Leukemia & Lymphoma, December 2014; 55(12): 2952–2954 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.897704
LETTER TO THE EDITOR
Visceral leishmaniasis mimicking Richter transformation Ester M. Orlandi1 & Antonello Malfitano2 1Hematology Unit, Department of Oncology-Hematology and 2Infectious and Tropical Diseases Unit, Department of Infectious
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/24/15 For personal use only.
Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
lymphocytes. Based on refractoriness to previous treatment and disruption of the TP53 pathway, an allogeneic stem cell transplant was considered to be a possible future option. The patient’s sister was evaluated as a potential donor, but unfortunately she was diagnosed with CLL-like monoclonal B-cell lymphocytosis. The patient could not be enrolled in any experimental clinical trials active at our center, so we decided to start alemtuzumab therapy, according to an individual patient access scheme in place after the license for alemtuzumab in CLL was voluntarily suspended by the producing company. Our patient received 18 doses of subcutaneous alemtuzumb (30 mg, twice a week). Supportive care included antimicrobial prophylaxis with acyclovir, trimethoprim–sulfamethoxazole and fluconazole, administration of granulocyte colony stimulating factor (G-CSF) and recombinant erythropoietin (EPO), and weekly surveillance for cytomegalovirus (CMV) and Epstein–Barr virus (EBV) reactivation. Alemtuzumab therapy was completed without complications despite grade 3 neutropenia and lymphocytopenia. The patient did fairly well for 2 months, but in May 2013 he started to complain of systemic symptoms, fatigue and abdominal discomfort. Peripheral blood counts were worsening (white blood cell count: 5.5 ⫻ 109/L, lymphocytes: 79%, neutrophils: 8%; Hb: 6.7 g/dL, platelet count: 37.0 ⫻ 109/L), the LDH value was 670 U/L, the ferritin level was 1270 ng/dL and massive splenomegaly was palpable (6 cm). No peripheral adenopathies were palpable, and a total body computed tomography (CT) scan documented only an increase in splenic longitudinal diameter (20 cm). Extensive work-up for infectious causes of fever including bacteria, mycobacteria, Aspergillus, cryptococci, adenovirus, CMV, EBV, parvovirus B19 and herpes viruses was negative. The patient was started on broad-spectrum antibiotic treatment. On the presumption that the clinical picture represented either progressive disease or RT or hemophagocytic lymphohistiocytosis, bone marrow evaluation was performed, as no peripheral lymph nodes were suitable for biopsy. Surprisingly, numerous intracellular amastigotes of Leishmania spp. were detected on bone marrow smears (Figure 1). A trephine biopsy confirmed the diagnosis of visceral leishmaniasis (VL) along with persistence of
We herein report the case of a patient with refractory high-risk chronic lymphocytic leukemia (CLL) who developed a clinical picture suggestive for transformation into diffuse large B-cell lymphoma (Richter transformation, [RT]) a few months after treatment with alemtuzumab. Surprisingly, he turned out to have a completely different diagnosis, related to the heavy immunosuppression that characterizes patients with advanced, pretreated CLL. A 56-year-old Italian man was initially diagnosed with Binet stage A CLL at a local hospital in 2007. He was monitored without any treatment until June 2009 when he underwent six courses of chemo-immunotherapy with rituximab, fludarabine and cyclophosphamide because of disease progression. At this time, del17(p13) and trisomy 12 were detected on fluorescence in situ hybridization (FISH) analysis. The patient attained only a partial response that lasted approximately 12 months. In 2011 his rapidly deteriorating clinical profile required additional treatment (chlorambucil as monotherapy, and subsequently rituximab–bendamustine combination for six courses). No response was achieved, and the patient on his own initiative referred himself to our hospital (a tertiary referral center) for salvage treatment. In October 2012, he was admitted to our institution with constitutional symptoms (low-grade fever, night sweats), moderate cervical and axillary lymphadenopathies and splenomegaly (2 cm below costal margin); the white blood cell count was 46.0 ⫻ 109/L (lymphocytes: 33.0 ⫻ 109/L; neutrophils: 3.5 ⫻ 109/L), hemoglobin (Hb) was 9.2 g/dL and the platelet count was 134.0 ⫻ 109/L. A direct antiglobulin test (DAT) was negative, the lactate dehydrogenase (LDH) value was 480 U/L (upper normal limit 240 U/L) and the gammaglobulin level was 0.2 g/dL. The immunophenotype was typical for CLL, and negative for CD38 and ZAP70 expression. FISH analysis on peripheral blood showed del17(p13) (72% of interphase nuclei), trisomy 12 (53%) and del13q (68%). Immunoglobulin heavy chain variable (IgHV) gene mutational status assessment documented 100% homology to germline (IgHV1–69 gene usage). Screening for TP53 gene mutations revealed mutation at exon 5 (c.523C ⬎ G, p.R175G ). Bone marrow biopsy documented massive involvement (70%) by CD5⫹, CD23 ⫹ small
Correspondence: Ester M. Orlandi, MD, Hematology Unit, Department of Oncology-Hematology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy. Tel: ⫹ 39-0382-503595. Fax: ⫹ 39-0382-502250. E-mail: [email protected] Received 12 February 2014; accepted 19 February 2014
2952
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/24/15 For personal use only.
