Leukemia Research 38 (2014) 284–285
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
Extramedullary manifestations of chronic lymphocytic leukaemia are not unusual
Chronic lymphocytic leukaemia shows a high variability in its clinical presentation and course of disease. Due to more frequent blood sampling in routine diagnostics, an increasing proportion of patients with chronic lymphocytic leukaemia (CLL) is diagnosed at an early disease stage due to elevated lymphocyte counts [1]. In addition to the lymphocytosis, anaemia and/or thrombocytopenia may be observed in the peripheral blood. These cytopenias occur either due to an infiltration of the bone marrow with suppression of normal haematopoiesis or due to immunological phenomena such as autoimmune haemolytic anaemia (AIHA). The most common finding in patients with CLL is enlargement of lymph nodes, liver and spleen, which can lead to symptoms due to compression of other organs or anatomic structures, such as abdominal pain due to splenomegaly with pressure on the stomach or compression of veins or lymphatic vessels due to lymphadenopathy in different localisations. At the time point of initial diagnosis 70–80% of patients have enlarged lymph nodes [2,3], which are predominantly located in cervical, but also in the axillary and inguinal region. Splenomegaly and hepatomegaly are present at initial diagnosis in 45–75% of patients [4,5]. In addition, approximately 20% of patients with CLL suffer from constitutional symptoms, such as fever, night sweats and weight loss as well as fatigue [2,4,5]. Other manifestations of CLL outside blood, bone marrow and lymphoid tissue are unusual. However, their incidence has not yet been described. Ratterman and colleagues performed a systematic literature search and identified 192 case reports of extramedullary CLL manifestations published between 1975 and 2012. Involvement of skin and central nervous system (CNS) were the most common extramedullary manifestations found in 63 (33%) and 51 patients (27%), followed by manifestations in the gastrointestinal tract (26 pts., 14%), genitourinary/gynaecological tract (20 pts., 10%), lung and eyes (10 pts., 5% each). Most of the patients with available treatment information received chemotherapy, while patients with CLL occurring in the CNS and eyes underwent radiotherapy more often. Patients with CLL manifestations in CNS, eyes, skin and lung had a worse survival in comparison to patients with manifestations in the gastrointestinal or genitourinary tract. Furthermore, patients with occurrence of extramedullary CLL at the time of relapse had a worse survival than those with an extramedullary CLL manifestation at initial diagnosis. However, one must caution that the analysis of Ratterman et al. was based on case reports from a literature search. Therefore no comparator group was available and the true incidence of extramedullary CLL could not be determined with accuracy. In addition, a publication bias needs to be taken into account as presumably mainly interesting, rare and/or more severe
0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.11.015
cases of extramedullary CLL manifestations were considered for publication. To obtain more information about the incidence of unusual CLL manifestations outside the bone marrow, peripheral blood and the lymphoid tissue in lymph nodes, spleen and liver, we analysed the disease status of patients before treatment initiation within three randomised phase-III-trials for first line treatment performed by the German CLL Study Group (GCLLSG). These trials were the CLL4 trial evaluating the combination of fludarabine and cyclophosphamide (FC) in comparison to fludarabine alone [6], the CLL5 trial comparing chlorambucil and fludarabine [7] and the CLL8 trial evaluating the addition of rituximab to fludarabine and cyclophosphamide [8]. Patients with CNS involvement of CLL were excluded from participation in all three trials. Extramedullary CLL manifestations were identified in 12 of the 362 patients (3.3%) from the CLL4 trial, 6 of the 193 patients (3.1%) from the CLL5 trial and in 22 of the 817 patients (2.7%) from the CLL8-trial. These extramedullary CLL manifestations were localised in the following organ systems: 15 patients had a pulmonary CLL involvement, mainly in the endobronchial system (8 pts.) or as a pleural effusion (5 pts.); 8 patients showed an involvement of the gastrointestinal tract, mainly of the oesophagus or stomach (4 patients) and pancreas (2 patients); 6 patients showed a skin infiltration; 5 patients had osteolytic lesions; three patients had a neuronal affection due to involvement of the spinal canal and one patient each had an involvement of the kidney, thyroid gland and parotid gland. In addition to these 40 of 1372 patients (2.9%), CLL manifestations outside lymph nodes, liver, spleen, bone marrow and blood were documented in another 10 patients but not further specified. When including these additional 10 patients, the rate of extramedullary CLL manifestations outside of the CNS was at 3.6% in this clinical trial patient population. In the systematic