallet M
      • Archimbaud E
      • Bandini G
      • et al.
      European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry.
      • Khouri IF
      • Keating MJ
      • Vriesendorp HM
      • et al.
      Autologous and allogcncic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results.
      Bone marrow transplant recipients may experience several additional immunosuppressive complications, such as graft-vs-host disease and graft rejection, which could further amplify their risk of severe opportunistic infections. In fact, the occurrence of serious infections similar to those encountered in patients who received fludarabine and prednisone suggests that BMT has a similar underlying pathophysiologic mechanism.
      • Zomas A
      • Mehta J
      • Powles R
      • et al.
      Unusual infeciions following allogeneic bone marrow transplantation for chronic lymphocytic leukemia.
      Rabinowe et al
      • Rabinowe SN
      • Soiffer RJ
      • Grrbben JG
      • et al.
      Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia.
      suggested that these patients may have more delayed or defective reconstitution of their immune system after BMT compared with patients who undergo BMT for other disorders, but so far, the number of cases of BMT in these patients has been too small to draw any definitive conclusions.

      PATHOGENESIS OF INFECTIONS IN CLL TREATED WITH THE NEWER PURINE ANALOGUES

      Defects in cell-mediated immunity resulting in severe, long-lasting immunosuppression are associated with the use of fludarabine, cladribine, and pentostatin (Table 2).
      • Cheson BD
      Infectious and immunosuppressive complications of purine analog therapy.
      Pronounced lymphopenia and lymphocyte dysfunction have been noted, usually associated with different opportunistic infections.

      Fludarabine

      The pathogenesis of severe opportunistic infections during fludarabine therapy seems to be complex, multifactorial, and poorly understood. Fludarabine can induce severe, prolonged immunosuppression.
      • Fenchel K
      • Bergmann L
      • Wijermans P
      • et al.
      Clinical experience with fludarabinc and its immunosuppressive effects in pretreated chronic lymphocytic leukemias and low-grade lymphomas.
      There is concern that the cell-mediated dysregulation of advanced-stage CLL with an abnormal baseline CD4/CD8 ratio may be further aggravated by agents that have a rapid, profound lympholytic action.
      • Schilling PJ
      Two views of the immunologie effects of fludarabine [letter].
      • Boldt DH
      • Von Hoff DD
      • Kuhn JG
      • Hersh M
      Effects on human peripheral lymphocytes of in vivo administration of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-monophosphate (NSC 312887). a new purine antimetabolite.
      Fludarabine is phosphorylated intracellularly to arabinosyl-2-fluoroadenine, which inhibits DNA synthesis and repair as well as RNA synthesis. In addition, it was recently discovered that fludarabine inhibits the cytokine-induced activation of STAT1, a molecule essential for cell-mediated immunity.
      • Frank DA
      • Mahajan S
      • Ritz J
      Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling.
      Additionally, fludarabine induces apoptosis in both proliferating and quiescent cells, and in a recent study, a differential effect on apoptosis between B and T lymphocytes in CLL was noted, which was dependent on the Rai stage.
      • Consoli U
      • El-Tounsi I
      • Sandoval A
      • et al.
      Differential induction of apoptosis by fludarabine monophosphate in leukemic B and normal T cells in chronic lymphocytic leukemia.
      In another study, a profound, rapid decrease in all T-cell subsets was seen in patients having advanced CLL treated with fludarabine
      • Wijermans PW
      • Gerrits WB
      • Haak HL
      Severe immunodeficiency in patients treated with fludarabine monophosphate.
      ; CD4 cell counts were still depressed 12 months after therapy ended. The spectrum of infections seen was similar to that in other studies and included PCP, cytomegalovirus, VZV, and invasive mycoses. Similarly, Bergmann et al
      • Bergmann L
      • Fenchel K
      • Jahn B
      • Mitrou PS
      • Hoelzer D
      Immunosuppressive effects and clinical response of fludarabine in refractory chronic lymphocytic leukemia.
      associated a rapid reduction in CD4 cell counts following fludarabine therapy with an identical spectrum of opportunistic infections in patients having advanced CLL.
      Although it seems that the combination of fludarabine and prednisone is associated with more severe opportunistic infections (particularly PCP and listeriosis) than is fludarabine alone,
      • Sawitsky A
      • Rai KR
      • Glidewell O
      • Silver RT
      Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia.
      • Schilling PJ
      • Vadhan-Raj S
      Concurrent cytomegalovirus and Pneumocystis pneumonia after fludarabine therapy for chronic lymphocytic leukemia [letter].
      • Anaissie E
      • Kontoyiannis DP
      • Kantarjian H
      • Elting L
      • Robertson LE
      • Keating M
      Listehosis in patients with chronic lymphocytic leukemia who were treated with fludarabine and prcdnisone.
      • Byrd JC
      • Hargis JB
      • Kester KE
      • Hospcnthal DR
      • Knutson SW
      • Diehl LF
      Opportunistic pulmonary infections with fludarabine in previously treated patients with low-grade lymphoid malignancies: a role for Pneumocystis carinii pneumonia prophylaxis.
      it is difficult to determine the exact role of each of these variables. Corticosteroid use is well known to be associated with such infections through multiple mechanisms, including lymphocytic action and suppression of the macrophage-monocyte axis.
      • Fauci AS
      • Dale DC
      • Balow JE
      Glucocorticosteroid therapy: mechanisms of action and clinical considerations.
      The therapeutic role of corticosteroids is in question, and it appears that their use predisposes patients to subsequent opportunistic infections when combined with fludarabine. That somewhat higher doses of prednisone administered previously to a comparable patient population at M. D. Anderson did not increase the risk of these unusual infection
      • Keating MJ
      • Scouros M
      • Murphy S
      • et al.
      Multiple agent chemotherapy (POACH) in previously treated and untreated patients with chronic lymphocytic leukemia.
      implicates the potential synergistic effect of prednisone plus fludarabine in lowering the threshold for such infections.

