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Clinical manifestations and infectious complications of hairy-cell leukaemia
Best Practice & Research Clinical Haematology Vol. 16, No. 1, pp. 33–40, 2003 doi:10.1053/ybeha.2003.238
3 Clinical manifestations and infectious complications of hairy-cell leukaemia Eric H. Kraut*
MD
Professor of Medicine Division of Hematology –Oncology, The Ohio State University, 320 W 10th Avenue, Columbus, OH 43210, USA
Hairy-cellleukaemiaisanindolentlymphoproliferativemalignancycharacterizedbyinfiltrationofthe bonemarrow,liver,spleen,andoccasionallylymphnodeswithamalignantBcellwithhair-likecytoplasmic projections.Thisinvolvementleadstosplenomegalywithsecondaryconsumptionofredcells,platelets and neutrophils as well as other complications of an enlarged spleen, including infarction-or-rarely rupture.Thecommonhaematologicalcomplicationsofanaemia,neutropeniaandthrombocytopenia are due not only to the enlarged spleen but probably also to hairy cells in the bone marrow inducing cytokine-mediated suppression of haematopoiesis. Hepatic involvement, although frequent, only occasionallyleadstoliverdysfunction.Infectionsareamajorcauseofmorbidityandmortalityinpatients withhairy-cellleukaemia,presumablyowingtoneutropeniaandmonocytopeniainthesepatients.The infectionsseenmaybeduetounusualpathogens,includingMycobacteriumandListeria. Autoimmune disease, including polyarthitis and vasculitis, occurs frequently and does not correlate with the severity of the disease. Other rare complications include bone involvement, meningitis and ascites. A wide range of secondary malignancies have been reported in patients with hairy-cell leukaemia, but it is still unclear whether the incidence is increased and whether they are related to the disease or treatment. Key words: complications; infections; hairy-cell leukaemia.
Hairy-cell leukaemia was first described in 1958 at The Ohio State University as a distinct clinical, pathological and haematological entity.1 We now know that it is a chronic B lymphoproliferative process which often presents with pancytopenia and splenomegaly. Although it is a rare disorder, accounting for about 400 new cases per year, increased interest in the disease has paralleled the dramatic improvement in treatment.2 The disease has changed from an often fatal one to a chronic process which has affected the natural history and the frequency of complications seen in the disease.3 – 5 In this chapter we present both common and rare complications associated with the disease itself and demonstrate where treatment may affect these complications (Table 1).
HAEMATOLOGICAL COMPLICATIONS The majority of patients with hairy-cell leukaemia present with some degree of cytopenia, with about 40% having true pancytopenia. As defined by a haemoglobin level * Corresponding author. Tel.: þ1-614-293-8723; Fax: þ1-614-293-7525. 1521-6926/03/$ - see front matter Q 2003 Published by Elsevier Science Ltd.
34 E. H. Kraut
Table 1. Clinical complications in hairy cell leukaemia. Commonly reported in more than 50% of patients Anaemia Leucopenia, neutropenia, monocytopenia Splenomegaly Infections Frequently reported in more than 25% of patients Hepatomegaly Autoimmune disease Uncommonly reported in less than 10% of patients Adenopathy, usually intra-abdominal Bone disease Ascites Pleural effusion Neurological complications such as meningitis or peripheral neuropathy
less than 11 g/dl, neutrophils less than 1000’ ml and platelets less than 100 000/mm23. An analysis of 517 patients accumulated from three large retrospective reviews documented the following.6 – 8 Anaemia defined as a haemoglobin level less than 12 g/dl was seen in 75– 84% of patients at presentation, with a normal haemoglobin in 16– 25% of patients. Significant anaemia with haemoglobin less than 8.5 g/dl, a level often considered appropriate for transfusion, was seen in almost 35% of 391 patients.7 The cause of the anaemia may be multifactorial. One should always rule out potential contributing factors such as iron deficiency especially in patients with severe thrombocytopenia or in pre-menopausal females who may have significant blood loss. Although anaemia related to malignancy is often explained by impaired erythropoietin response, and is thus responsive to synthetic erythropoiein9, the only study of erthropoietin levels in hairy-cell leukaemia patients10 did not document this. Autoimmune haemolytic anaemia does occur but it is a rare complication of the disease.11 The most common cause of anaemia in hairy-cell patients is presumed to be due to hypersplenism and/or secondary to bone marrow involvement. Evidence for the role of the spleen in the development of the anaemia is best demonstrated by the changes after splenectomy.7,12 Twenty-eight of 56 patients with starting haemoglobins less than 8.5 g/dl showed improvement after splenectomy above 11 g/dl, suggesting that sequestration and possibly expanded blood volume due to splenic pooling caused the anaemia. The remaining patients who do not respond to splenectomy have reduced red cell production due to marrow replacement and cytokine-mediated suppression of erythroid progenitors.13 Thrombocytopenia is also a frequent complication in patients with hairy-cell leukaemia, although usually less often than anaemia. Platelets less than 100 000/ ml were seen in 57– 79% of patients at presentation.7,8 Severe thrombocytopenia of less than 50 000/ ml occurred in 30 – 33% of patients, with 10% having counts under 20 000/ ml. The spleen appears to play a significant role—initially with complete responses to splenectomy occurring almost 70% of the time—and is especially important in patients with very large spleens. However, patients post-splenectomy often develop progressive thrombocytopenia due to marrow infiltration which will