Letter to the Editor 2953
Figure 1. Bone marrow smear showing infiltration of an infected histiocyte with Leishmania amistigotes.
leukemic infiltration (30–40%) without any morphologic evidence of transformation into large B-cell lymphoma. The pre-alemtuzumab bone marrow biopsy was revised and no Leishmania amastigotes could be detected. Liposomal amphotericin B treatment was started according to an intensive schedule as adopted in the human immunodeficiency virus (HIV) setting (5 mg/kg for 7 days, followed by six weekly infusions). Indeed, the degree of immunosuppression in our patient was comparable to that in patients with HIV because of the low level of CD4 lymphocytes (120 cells/mL), hypogammaglobulinemia and neutropenia. Under amphotericin B treatment his clinical condition and whole blood counts gradually improved, while on serial bone marrow evaluations the burden of Leishmania amastigotes decreased to undetectable. The patient remained stable with Hb level, platelet count and neutrophil count in normal ranges, despite a high B-lymphocyte count (34.0 ⫻ 109/L) and persistent splenomegaly (4 cm). In the mean time a full-matched unrelated donor was identified, but the patient was judged ineligible for allogeneic stem cell transplant. Currently, he is receiving combination chemotherapy under VL reactivation prophylaxis with liposomal amphotericin B administered every 15 days and immunoglobulin replacement therapy. Some aspects of this case deserve consideration. In patients with refractory CLL the occurrence of cytopenias associated with rapidly enlarging splenomegaly and constitutional symptoms raises the concern for RT. The incidence of RT in patients with CLL ranges from 2 to 11%, according to how aggressively biopsies were performed in patients with rapidly aggressive disease [1], and is likely to increase due to the prolonged survival of patients. Among clinical and biologic features, TP53 dysfunction has been recognized as a definite poor prognostic marker for CLL transformation [2]. Although in our patient the clinical–biologic profile was suggestive for RT, he turned out to have an entirely
different diagnosis. This case underlines that histopathologic confirmation is important for a definite diagnosis of RT (which entails a dismal prognosis and requires aggressive treatment) and underscores that uncommon opportunistic infections (suitable for effective targeted treatment) can mimic the clinical picture of CLL transformation [3]. Infectious complications are a major cause of morbidity and mortality in CLL. Patients with CLL are predisposed to infections because of both humoral immunodepression related to the disease and immunosuppression related to therapy with steroids, cytotoxic drugs and monoclonal antibodies. Moreover, the broader use of immunosuppressive agents for CLL treatment has changed the spectrum of infectious complications from predominantly bacterial to unusual opportunistic infections. Alemtuzumab is a humanized monoclonal antibody binding to CD52 antigen on B and T lymphocytes, monocytes and macrophages. It triggers CLL cell death through TP53 independent mechanisms, and is one of the small number of agents with activity in fludarabine-refractory CLL or in patients with TP53 abnormality [4]. Alemtuzumab is intensively immunosuppressive, particularly in pretreated patients [5] and when used in combination regimens [6]. In the past, serious infections caused by opportunistic agents were quite common in alemtuzumab-treated patients, and currently it is well recognized that this treatment should be undertaken only if appropriate antimicrobial prophylaxis and strict microbiologic surveillance can be provided. Despite the correct prophylactic management, our patient developed a severe opportunistic parasitic infection that would have escaped our local standard assessment for underlying infection. VL is a vector-borne infection displaying a worldwide distribution; although 90% of cases occur