analysis of Ratterman et al., CNS and gastrointestinal involvement were the most common manifestations of all case reports of extramedullary CLL published during the last 37 years. Similarly, our analysis of the CLL manifestations of patients in three large clinical trials showed that pulmonary and gastrointestinal involvements may be common extramedullary localisations. Because the rate of the extramedullary CLL manifestations was 3.6% in the patient population from clinical trials the rate of patients with extramedullary manifestations of CLL in clinical practice may even be higher. Therefore unusual CLL manifestations are probably not infrequent and might remain undiagnosed. Hence these manifestations constitute a clinical challenge as they require individualised and often uncommon treatment decisions, such as the intrathecal or intracavital application of treatment or radiation. Physicians should be encouraged to include their patients in clinical
Editorial / Leukemia Research 38 (2014) 284–285
trials or registries in order to learn more about these unusual CLL manifestations and potential treatment approaches and to improve the care of patients in these challenging situations. Acknowledgements Contributors: B.E., K.F. and M.H. perfomed the three trials; P.C. and J.B. prepared the data and did the statistical analysis, P.C. wrote the manuscript and J.B., B.E., K.F. and M.H. reviewed and agreed to the manuscript. References [1] Mauro FR, Foa R, Giannarelli D, et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood 1999;94:448–54. [2] Hansen MM. Chronic lymphocytic leukemia. Scand J Haematol 1973;18(Suppl.). [3] Lima de M, ÓBrien S, Lerner S, Meating MJ. Chronic lymphocytic leukemia in the young patient. Semin Oncol 1998;25:107–16. [4] Scott BB. Leukemia. Chronic lymphatic leukemia. Lancet 1957;I:1162. [5] Pisicotta AV, Hirschboeck JS. Therapeutic considerations in chronic lymphocytic leukemia. Arch Intern Med 1957;99:334. [6] Eichhorst BE, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006;107(3):885–91. [7] Eichhorst BE, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit
285
for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114(16):3382–91. [8] Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376(9747): 1164–74.
Paula Cramer ∗ Jasmin Bahlo Barbara Eichhorst Kirsten Fischer Michael Hallek Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Cologne, Germany ∗ Corresponding
author. Tel.: +49 221478 88220. E-mail address: [email protected] (P. Cramer) 17 November 2013 20 November 2013 Available online 1 December 2013
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
Extramedullary manifestations of chronic lymphocytic leukaemia are not unusual
Chronic lymphocytic leukaemia shows a high variability in its clinical presentation and course of disease. Due to more frequent blood sampling in routine diagnostics, an increasing proportion of patients with chronic lymphocytic leukaemia (CLL) is diagnosed at an early disease stage due to elevated lymphocyte counts [1]. In addition to the lymphocytosis, anaemia and/or thrombocytopenia may be observed in the peripheral blood. These cytopenias occur either due to an infiltration of the bone marrow with suppression of normal haematopoiesis or due to immunological phenomena such as autoimmune haemolytic anaemia (AIHA). The most common finding in patients with CLL is enlargement of lymph nodes, liver and spleen, which can lead to symptoms due to compression of other organs or anatomic structures, such as abdominal pain due to splenomegaly with pressure on the stomach or compression of veins or lymphatic vessels due to lymphadenopathy in different localisations. At the time point of initial diagnosis 70–80% of patients have enlarged lymph nodes [2,3], which are predominantly located in cervical, but also in the axillary and inguinal region. Splenomegaly and hepatomegaly are present at initial diagnosis in 45–75% of patients [4,5]. In addition, approximately 20% of patients with CLL suffer from constitutional symptoms, such as fever, night sweats and weight loss as well as fatigue [2,4,5]. Other manifestations of CLL outside blood, bone marrow and lymphoid tissue are unusual. However, their incidence has not yet been described. Ratterman and colleagues performed a systematic literature search and identified 192 case reports of extramedullary CLL manifestations published between 1975 and 2012. Involvement of skin and central nervous system (CNS) were the most common extramedullary manifestations found in 63 (33%) and 51 patients (27%), followed by manifestations in the gastrointestinal tract (26 pts., 14%), genitourinary/gynaecological tract (20 pts., 10%), lung and eyes (10 pts., 5% each). Most of the patients with available treatment information received chemotherapy, while patients with CLL occurring in the CNS and eyes underwent radiotherapy more often. Patients with CLL manifestations in CNS, eyes, skin and lung had a worse survival in comparison to patients with manifestations in the gastrointestinal or genitourinary tract. Furthermore, patients with occurrence of extramedullary CLL at the time of relapse had a worse survival than those with an extramedullary CLL manifestation at initial diagnosis. However, one must caution that the analysis of Ratterman et al. was based on case reports from a literature search. Therefore no comparator group was available and the true incidence of extramedullary CLL could not be determined with accuracy. In addition, a publication bias needs to be taken into account as presumably mainly interesting, rare and/or more severe