Clinical manifestations and infectious complications 35
respond to effective treatment.2 Immune thrombocytopenia has also been reported in hairy-cell leukaemia patients.14 Leucopenia and neutropenia are also described, with leucopenia seen in 60% of patients and life-threatening neutropenia of less than 500/ ml in 37%. Responses to splenectomy occurred in 45% of patients with neutrophils less than 500/ ml increased above 1000/ ml. Patients with hairy-cell leukaemia also may respond to granulocyte colony stimulating factor, confirming that part of the neutropenia is due to splenic sequestration.15,16 An additional diagnostic and unusual finding in haematological malignancies is the presence of profound monocytopenia which may contribute to the immune deficiency state of these patients.17 The explanation for selective reduction in monocytes is unknown, but there is evidence from in vitro studies that cytokines from hairy cells can suppress monocyte colony growth and that reduced monocyte colony stimulating factor is found.18 Moreover, response to chemotherapy treatment is associated with improvement in monocyte counts.19
SPLENOMEGALY Splenomegaly is one the classical findings found at presentation in patients with hairycell leukaemia. Using physical examination rather than radiographic imaging, splenomegaly has been noted in 80– 90% of patients, with marked splenomegaly of greater than 10 cm below the left costal margin in up to 20% of patients.7,8 The histological examination of the spleen is distinctive, with diffuse infiltration of the red pulp by a homogeneous population of mononuclear cells causing widening of the pulp cords.20 This is in contrast to the spleen in chronic lymphocytic leukaemia— which predominantly involves the white pulp. There is often hypertrophy of the splenic macrophages with erythrophagocytosis sometimes seen, and this may account for the increased haemolysis that can be noted in these patients.21 The splenic red cell pool is often increased with up to nine times the normal splenic red cell volume also contributing to the reduced circulating red cell mass. As previously noted splenomegaly accounts in part for the reduction in circulating blood elements, although the response to splenectomy did not correlate with the size of the spleen.12 The enlarged spleen may cause early satiety with subsequent weight loss and rarely is associated with splenic infarction or spontaneous rupture.22
HEPATOMEGALY Hepatomegaly is much less prominent in hairy-cell patients, with enlargement noted about one-third of the time and marked hepatomegaly greater than 10 cm below the costal margin only 2% of the time.7 Despite this the liver is almost always involved histologically without significantly altering hepatic function or elevating liver enzymes.21 Liver biopsy specimens show microscopic mononuclear infiltrates in the sinusoids, portal areas, or both. The development of marked hyperbilirubinaemia and elevated liver enzyme elevations does occur23, but its rarity should make one consider an infectious aetiology.24
36 E. H. Kraut
INFECTIOUS COMPLICATIONS One of the most recognized and important clinical problems in patients with hairy-cell leukaemia is the development of severe life-threatening and unusual infections.25,26 These may involve the common sites of lung and urinary tract as well as less common involvement of the liver and central nervous system. Since the development of effective therapy, the reduced incidence of infections over the course of the patient’s disease correlates with the response to therapy and improvement in survival.2,3 In a follow-up of 127 patients in the pre-chemotherapy era, almost 70% of patients had culture-proven or suspected infections, with multiple infections seen in the same patients.25 An additional series of 22 patients identified 18 life-threatening infections.26 In the follow-up after effective treatment of 24 patients over a 7-year period no serious infections were seen.5 The high incidence of infection in these patients is due to the multiple immune deficiencies seen. These include profound granulocytopenia, monocytopenia, natural killer cell and dendritic cell deficiency, and the alteration in host defence associated with splenectomy.17,27,28 Patients develop a wide range of infections (Table 2), including those commonly seen in the neutropenic host such as Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. These pyogenic infections are reported to make up about 50% of the infections seen. Additionally, there is a marked increase in atypical mycobacterial infections, not usually seen in other lymphoproliferative diseases. For example, in a study of 201 cases of leukaemia and lymphoma in the early 1970s, the incidence of infection was 0.9% in lymphoma. In hairy-cell leukaemia the incidence was as high as 9 – 18%.26,29 However, these infections are seen only in patients with active disease and are not noted in longterm survivors after successful treatment. Other infections noted in patients with active disease include Listeria, Aspergillus, Pneumocystis, Legionella, and cytomegalovirus.29 Herpes zoster has been reported after