in South-East Asia, Central Africa and Brazil, it is diagnosed with increasing frequency also in Western countries [7,8]. Leishmania spp. are obligate intracellular protozoa that infect the monocyte/macrophage lineage, and immunosuppression, particularly T-cell dysfunction, interferes with defense mechanisms against intracellular microrganisms. Our patient had always lived in a rural region of southern Italy where leishmaniasis is endemic, and it might be postulated that the immunosuppression related both to advanced CLL and multiple lines of therapy caused reactivation of a dormant infection. VL is a wellknown co-infection in HIV-infected patients living in, or who have travelled to, endemic areas [9]. Cases have been documented also in non-endemic areas in clinical settings characterized by profound immunosuppression, such as solid organ/bone marrow transplant and autoimmune diseases being treated with biological agents [10–12]. Since a global surveillance and reporting system is lacking, the burden of leishmaniasis in immunosuppressed individuals is probably underestimated. Interestingly, VL was recently reported after alemtuzumab treatment in a patient with CLL living in southern Italy [13] and after bortezomib in an Italian patient with refractory multiple myeloma [14]. Clinical presentation can be atypical in immunosuppressed individuals, misdiagnosed as a progression of the underlying disease, and life-threatening. Thus, for patients living in
2954
E. M. Orlandi & A. Malfitano
or migrating from countries where leishmaniasis is endemic, leishmaniasis reactivation or primary infection should be considered among potential opportunistic infectious complications under immunosuppressive therapies, to enable prompt targeted therapy. An aggressive amphotericin B schedule could achieve apparently complete clearance of the protozoan parasites and definitely improve quality of life, although relapse might be likely in our heavily pretreated patient.
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/24/15 For personal use only.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Parikh SA , Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol 2013;162:774–782. [2] Rossi D, Cerri M, Capello D, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol 2008;142:202–215. [3] Parikh SA , Bhusal Y, Faderl SH, et al. The great imitator: systemic nocardiosis mimicking Richter’s transformation in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2010;28:e732–e734.
[4] Sellner L, Denzinger S, Dietrich S, et al. What do we do with chronic lymphocytic leukemia with 17p deletion? Curr Hematol Malig Rep 2013;8:81–90. [5] Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002 ;99:3554–3561. [6] Elter T, Gercheva-Kyuchukova L, Pylylpenko H, et al. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol 2011;12:1204–1213. [7] van Griensven J, Diro E. Visceral leishmaniasis. Infect Dis Clin North Am 2012;26:309–322. [8] Antinori S, Schifanella L, Corbellino M. Leishmaniasis: new insights from an old and neglected disease. Eur J Clin Microbiol Infect Dis 2012;31:109–118. [9] Alvar J, Aparicio P, Aseffa A , et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 2008;21:334–359. [10] Antinori S, Cascio A , Parravicini C, et al. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008 ;8:191–199. [11] Xynos ID, Tektonidou MG, Pikazis D, et al. Leishmaniasis, autoimmune rheumatic disease, and anti-tumor necrosis factor therapy, Europe. Emerg Infect Dis 2009;15:956–959. [12] van Griensven J, Carrillo E, López-Vélez R, et al. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 2014 Jan 23. [Epub ahead of print] [13] Pitini V, Cascio A , Arrigo C, et al. Visceral leishmaniasis after alemtuzumab in a patient with chronic lymphocytic leukaemia. Br J Haematol 2012;156:1. [14] Piro E, Kropp M, Cantaffa R, et al. Visceral leishmaniasis infection in a refractory multiple myeloma patient treated with bortezomib. Ann Hematol 2012;91:1827–1828.