      Cladribine

      Ribonucleotide reductase, which is active mainly in dividing cells, is inhibited by the excess 2-chlorodeoxyadenosine (2-CdA) 5′-triphosphate that accumulates after administration of cladribine.
      • Saven A
      • Piro L
      Newer purine analogues for the treatment of hairy-cell leukemia.
      Consequently, the intracellular pool of deoxynucleotides is depleted, and DNA synthesis is impaired.
      • Avery TL
      • Rehg JE
      • Lumm WC
      • Harwood FC
      • Santana VM
      • Blakley RL
      Biochemical pharmacology of 2-chlorodeoxy-adenosine in malignant human hematopoietic cell lines and therapeutic effects of 2-bromodeoxyadenosine in drug combinations in mice.
      It also appears that 2-CdA 5′ -triphos­phate is incorporated into the DNA of dividing cells.
      • Carson DA
      • Wasson DB
      • Taetle R
      • Yu A
      Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes.
      Furthermore, lymphocytes and monocytes are exquisitely sensitive to 2-CdA.
      • Carson DA
      • Wasson DB
      • Taetle R
      • Yu A
      Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes.
      • Carrera CJ
      • Terai C
      • Lot M
      • et al.
      Potent toxicity of 2-chlorodeoxyadenosine toward human monocyles in vitro and in vivo: a novel approach to immunosuppressive therapy.
      A profound, long-lasting suppressive effect on CD4 and CD8 lymphocytes and the immune dysfunction induced by the underlying malignancy both, appear to play a major role in the pathogenesis of 2-CdA-related immunosuppression and subsequent infection.
      • Carrera CJ
      • Piro LD
      • Savcn A
      • et al.
      Restoration of lymphocyte subsets following 2-chlorodeoxyadenosine remission induction in hairy cell leukemia [abstract].
      • Seymour JF
      • Kurzrock R
      • Freireich EJ
      • Estey EH
      2-Chloro-deoxyadenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia.
      • Juliusson G
      • Lenkei R
      • Liliemark J
      Flow cytometry of blood and bone marrow cells from patients with hairy cell leukemia: pheno-type of hairy cells and lymphocyte subsets after treatment with 2-chlorodeoxyadenosine.