Table 2. Infectious complications. Frequently reported P. aeruginosa E. Coli Less common S. aureus S. pneumoniae Atypical mycobacteria Rare Aspergillus fumigatus Candida albicans Blastomycosis Coccidioidomycosis Cytomegalovirus Pneumocytis carinii Toxoplasmosis
Clinical manifestations and infectious complications 37
treatment with purine antimetabolites but not in untreated disease.5 Thus, in hairy-cell patients with fever of unknown origin, abnormal chest X-rays or liver abnormalities, a thorough evaluation for bacterial, fungal and viral infections is necessary. AUTOIMMUNE DISEASE The development of immunological disorders in association with hairy-cell leukaemia has been documented in individual case presentations as well as in a retrospective review of patients followed at a university centre.30 Patients may present with polyarthritis, erythema nodosum, skin rash, or pulmonary infiltrates. In some cases a diagnosis of lupus or rheumatoid arthritis was entertained before the diagnosis of hairycell leukaemia. In an attempt to document the frequency of autoimmune disease not including haematological disorders, Westbrook evaluated 37 patients for evidence of autoimmune disease.31 Ten patients were identified with two different types of presentation. One group of six patients had arthritis and arthralgias with nodular skin lesions. The arthritis was generally of acute onset, oligoarticular and affecting knees, shoulders and elbows. The episodes were limited and required little or no therapy. The remaining four patients had a more severe course, including systemic symptoms of fever, weight loss and visceral involvement. Patients were treated as necessary with anti-inflammatories, including steroids, with clinical improvement. The autoimmune disease in these patients did not parallel the activity of the leukaemia, although none of the patients were treated with purine antimetabolites. The one patient followed at Ohio State with leukocytoclastic vasculitis did not show improvement even though he had a clinical remission after pentostatin treatment. SECOND MALIGNANCIES A variety of second malignancies have been reported in patients with hairy-cell leukaemia both prior to and following diagnosis and treatment.3,21,32 – 35 They include non-Hodgkin’s lymphoma, plasma cell dyscrasias, chronic myeloid leukaemia, acute myeloid and lymphoid leukaemia, prostate cancer, skin cancer, thyroid cancer, gastrointestinal malignancies and lung cancer. These have been observed in the pre-chemotherapy era – as well as in longterm follow-up after treatment with chemotherapy. Besides the individual case reports, several papers have tried to answer the question of whether second malignancy risk is inherently increased in hairy-cell patients and/or does treatment with interferon or purine antimetabolites increase the risk. In a 20-year experience with a median follow-up of 5 years, 117 patients from British Columbia were retrospectively evaluated.32 There were 44 malignancies in 36 patients which, when compared to age-matched controls, was increased. There did not appear to be a relationship to treatment with interferon or purine analogues. In a study from the University of Chicago, following 69 patients treated with interferon, there were 13 malignancies, including six haematological malignancies and seven adenocarcinomas.36 With an expected number of malignancies of three for this population, they concluded that this excess number was a consequence of longer survival in hairy-cell patientsand/or related to interferon. In the follow-up of 241 patients treated in a multicentre study of pentostatin or interferon, there were 39 malignancies, including eight haematological malignancies.3 This was slightly greater than the expected 26 patients for this age-matched population, but when only solid tumours were evaluated there was no increase above that expected. The authors concluded that there was no increase due to treatment and also no increase due to hairy-cell leukaemia. Finally, in a retrospective
38 E. H. Kraut
review of 725 patients, including patients treated with interferon and chemotherapy, the incidence of second malignancies was only 3.7% of patients.37 Thus, there is no conclusive evidence that hairy-cell leukaemia is associated with an increased risk of second malignancies or a clear-cut relationship between treatment and the development of second malignancies. Long-term evaluation of patients should be continued because it may take many years of follow-up to define the true risk of second malignancies. OTHER COMPLICATIONS There are several other unusual complications seen in patients with hairy-cell leukaemia. Neurological complications, including meningitis and nerve compression, have been reported secondary to hairy-cell infiltration but their rarity should make one consider infection or drug toxicity as the aetiology for these problems.38 Lymphadenopathy is an infrequent finding and, when present, usually involves intrathoracic or intra-abdominal nodes rather than peripheral lymph nodes.39 These nodes can be bulky and cause compression of vital structures and will respond to therapy. Osteolytic bone lesions have been reported typically to involve the axial skeleton and proximal long bones.40 Treatment with local irradiation has been effective. Involvement of pleural and peritoneal surfaces with pleural effusions and ascites containing hairy cells are occasionally seen.22 In our original patient treated with pentostatin, the effusions resolved after treatment.