0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.11.015
cases of extramedullary CLL manifestations were considered for publication. To obtain more information about the incidence of unusual CLL manifestations outside the bone marrow, peripheral blood and the lymphoid tissue in lymph nodes, spleen and liver, we analysed the disease status of patients before treatment initiation within three randomised phase-III-trials for first line treatment performed by the German CLL Study Group (GCLLSG). These trials were the CLL4 trial evaluating the combination of fludarabine and cyclophosphamide (FC) in comparison to fludarabine alone [6], the CLL5 trial comparing chlorambucil and fludarabine [7] and the CLL8 trial evaluating the addition of rituximab to fludarabine and cyclophosphamide [8]. Patients with CNS involvement of CLL were excluded from participation in all three trials. Extramedullary CLL manifestations were identified in 12 of the 362 patients (3.3%) from the CLL4 trial, 6 of the 193 patients (3.1%) from the CLL5 trial and in 22 of the 817 patients (2.7%) from the CLL8-trial. These extramedullary CLL manifestations were localised in the following organ systems: 15 patients had a pulmonary CLL involvement, mainly in the endobronchial system (8 pts.) or as a pleural effusion (5 pts.); 8 patients showed an involvement of the gastrointestinal tract, mainly of the oesophagus or stomach (4 patients) and pancreas (2 patients); 6 patients showed a skin infiltration; 5 patients had osteolytic lesions; three patients had a neuronal affection due to involvement of the spinal canal and one patient each had an involvement of the kidney, thyroid gland and parotid gland. In addition to these 40 of 1372 patients (2.9%), CLL manifestations outside lymph nodes, liver, spleen, bone marrow and blood were documented in another 10 patients but not further specified. When including these additional 10 patients, the rate of extramedullary CLL manifestations outside of the CNS was at 3.6% in this clinical trial patient population. In the systematic analysis of Ratterman et al., CNS and gastrointestinal involvement were the most common manifestations of all case reports of extramedullary CLL published during the last 37 years. Similarly, our analysis of the CLL manifestations of patients in three large clinical trials showed that pulmonary and gastrointestinal involvements may be common extramedullary localisations. Because the rate of the extramedullary CLL manifestations was 3.6% in the patient population from clinical trials the rate of patients with extramedullary manifestations of CLL in clinical practice may even be higher. Therefore unusual CLL manifestations are probably not infrequent and might remain undiagnosed. Hence these manifestations constitute a clinical challenge as they require individualised and often uncommon treatment decisions, such as the intrathecal or intracavital application of treatment or radiation. Physicians should be encouraged to include their patients in clinical
Editorial / Leukemia Research 38 (2014) 284–285
trials or registries in order to learn more about these unusual CLL manifestations and potential treatment approaches and to improve the care of patients in these challenging situations. Acknowledgements Contributors: B.E., K.F. and M.H. perfomed the three trials; P.C. and J.B. prepared the data and did the statistical analysis, P.C. wrote the manuscript and J.B., B.E., K.F. and M.H. reviewed and agreed to the manuscript. References [1] Mauro FR, Foa R, Giannarelli D, et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood 1999;94:448–54. [2] Hansen MM. Chronic lymphocytic leukemia. Scand J Haematol 1973;18(Suppl.). [3] Lima de M, ÓBrien S, Lerner S, Meating MJ. Chronic lymphocytic leukemia in the young patient. Semin Oncol 1998;25:107–16. [4] Scott BB. Leukemia. Chronic lymphatic leukemia. Lancet 1957;I:1162. [5] Pisicotta AV, Hirschboeck JS. Therapeutic considerations in chronic lymphocytic leukemia. Arch Intern Med 1957;99:334. [6] Eichhorst BE, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006;107(3):885–91. [7] Eichhorst BE, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit
285
for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114(16):3382–91. [8] Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376(9747): 1164–74.
Paula Cramer ∗ Jasmin Bahlo Barbara Eichhorst Kirsten Fischer Michael Hallek Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Cologne, Germany ∗ Corresponding
author. Tel.: +49 221478 88220. E-mail address: [email protected] (P. Cramer) 17 November 2013 20 November 2013 Available online 1 December 2013