LETTER TO THE EDITOR
Visceral leishmaniasis mimicking Richter transformation Ester M. Orlandi1 & Antonello Malfitano2 1Hematology Unit, Department of Oncology-Hematology and 2Infectious and Tropical Diseases Unit, Department of Infectious
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/24/15 For personal use only.
Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
lymphocytes. Based on refractoriness to previous treatment and disruption of the TP53 pathway, an allogeneic stem cell transplant was considered to be a possible future option. The patient’s sister was evaluated as a potential donor, but unfortunately she was diagnosed with CLL-like monoclonal B-cell lymphocytosis. The patient could not be enrolled in any experimental clinical trials active at our center, so we decided to start alemtuzumab therapy, according to an individual patient access scheme in place after the license for alemtuzumab in CLL was voluntarily suspended by the producing company. Our patient received 18 doses of subcutaneous alemtuzumb (30 mg, twice a week). Supportive care included antimicrobial prophylaxis with acyclovir, trimethoprim–sulfamethoxazole and fluconazole, administration of granulocyte colony stimulating factor (G-CSF) and recombinant erythropoietin (EPO), and weekly surveillance for cytomegalovirus (CMV) and Epstein–Barr virus (EBV) reactivation. Alemtuzumab therapy was completed without complications despite grade 3 neutropenia and lymphocytopenia. The patient did fairly well for 2 months, but in May 2013 he started to complain of systemic symptoms, fatigue and abdominal discomfort. Peripheral blood counts were worsening (white blood cell count: 5.5 ⫻ 109/L, lymphocytes: 79%, neutrophils: 8%; Hb: 6.7 g/dL, platelet count: 37.0 ⫻ 109/L), the LDH value was 670 U/L, the ferritin level was 1270 ng/dL and massive splenomegaly was palpable (6 cm). No peripheral adenopathies were palpable, and a total body computed tomography (CT) scan documented only an increase in splenic longitudinal diameter (20 cm). Extensive work-up for infectious causes of fever including bacteria, mycobacteria, Aspergillus, cryptococci, adenovirus, CMV, EBV, parvovirus B19 and herpes viruses was negative. The patient was started on broad-spectrum antibiotic treatment. On the presumption that the clinical picture represented either progressive disease or RT or hemophagocytic lymphohistiocytosis, bone marrow evaluation was performed, as no peripheral lymph nodes were suitable for biopsy. Surprisingly, numerous intracellular amastigotes of Leishmania spp. were detected on bone marrow smears (Figure 1). A trephine biopsy confirmed the diagnosis of visceral leishmaniasis (VL) along with persistence of
We herein report the case of a patient with refractory high-risk chronic lymphocytic leukemia (CLL) who developed a clinical picture suggestive for transformation into diffuse large B-cell lymphoma (Richter transformation, [RT]) a few months after treatment with alemtuzumab. Surprisingly, he turned out to have a completely different diagnosis, related to the heavy immunosuppression that characterizes patients with advanced, pretreated CLL. A 56-year-old Italian man was initially diagnosed with Binet stage A CLL at a local hospital in 2007. He was monitored without any treatment until June 2009 when he underwent six courses of chemo-immunotherapy with rituximab, fludarabine and cyclophosphamide because of disease progression. At this time, del17(p13) and trisomy 12 were detected on fluorescence in situ hybridization (FISH) analysis. The patient attained only a partial response that lasted approximately 12 months. In 2011 his rapidly deteriorating clinical profile required additional treatment (chlorambucil as monotherapy, and subsequently rituximab–bendamustine combination for six courses). No response was achieved, and the patient on his own initiative referred himself to our hospital (a tertiary referral center) for salvage treatment. In October 2012, he was admitted to our institution with constitutional symptoms (low-grade fever, night sweats), moderate cervical and axillary lymphadenopathies and splenomegaly (2 cm below costal margin); the white blood cell count was 46.0 ⫻ 109/L (lymphocytes: 33.0 ⫻ 109/L; neutrophils: 3.5 ⫻ 109/L), hemoglobin (Hb) was 9.2 g/dL and the platelet count was 134.0 ⫻ 109/L. A direct antiglobulin test (DAT) was negative, the lactate dehydrogenase (LDH) value was 480 U/L (upper normal limit 240 U/L) and the gammaglobulin level was 0.2 g/dL. The immunophenotype was typical for CLL, and negative for CD38 and ZAP70 expression. FISH analysis on peripheral blood showed del17(p13) (72% of interphase nuclei), trisomy 12 (53%) and del13q (68%). Immunoglobulin heavy chain variable (IgHV) gene mutational status assessment documented 100% homology to germline (IgHV1–69 gene usage). Screening for TP53 gene mutations revealed mutation at exon 5 (c.523C ⬎ G, p.R175G ). Bone marrow biopsy documented massive involvement (70%) by CD5⫹, CD23 ⫹ small
Correspondence: Ester M. Orlandi, MD, Hematology Unit, Department of Oncology-Hematology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy. Tel: ⫹ 39-0382-503595. Fax: ⫹ 39-0382-502250. E-mail: [email protected] Received 12 February 2014; accepted 19 February 2014
2952
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/24/15 For personal use only.