SUMMARY Hairy-cell leukaemia remains one of the most distinctive of the lymphoproliferative disorders, presenting in most patients with splenomegaly and cytopenia. The cytopenias are often severe, especially the anaemia and neutropenia, and are the usual reasons for initiating therapy. Splenomegaly can be massive and can be the initial finding leading to the diagnostic work-up. By infiltrating organs and producing cytokines, the characteristic abnormal lymphocyte or hairy cell not only suppresses haematopoiesis but also produces profound immune suppression in the affected individual. This leads to a high risk of infection which, 20 years ago, led to death in up to 60% of patients.21 The risk of infection should always be considered when evaluating hairy-cell patients for fever, hepatic dysfunction or neurological changes, because, unlike other lymphoproliferative diseases, these clinical problems are rarely due to the disease itself. Moreover, the infections seen in these patients include unusual ones such as systemic mycobacterial infections and those due to fungi and viruses. Many patients will develop symptoms of autoimmune disease—especially affecting joints or the skin— which do not parallel the course of the illness. The hairy cell can infiltrate extramedullary sites, including lymph nodes, bones and peritoneal surfaces. Tissue biopsy should be considered to confirm the involvement. With the development of highly effective therapy, the course of the illness has been radically changed, with marked reduction in both infectious complications and partial resolution of the immune deficient state. The development of second malignancies, previously reported as individual cases, has been well documented in large series of patients evaluated in clinical trials. The relationship of these malignancies to the disease and treatment is still not defined.
Clinical manifestations and infectious complications 39
Practice points † infiltration of organs with the malignant hairy cell explains many of the complications seen, including pancytopenia and organomegaly † patients with hairy-cell leukaemia are profoundly immunosuppressed due to neutropenia, monocytopenia, and a deficiency of natural killer cells and dendritic cells. This should be taken into account when evaluating patients for fever † most clinical complications are resolved when patients are treated effectively
Research agenda † evaluation of reduced levels of erythropoietin in patients with hairy cell leukaemia as a factor contributing to anaemia, and use of synthetic erythropoietin as a treatment for anaemia, need further evaluation † the causes of autoimmune disease in hairy-cell leukaemia and appropriate treatment require further study
REFERENCES 1. Bouroncle BA, Wiseman B & Doan CA. Leukemic reticuloendotheliosis. Blood 1958; 13: 609–630. 2. Saven A & Piro LD. Treatment of hairy cell leukemia. Blood 1992; 79: 1111–1120. 3. Flinn IW, Kopecky KJ, Foucar KM et al. Long-term follow-up of remission duration, mortality, and second malignancies in hariy cell leukemia patients treated with pentostatin. Blood 2000; 96: 2981–2986. 4. Dearden CE, Matutes E, Hilditch BL et al. Long term followup of patients with hairy cell leukemia after treatment with pentostatin or cladribine. British Journal of Haematology 1999; 106: 515–519. 5. Kraut EH, Grever MR & Bourouncle B. Long term follow-up of patients with hairy cell leukemia after treatment with 200 deoxycoformycin. Blood 1994; 84: 4061–4063. 6. Golomb HM, Catovsky D & Golde D. Hairy cell leukemia: a clinical review based on 71 cases. Annals of Internal Medicine 1978; 89: 677–683. 7. Jansen J & Hermans J. Splenectomy in hairy cell leukemia: a retrospective multicenter analysis. Cancer 1981; 47: 2066–2069. 8. Bouroncle B. Leukemic reticuloendoltheliosis. Blood 1979; 53: 412. 9. Osterborg A, Brandberg Y & Molostova V. Randomized double blind placebo controlled trial of recombinant human erythropoietin epoietin beta in haematological malignanices. Journal of Clinical Oncology 2002; 15: 2486–2494. 10. Jansen JH, Wientjens GJ & We F. Serum monocyte colony stimulating factor, erythropoietin and interleukin-6 in relation to pancytopenia. Leukemia 1992; 6: 735–737. 11. Domingo A, Crespo N, Desilvia A et al. Hairy cell leukemia and autoimmune hemolytic anemia. Leukemia 1992; 6: 606–607. 12. Golomb HM & Vardiman J. Response to splenectomy in 65 patients with hairy cell leukemia: an evaluation of spleen weight and bone marrow involvement. Blood 1983; 61: 349 –352. 13. Lauria FBG, Catani L, Gaggioli L et al. The inhibitory effect of serum from hairy cell leukemia patients on progenitor cells may disappear following prolonged treatment with alpha interferon. British Journal of Haematology 1989; 72: 497 –501. 14. Virchis AE, Jan-Mohamed R, Kaczmarski KS et al. Primary splenic hairy cell leukaemia variant presenting as immune thrombocytopenic purpura. European Journal of Haematology 1998; 61: 288–291. 15. Christopoulos C, Fortis A, Rikzas D & Anevlavis E. The place of myeloid growth factors in treatment of hairy cell leukaemia. Clinical Laboratory Haematology 1997; 19: 149 –150. 16. Ishizione S, Makuuchi M, Kawasaki S et al. Effect of granulocyte colony stimulating factor on neutropenia in liver transplant patients with hypersplenism. Journal of Pediatric Surgery 1994; 29: 510 –513. 17. Seshadri R, Brown E & Zipursky A. Leukemic reticuloendotheliosis—a failure of monocyte production. New England Journal of Medicine 1976; 295: 181–184.