      Pentostatin

      Severe combined immunodeficiency (SCID)-like syndrome
      • O'Dwyer PJ
      • SpieTs AS
      • Marsoni S
      Association of severe and fatal infections and treatment with pentostatin.
      may develop in CLL patients who receive pentostatin. This is easily explained by the binding action pentostatin exerts on adenosine deaminase (ADA), an enzyme having a genetic deficiency that results in SCID.
      • Giblett ER
      • Anderson JE
      • Cohen F
      • Pollara B
      • Meuwissen HJ
      Adenosine-dcaminase deficiency in two patients with severely impaired cellular immunity.
      The inhibition of ADA by pentostatin, together with the impairment of lymphocytes,
      • Snyder FF
      • Hershfield MS
      • Seegmiller JE
      Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts.
      monocytes,
      • Grever MR
      • Krause MA
      • Balcerzak SP
      Adenosine deammase inhibition impairs monocyte cytotoxicity [abstract].
      macrophages,
      • Gray DP
      • Coleman MS
      • Siaw MFE
      • Rinehart JJ
      • O'Dorisio MS
      • Grever MR
      Macrophage biochemical abnormalities and impaired phagocytosis associated with 2'deoxycoformycin and deoxyadenosine culture [abstract].
      and NK cells,
      • Grever R, M
      • Siaw MF
      • Coleman MS
      • Whisler RL
      • Balcerzak SP
      Inhibition of K and NK lymphocyte cytotoxicity by an inhibitor of adenosine dcaminase and deoxyadenosine.
      may explain this new spectrum of infections. T cells are typically more sensitive than B cells, and both the CD4 and CD8 subsets of T cells are affected.
      • Snyder FF
      • Hershfield MS
      • Seegmiller JE
      Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts.
      • Urba WJ
      • Baseler MW
      • Kopp WC
      • et al.
      Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia.
      The striking resemblance between the infectious complications in patients who receive fludarabine and prednisone and those who receive Pentostatin may be explained by the effect these agents have on CD4 cells. This persistent immunosuppressive effect of pentostatin has also been studied in patients having hairy cell leukemia.
      • Urba WJ
      • Baseler MW
      • Kopp WC
      • et al.
      Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia.
      • Kraut EH
      • Neff JC
      • Bouroncle BA
      • Gochnour D
      • Grever MR
      Immunosuppressive effects of pentostatin.

      PROPHYLACTIC STRATEGIES

      Marked differences in risk of infection and prophylactic strategies exist among patients having different stages of CLL (Table 4). Because patients with early-stage disease do not usually require intensive chemotherapy, antimicrobial prophylaxis may not be necessary unless the patients suffer repeated moderate or severe infections. On the other hand, patients with advanced disease who receive intensive cytotoxic chemotherapy have a higher risk of infection and should be considered candidates for antibacterial, antifungal, and antiviral prophylaxis. Special care and close follow-up should be performed in CLL patients who have the highest risk of death due to infectious cause, such as those having refractory disease, a history of prior severe infections, neutropenia, and a history of prior treatment using alkylating agents, corticosteroids, and purine analogues.
      Table 4Proposed Prophylactic Strategies for Patients Having Early and Advanced Chronic Lymphocytic Leukemia at Risk for Infection
      CLL = chronic lymphocytic leukemia; G-CSF = granulocyle colony-stimulating factor; GM-CSF = granulocytc-macrophage colony-stimulating factor; IVFG = intravenous immunoglobulin; PCP = P carinii pneumonia.
      StrategyProblemsBest candidatesSpecific approach
      Counseling for early signs and symptoms of infectionAll patients
      Antibacterial prophylaxisPotential for emergence of resistancePatients having frequent upper respiratory tract infectionsAmoxicillin-clavulanic acid; trimethoprim-sulfamethoxazole
      PCP prophylaxisLate-stage CLL treated using purine analoguesTrimcthoprim-sulfamethoxazole, 1 double-strength tablet x 3/wk for 2 mo after fludarabine therapy
      Anlifungal prophylaxisPotential for development of antifungal drug resistanceLate-stage CLL treated using cytotoxic agents and/or purine analoguesFluconazole ± itraconazole
      Antiviral prophylaxisLate-stage CLL treated using purine analoguesAcyclovir or valacyclovir
      Growth factors?Not cost-effectivePatients having prolonged, profound neutropeniaGM-CSForG-CSF
      IVFGNot cost-effective; IgM and IgA, not replacedPatients having hypogamma-globulinemia and frequent serious bacterial infections; history of recurrent bacterial infections; IgG tilers <400 mg/dL; low titers of antibodies against encapsulated bacteriaIVIG (400 mg/kg) at 3-wk intervals 1 y; alternatively, 10 g of IVIG every 3 wk
      VaccinationPoor antibody response vaccination of live attenuated viruses contraindicaiedPatients having carly-stagc CLL, patients having normal immunoglobulin levelsPneumococcal, influenza vaccine; H influenzae type B, influenza virus vaccine
      * CLL = chronic lymphocytic leukemia; G-CSF = granulocyle colony-stimulating factor; GM-CSF = granulocytc-macrophage colony-stimulating factor; IVFG = intravenous immunoglobulin; PCP = P carinii pneumonia.