Letter to the Editor 2953
Figure 1. Bone marrow smear showing infiltration of an infected histiocyte with Leishmania amistigotes.
leukemic infiltration (30–40%) without any morphologic evidence of transformation into large B-cell lymphoma. The pre-alemtuzumab bone marrow biopsy was revised and no Leishmania amastigotes could be detected. Liposomal amphotericin B treatment was started according to an intensive schedule as adopted in the human immunodeficiency virus (HIV) setting (5 mg/kg for 7 days, followed by six weekly infusions). Indeed, the degree of immunosuppression in our patient was comparable to that in patients with HIV because of the low level of CD4 lymphocytes (120 cells/mL), hypogammaglobulinemia and neutropenia. Under amphotericin B treatment his clinical condition and whole blood counts gradually improved, while on serial bone marrow evaluations the burden of Leishmania amastigotes decreased to undetectable. The patient remained stable with Hb level, platelet count and neutrophil count in normal ranges, despite a high B-lymphocyte count (34.0 ⫻ 109/L) and persistent splenomegaly (4 cm). In the mean time a full-matched unrelated donor was identified, but the patient was judged ineligible for allogeneic stem cell transplant. Currently, he is receiving combination chemotherapy under VL reactivation prophylaxis with liposomal amphotericin B administered every 15 days and immunoglobulin replacement therapy. Some aspects of this case deserve consideration. In patients with refractory CLL the occurrence of cytopenias associated with rapidly enlarging splenomegaly and constitutional symptoms raises the concern for RT. The incidence of RT in patients with CLL ranges from 2 to 11%, according to how aggressively biopsies were performed in patients with rapidly aggressive disease [1], and is likely to increase due to the prolonged survival of patients. Among clinical and biologic features, TP53 dysfunction has been recognized as a definite poor prognostic marker for CLL transformation [2]. Although in our patient the clinical–biologic profile was suggestive for RT, he turned out to have an entirely
different diagnosis. This case underlines that histopathologic confirmation is important for a definite diagnosis of RT (which entails a dismal prognosis and requires aggressive treatment) and underscores that uncommon opportunistic infections (suitable for effective targeted treatment) can mimic the clinical picture of CLL transformation [3]. Infectious complications are a major cause of morbidity and mortality in CLL. Patients with CLL are predisposed to infections because of both humoral immunodepression related to the disease and immunosuppression related to therapy with steroids, cytotoxic drugs and monoclonal antibodies. Moreover, the broader use of immunosuppressive agents for CLL treatment has changed the spectrum of infectious complications from predominantly bacterial to unusual opportunistic infections. Alemtuzumab is a humanized monoclonal antibody binding to CD52 antigen on B and T lymphocytes, monocytes and macrophages. It triggers CLL cell death through TP53 independent mechanisms, and is one of the small number of agents with activity in fludarabine-refractory CLL or in patients with TP53 abnormality [4]. Alemtuzumab is intensively immunosuppressive, particularly in pretreated patients [5] and when used in combination regimens [6]. In the past, serious infections caused by opportunistic agents were quite common in alemtuzumab-treated patients, and currently it is well recognized that this treatment should be undertaken only if appropriate antimicrobial prophylaxis and strict microbiologic surveillance can be provided. Despite the correct prophylactic management, our patient developed a severe opportunistic parasitic infection that would have escaped our local standard assessment for underlying infection. VL is a vector-borne infection displaying a worldwide distribution; although 90% of cases occur