40 E. H. Kraut 18. Gasche C, Reinish GC & Schearzmeier J. Evidence of colony suppressor activity and deficiency of hematopoietic growth factors in hairy cell leukemia. Hematology & Oncology 1993; 11: 97–104. 19. Kraut EH, Neff JC, Bourouncle BA & Grever M. Immunosuppresive effect of pentostatin. Journal of Clinical Oncology 1990; 8: 848–855. 20. Burke JS, Byrne GE & Rappaport H. Hairy cell leukemia. Cancer 1974; 33: 1399–1410. 21. Offerman MK, Golomb H, Hairy Cell Leukemia, vol. 8.; 1984. pp. 3–38. 22. Bouroncle B. Unusual presentations and complications of hairy cell leukemia. Leukemia 1987; 1: 288–293. 23. Evans MA, Gastineau DA & Ludwig J. Relapsing hairy cell leukemia presenting as fulminant hepatitis. American Journal of Medicine 1992; 92: 209–212. 24. Bennett C, Vardiman JW & Golomb H. Disseminated atypical mycobacterial infection in patients with hairy cell leukemia. Amercian Journal of Medicine 1986; 80: 891 –896. 25. Golomb HM & Hadad L. Infectious complications in 127 patients with hairy cell leukemia. American Journal of Hematology 1984; 16: 393 –401. 26. Stewart DJ & Gp B. Infections in hairy cell leukemia. Cancer 1981; 15: 801– 805. 27. Ruco LP, Procopio A, Maccanallini V et al. Severe deficiency of natural killer activity in the peripheral blood of patients with hairy cell leukemia. Blood 1983; 61: 1131–1137. 28. Bourguin-Pionquet A, Rouard H, Roudot-Thoraval F et al. Severe decrease in peripheral blood dendritic cells in hairy cell leukemia. British Journal of Haematology 2002; 116: 595–597. 29. Golomb HM & Hanauer S. Infectious complications associated with hairy cell leukemia. Journal of Infectious Diseases 1981; 143: 639– 643. 30. Dorsey JK & Penick G. The association of hairy cell leukemia with unusual immunologic disorders. Archives of Internal Medicine 1982; 142: 902–903. 31. Westbrook C & Golde D. Autoimmune disease in hairy cell leukaemia: clinical syndromes and treatment. British Journal of Haematology 1985; 61: 349 –356. 32. Au WY, Klasa RJ, Gallagher R et al. Second malignancies in patients with hairy cell leukemia in British Columbia: a 20 year experience. Blood 1998; 92: 1160–1164. 33. Frederico M, Zinzani PL, Frassoldati A et al. Risk of second cancer in patients with hairy cell leukemia. Journal of Clinical Oncology 2002; 20: 638– 646. 34. Golde DW, Saxon A & Stevens R. Macroglobulinemia and hairy cell leukemia. New England Journal of Medicine 1977; 296: 92– 93. 35. Kurzrock R, Strom SS, Estey E et al. Second cancer risk in hairy cell leukemia: analysis of 350 patients. Journal of Clinical Oncology 1997; 15: 1803– 1810. 36. Kampmeier P, Spielberger R, Dickstein J et al. Increased incidence of second neoplasms in patients treated with interferon 2b for hairy cell leukemia: a clinical pathologic assessment. Blood 1994; 84: 3242–3245. 37. Frassoldati A, Lamparelli T, Federico M et al. Hairy cell leukemia: a clinical review based on 725 cases of the Italian cooperative group for hairy cell leukemia. Leukemia & Lymphoma 1994; 12: 307– 316. 38. Kimmel DW, Hermann RC & O’Neill B. Neurologic complications of hairy cell leukemia. Archives of Neurology 1984; 41: 202 –203. 39. Mercieca J, Matutes E, Moskivic E et al. Massive abdomnal lymphadenopathy in hairy cell leukemia: a report of 12 cases. British Journal of Haematology 1992; 82: 547–554. 40. Quesada JRKM, Libshitz AI & Llamas L. Bone involvement in hairy cell leukemia. American Journal of Medicine 1983; 74: 228–231.
3 Clinical manifestations and infectious complications of hairy-cell leukaemia Eric H. Kraut*
MD
Professor of Medicine Division of Hematology –Oncology, The Ohio State University, 320 W 10th Avenue, Columbus, OH 43210, USA
Hairy-cellleukaemiaisanindolentlymphoproliferativemalignancycharacterizedbyinfiltrationofthe bonemarrow,liver,spleen,andoccasionallylymphnodeswithamalignantBcellwithhair-likecytoplasmic projections.Thisinvolvementleadstosplenomegalywithsecondaryconsumptionofredcells,platelets and neutrophils as well as other complications of an enlarged spleen, including infarction-or-rarely rupture.Thecommonhaematologicalcomplicationsofanaemia,neutropeniaandthrombocytopenia are due not only to the enlarged spleen but probably also to hairy cells in the bone marrow inducing cytokine-mediated suppression of haematopoiesis. Hepatic involvement, although frequent, only occasionallyleadstoliverdysfunction.Infectionsareamajorcauseofmorbidityandmortalityinpatients withhairy-cellleukaemia,presumablyowingtoneutropeniaandmonocytopeniainthesepatients.The infectionsseenmaybeduetounusualpathogens,includingMycobacteriumandListeria. Autoimmune disease, including polyarthitis and vasculitis, occurs frequently and does not correlate with the severity of the disease. Other rare complications include bone involvement, meningitis and ascites. A wide range of secondary malignancies have been reported in patients with hairy-cell leukaemia, but it is still unclear whether the incidence is increased and whether they are related to the disease or treatment. Key words: complications; infections; hairy-cell leukaemia.