      Antibacterial Prophylaxis

      Although no controlled studies of the cost-effectiveness of antibiotic prophylaxis in CLL have been done, there is some anecdotal evidence that the practice is beneficial.
      • Miller DG
      • Budinger JM
      • Karnofsky DA
      A clinical and pathological study of resistance to infection in chronic lymphatic leukemia.
      However, early studies of patients having chronic bronchiectasis produced conflicting results and raised concerns about the possible selection of antibiotic-resistant flora.
      Value of chemoprophylaxis and chemotherapy in early chronic bronchitis: a report to the Medical Research Council by their Working Party on trials of chemotherapy in early chronic bronchitis.
      • Stott NC
      • West RR
      Randomised controlled trial of arntibiotics in patients with cough and purulent sputum.
      Cost-effectiveness analysis of antibiotic prophylaxis in patients having CLL and recurrent respiratory tract or soft tissue infections is needed. The ideal prophylactic agent should offer adequate empiric coverage against commonly encountered upper respiratory tract pathogens, such as H influenzae, S pneumoniae, and S aureus. Combina­tions of amoxicillin and clavulanic acid or trimethoprim and sulfamethoxazole would therefore seem to be reasonable prophylactic choices to target most of these pathogens.
      • Sudhoff T
      • Anting M
      • Schneider W
      Prophylactic strategies to meet infectious complications in fludarabine-treated CLL.
      Also, patients should be educated about their risk of infection with encapsulated organisms. When having signs of infection, such as high fever or rigors, they should be prepared to start receiving a course of antibiotics immediately. It would therefore be advisable for them to have a short supply of an antibiotic for immediate use. In addition, the increased risk of certain other bacterial and nonbacterial opportunistic infections in patients who receive new purine analogues must not be overlooked. This problem would dictate another strategy aimed at preventing L mono­cytogenes, P carinii, VZV, and fungal infections. However, there are no placebo-controlled studies evaluating the cost-effectiveness of PCP prophylaxis in this population. Given the high fatality rate among infected patients, some researchers recommend taking 1 trimethoprim-sulfamethoxazole double-strength tablet (80 mg of trimethoprim, 400 mg of sulfamethoxazole) 3 times a week for up to 2 months after stopping fludarabine therapy.
      • Byrd JC
      • Hargis JB
      • Kester KE
      • Hospcnthal DR
      • Knutson SW
      • Diehl LF
      Opportunistic pulmonary infections with fludarabine in previously treated patients with low-grade lymphoid malignancies: a role for Pneumocystis carinii pneumonia prophylaxis.
      • Sudhoff T
      • Anting M
      • Schneider W
      Prophylactic strategies to meet infectious complications in fludarabine-treated CLL.
      Additionally, neutropenia is a common finding in early cycles of fludarabine therapy. The use of granulocyte colony-stimulating factor was studied in a small cohort of CLL patients (Rai stage II-IV) at our institution, resulting in a decrease in myelosuppression and pneumonia. The incidence of pneumonia was 8%, in contrast with an incidence of 37% in a historical cohort who received fludarabine alone.
      • O'Brien S
      • Kantarjian H
      • Beran M
      • et al.
      Fludarabine and granu-locyte colony-stimulating factor (G-CSF) in patients with chronic lymphocytic leukemia.
      Administration of granulocyte-macrophage colony-stimulating factor improved neutropenia in CLL patients having chronic neutropenia and recurrent infections.
      • Itala M
      • Petliniemi TT
      • Remes K
      • Vanhatalo S
      • Vainio O
      Long-term treatment with GM-CSF in patients with chronic lymphocytic leukemia and recurrent neutropenic infections.
      These findings await confirmation from future larger trials. The cost-effectiveness of this strategy also warrants further investigation.

      Immunoglobulin Replacement

      The early results of uncontrolled studies of intravenous immunoglobulin (IVIG) in CLL patients having hypogammaglobulinemia and serious or chronic persistent infections were encouraging.
      • Besa EC
      Use of intravenous immunoglobulin in chronic lymphocytic leukemia.
      • Chapel HM
      • Lee M
      immunoglobulin replacement in patients with chronic lymphocytic leukemia (CLL): kinetics of immunoglobulin metabolism.
      A large randomized, double-blind, placebo-controlled multicenter trial of IVIG replacement in this patient population has provided the most insight into an issue that remains controversial.
      • Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia
      Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia: a randomized, controlled clinical trial.
      Patients having an increased risk of infection because of hypogammaglobulinemia, a history of infection, or both were included. Moderately severe bacterial infections were reduced by 50% in this study, while minor and severe bacterial infections remained unchanged. Also, no reduction in mortality was noted. A subset of patients from this trial then continued receiving treatment in a crossover double-blind study using the same inclusion schedule.
      • Griffiths H
      • Brennan V
      • Lea J
      • Bunch C
      • Lee M
      • Chapel H
      Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors.
      Serious bacterial infections were less frequent in the months in which patients received IgG (P=.001) and in patients whose IgG level remained higher than 6.49 mg/dL. T