in South-East Asia, Central Africa and Brazil, it is diagnosed with increasing frequency also in Western countries [7,8]. Leishmania spp. are obligate intracellular protozoa that infect the monocyte/macrophage lineage, and immunosuppression, particularly T-cell dysfunction, interferes with defense mechanisms against intracellular microrganisms. Our patient had always lived in a rural region of southern Italy where leishmaniasis is endemic, and it might be postulated that the immunosuppression related both to advanced CLL and multiple lines of therapy caused reactivation of a dormant infection. VL is a wellknown co-infection in HIV-infected patients living in, or who have travelled to, endemic areas [9]. Cases have been documented also in non-endemic areas in clinical settings characterized by profound immunosuppression, such as solid organ/bone marrow transplant and autoimmune diseases being treated with biological agents [10–12]. Since a global surveillance and reporting system is lacking, the burden of leishmaniasis in immunosuppressed individuals is probably underestimated. Interestingly, VL was recently reported after alemtuzumab treatment in a patient with CLL living in southern Italy [13] and after bortezomib in an Italian patient with refractory multiple myeloma [14]. Clinical presentation can be atypical in immunosuppressed individuals, misdiagnosed as a progression of the underlying disease, and life-threatening. Thus, for patients living in
2954
E. M. Orlandi & A. Malfitano
or migrating from countries where leishmaniasis is endemic, leishmaniasis reactivation or primary infection should be considered among potential opportunistic infectious complications under immunosuppressive therapies, to enable prompt targeted therapy. An aggressive amphotericin B schedule could achieve apparently complete clearance of the protozoan parasites and definitely improve quality of life, although relapse might be likely in our heavily pretreated patient.
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/24/15 For personal use only.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Parikh SA , Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol 2013;162:774–782. [2] Rossi D, Cerri M, Capello D, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol 2008;142:202–215. [3] Parikh SA , Bhusal Y, Faderl SH, et al. The great imitator: systemic nocardiosis mimicking Richter’s transformation in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2010;28:e732–e734.
[4] Sellner L, Denzinger S, Dietrich S, et al. What do we do with chronic lymphocytic leukemia with 17p deletion? Curr Hematol Malig Rep 2013;8:81–90. [5] Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002 ;99:3554–3561. [6] Elter T, Gercheva-Kyuchukova L, Pylylpenko H, et al. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol 2011;12:1204–1213. [7] van Griensven J, Diro E. Visceral leishmaniasis. Infect Dis Clin North Am 2012;26:309–322. [8] Antinori S, Schifanella L, Corbellino M. Leishmaniasis: new insights from an old and neglected disease. Eur J Clin Microbiol Infect Dis 2012;31:109–118. [9] Alvar J, Aparicio P, Aseffa A , et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 2008;21:334–359. [10] Antinori S, Cascio A , Parravicini C, et al. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008 ;8:191–199. [11] Xynos ID, Tektonidou MG, Pikazis D, et al. Leishmaniasis, autoimmune rheumatic disease, and anti-tumor necrosis factor therapy, Europe. Emerg Infect Dis 2009;15:956–959. [12] van Griensven J, Carrillo E, López-Vélez R, et al. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 2014 Jan 23. [Epub ahead of print] [13] Pitini V, Cascio A , Arrigo C, et al. Visceral leishmaniasis after alemtuzumab in a patient with chronic lymphocytic leukaemia. Br J Haematol 2012;156:1. [14] Piro E, Kropp M, Cantaffa R, et al. Visceral leishmaniasis infection in a refractory multiple myeloma patient treated with bortezomib. Ann Hematol 2012;91:1827–1828.