Hairy-cell leukaemia was first described in 1958 at The Ohio State University as a distinct clinical, pathological and haematological entity.1 We now know that it is a chronic B lymphoproliferative process which often presents with pancytopenia and splenomegaly. Although it is a rare disorder, accounting for about 400 new cases per year, increased interest in the disease has paralleled the dramatic improvement in treatment.2 The disease has changed from an often fatal one to a chronic process which has affected the natural history and the frequency of complications seen in the disease.3 – 5 In this chapter we present both common and rare complications associated with the disease itself and demonstrate where treatment may affect these complications (Table 1).
HAEMATOLOGICAL COMPLICATIONS The majority of patients with hairy-cell leukaemia present with some degree of cytopenia, with about 40% having true pancytopenia. As defined by a haemoglobin level * Corresponding author. Tel.: þ1-614-293-8723; Fax: þ1-614-293-7525. 1521-6926/03/$ - see front matter Q 2003 Published by Elsevier Science Ltd.
34 E. H. Kraut
Table 1. Clinical complications in hairy cell leukaemia. Commonly reported in more than 50% of patients Anaemia Leucopenia, neutropenia, monocytopenia Splenomegaly Infections Frequently reported in more than 25% of patients Hepatomegaly Autoimmune disease Uncommonly reported in less than 10% of patients Adenopathy, usually intra-abdominal Bone disease Ascites Pleural effusion Neurological complications such as meningitis or peripheral neuropathy
less than 11 g/dl, neutrophils less than 1000’ ml and platelets less than 100 000/mm23. An analysis of 517 patients accumulated from three large retrospective reviews documented the following.6 – 8 Anaemia defined as a haemoglobin level less than 12 g/dl was seen in 75– 84% of patients at presentation, with a normal haemoglobin in 16– 25% of patients. Significant anaemia with haemoglobin less than 8.5 g/dl, a level often considered appropriate for transfusion, was seen in almost 35% of 391 patients.7 The cause of the anaemia may be multifactorial. One should always rule out potential contributing factors such as iron deficiency especially in patients with severe thrombocytopenia or in pre-menopausal females who may have significant blood loss. Although anaemia related to malignancy is often explained by impaired erythropoietin response, and is thus responsive to synthetic erythropoiein9, the only study of erthropoietin levels in hairy-cell leukaemia patients10 did not document this. Autoimmune haemolytic anaemia does occur but it is a rare complication of the disease.11 The most common cause of anaemia in hairy-cell patients is presumed to be due to hypersplenism and/or secondary to bone marrow involvement. Evidence for the role of the spleen in the development of the anaemia is best demonstrated by the changes after splenectomy.7,12 Twenty-eight of 56 patients with starting haemoglobins less than 8.5 g/dl showed improvement after splenectomy above 11 g/dl, suggesting that sequestration and possibly expanded blood volume due to splenic pooling caused the anaemia. The remaining patients who do not respond to splenectomy have reduced red cell production due to marrow replacement and cytokine-mediated suppression of erythroid progenitors.13 Thrombocytopenia is also a frequent complication in patients with hairy-cell leukaemia, although usually less often than anaemia. Platelets less than 100 000/ ml were seen in 57– 79% of patients at presentation.7,8 Severe thrombocytopenia of less than 50 000/ ml occurred in 30 – 33% of patients, with 10% having counts under 20 000/ ml. The spleen appears to play a significant role—initially with complete responses to splenectomy occurring almost 70% of the time—and is especially important in patients with very large spleens. However, patients post-splenectomy often develop progressive thrombocytopenia due to marrow infiltration which will
Clinical manifestations and infectious complications 35
respond to effective treatment.2 Immune thrombocytopenia has also been reported in hairy-cell leukaemia patients.14 Leucopenia and neutropenia are also described, with leucopenia seen in 60% of patients and life-threatening neutropenia of less than 500/ ml in 37%. Responses to splenectomy occurred in 45% of patients with neutrophils less than 500/ ml increased above 1000/ ml. Patients with hairy-cell leukaemia also may respond to granulocyte colony stimulating factor, confirming that part of the neutropenia is due to splenic sequestration.15,16 An additional diagnostic and unusual finding in haematological malignancies is the presence of profound monocytopenia which may contribute to the immune deficiency state of these patients.17 The explanation for selective reduction in monocytes is unknown, but there is evidence from in vitro studies that cytokines from hairy cells can suppress monocyte colony growth and that reduced monocyte colony stimulating factor is found.18 Moreover, response to chemotherapy treatment is associated with improvement in monocyte counts.19
SPLENOMEGALY Splenomegaly is one the classical findings found at presentation in patients with hairycell leukaemia. Using physical examination rather than radiographic imaging, splenomegaly has been noted in 80– 90% of patients, with marked splenomegaly of greater than 10 cm below the left costal margin in up to 20% of patients.7,8 The histological examination of the spleen is distinctive, with diffuse infiltration of the red pulp by a homogeneous population of mononuclear cells causing widening of the pulp cords.20 This is in contrast to the spleen in chronic lymphocytic leukaemia— which predominantly involves the white pulp. There is often hypertrophy of the splenic macrophages with erythrophagocytosis sometimes seen, and this may account for the increased haemolysis that can be noted in these patients.21 The splenic red cell pool is often increased with up to nine times the normal splenic red cell volume also contributing to the reduced circulating red cell mass. As previously noted splenomegaly accounts in part for the reduction in circulating blood elements, although the response to splenectomy did not correlate with the size of the spleen.12 The enlarged spleen may cause early satiety with subsequent weight loss and rarely is associated with splenic infarction or spontaneous rupture.22
HEPATOMEGALY Hepatomegaly is much less prominent in hairy-cell patients, with enlargement noted about one-third of the time and marked hepatomegaly greater than 10 cm below the costal margin only 2% of the time.7 Despite this the liver is almost always involved histologically without significantly altering hepatic function or elevating liver enzymes.21 Liver biopsy specimens show microscopic mononuclear infiltrates in the sinusoids, portal areas, or both. The development of marked hyperbilirubinaemia and elevated liver enzyme elevations does occur23, but its rarity should make one consider an infectious aetiology.24
36 E. H. Kraut
INFECTIOUS COMPLICATIONS One of the most recognized and important clinical problems in patients with hairy-cell leukaemia is the development of severe life-threatening and unusual infections.25,26 These may involve the common sites of lung and urinary tract as well as less common involvement of the liver and central nervous system. Since the development of effective therapy, the reduced incidence of infections over the course of the patient’s disease correlates with the response to therapy and improvement in survival.2,3 In a follow-up of 127 patients in the pre-chemotherapy era, almost 70% of patients had culture-proven or suspected infections, with multiple infections seen in the same patients.25 An additional series of 22 patients identified 18 life-threatening infections.26 In the follow-up after effective treatment of 24 patients over a 7-year period no serious infections were seen.5 The high incidence of infection in these patients is due to the multiple immune deficiencies seen. These include profound granulocytopenia, monocytopenia, natural killer cell and dendritic cell deficiency, and the alteration in host defence associated with splenectomy.17,27,28 Patients develop a wide range of infections (Table 2), including those commonly seen in the neutropenic host such as Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. These pyogenic infections are reported to make up about 50% of the infections seen. Additionally, there is a marked increase in atypical mycobacterial infections, not usually seen in other lymphoproliferative diseases. For example, in a study of 201 cases of leukaemia and lymphoma in the early 1970s, the incidence of infection was 0.9% in lymphoma. In hairy-cell leukaemia the incidence was as high as 9 – 18%.26,29 However, these infections are seen only in patients with active disease and are not noted in longterm survivors after successful treatment. Other infections noted in patients with active disease include Listeria, Aspergillus, Pneumocystis, Legionella, and cytomegalovirus.29 Herpes zoster has been reported after
Table 2. Infectious complications. Frequently reported P. aeruginosa E. Coli Less common S. aureus S. pneumoniae Atypical mycobacteria Rare Aspergillus fumigatus Candida albicans Blastomycosis Coccidioidomycosis Cytomegalovirus Pneumocytis carinii Toxoplasmosis
Clinical manifestations and infectious complications 37
treatment with purine antimetabolites but not in untreated disease.5 Thus, in hairy-cell patients with fever of unknown origin, abnormal chest X-rays or liver abnormalities, a thorough evaluation for bacterial, fungal and viral infections is necessary. AUTOIMMUNE DISEASE The development of immunological disorders in association with hairy-cell leukaemia has been documented in individual case presentations as well as in a retrospective review of patients followed at a university centre.30 Patients may present with polyarthritis, erythema nodosum, skin rash, or pulmonary infiltrates. In some cases a diagnosis of lupus or rheumatoid arthritis was entertained before the diagnosis of hairycell leukaemia. In an attempt to document the frequency of autoimmune disease not including haematological disorders, Westbrook evaluated 37 patients for evidence of autoimmune disease.31 Ten patients were identified with two different types of presentation. One group of six patients had arthritis and arthralgias with nodular skin lesions. The arthritis was generally of acute onset, oligoarticular and affecting knees, shoulders and elbows. The episodes were limited and required little or no therapy. The remaining four patients had a more severe course, including systemic symptoms of fever, weight loss and visceral involvement. Patients were treated as necessary with anti-inflammatories, including steroids, with clinical improvement. The autoimmune disease in these patients did not parallel the activity of the leukaemia, although none of the patients were treated with purine antimetabolites. The one patient followed at Ohio State with leukocytoclastic vasculitis did not show improvement even though he had a clinical remission after pentostatin treatment. SECOND MALIGNANCIES A variety of second malignancies have been reported in patients with hairy-cell leukaemia both prior to and following diagnosis and treatment.3,21,32 – 35 They include non-Hodgkin’s lymphoma, plasma cell dyscrasias, chronic myeloid leukaemia, acute myeloid and lymphoid leukaemia, prostate cancer, skin cancer, thyroid cancer, gastrointestinal malignancies and lung cancer. These have been observed in the pre-chemotherapy era – as well as in longterm follow-up after treatment with chemotherapy. Besides the individual case reports, several papers have tried to answer the question of whether second malignancy risk is inherently increased in hairy-cell patients and/or does treatment with interferon or purine antimetabolites increase the risk. In a 20-year experience with a median follow-up of 5 years, 117 patients from British Columbia were retrospectively evaluated.32 There were 44 malignancies in 36 patients which, when compared to age-matched controls, was increased. There did not appear to be a relationship to treatment with interferon or purine analogues. In a study from the University of Chicago, following 69 patients treated with interferon, there were 13 malignancies, including six haematological malignancies and seven adenocarcinomas.36 With an expected number of malignancies of three for this population, they concluded that this excess number was a consequence of longer survival in hairy-cell patientsand/or related to interferon. In the follow-up of 241 patients treated in a multicentre study of pentostatin or interferon, there were 39 malignancies, including eight haematological malignancies.3 This was slightly greater than the expected 26 patients for this age-matched population, but when only solid tumours were evaluated there was no increase above that expected. The authors concluded that there was no increase due to treatment and also no increase due to hairy-cell leukaemia. Finally, in a retrospective
38 E. H. Kraut
review of 725 patients, including patients treated with interferon and chemotherapy, the incidence of second malignancies was only 3.7% of patients.37 Thus, there is no conclusive evidence that hairy-cell leukaemia is associated with an increased risk of second malignancies or a clear-cut relationship between treatment and the development of second malignancies. Long-term evaluation of patients should be continued because it may take many years of follow-up to define the true risk of second malignancies. OTHER COMPLICATIONS There are several other unusual complications seen in patients with hairy-cell leukaemia. Neurological complications, including meningitis and nerve compression, have been reported secondary to hairy-cell infiltration but their rarity should make one consider infection or drug toxicity as the aetiology for these problems.38 Lymphadenopathy is an infrequent finding and, when present, usually involves intrathoracic or intra-abdominal nodes rather than peripheral lymph nodes.39 These nodes can be bulky and cause compression of vital structures and will respond to therapy. Osteolytic bone lesions have been reported typically to involve the axial skeleton and proximal long bones.40 Treatment with local irradiation has been effective. Involvement of pleural and peritoneal surfaces with pleural effusions and ascites containing hairy cells are occasionally seen.22 In our original patient treated with pentostatin, the effusions resolved after treatment.
SUMMARY Hairy-cell leukaemia remains one of the most distinctive of the lymphoproliferative disorders, presenting in most patients with splenomegaly and cytopenia. The cytopenias are often severe, especially the anaemia and neutropenia, and are the usual reasons for initiating therapy. Splenomegaly can be massive and can be the initial finding leading to the diagnostic work-up. By infiltrating organs and producing cytokines, the characteristic abnormal lymphocyte or hairy cell not only suppresses haematopoiesis but also produces profound immune suppression in the affected individual. This leads to a high risk of infection which, 20 years ago, led to death in up to 60% of patients.21 The risk of infection should always be considered when evaluating hairy-cell patients for fever, hepatic dysfunction or neurological changes, because, unlike other lymphoproliferative diseases, these clinical problems are rarely due to the disease itself. Moreover, the infections seen in these patients include unusual ones such as systemic mycobacterial infections and those due to fungi and viruses. Many patients will develop symptoms of autoimmune disease—especially affecting joints or the skin— which do not parallel the course of the illness. The hairy cell can infiltrate extramedullary sites, including lymph nodes, bones and peritoneal surfaces. Tissue biopsy should be considered to confirm the involvement. With the development of highly effective therapy, the course of the illness has been radically changed, with marked reduction in both infectious complications and partial resolution of the immune deficient state. The development of second malignancies, previously reported as individual cases, has been well documented in large series of patients evaluated in clinical trials. The relationship of these malignancies to the disease and treatment is still not defined.
Clinical manifestations and infectious complications 39
Practice points † infiltration of organs with the malignant hairy cell explains many of the complications seen, including pancytopenia and organomegaly † patients with hairy-cell leukaemia are profoundly immunosuppressed due to neutropenia, monocytopenia, and a deficiency of natural killer cells and dendritic cells. This should be taken into account when evaluating patients for fever † most clinical complications are resolved when patients are treated effectively
Research agenda † evaluation of reduced levels of erythropoietin in patients with hairy cell leukaemia as a factor contributing to anaemia, and use of synthetic erythropoietin as a treatment for anaemia, need further evaluation † the causes of autoimmune disease in hairy-cell leukaemia and appropriate treatment require further study
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