- Email: [email protected]
Hepatic microabscesses during CMV reactivation in a multiple sclerosis patient after alemtuzumab treatment
Multiple Sclerosis and Related Disorders 20 (2018) 6–8
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Case report
Hepatic microabscesses during CMV reactivation in a multiple sclerosis patient after alemtuzumab treatment
T
Stefania Baronea, Sara Scannapiecoa, Carlo Tortib, Enrica Filippellia, Vincenzo Pisanib, Alfredo Granataa, Domenico Consolec, Giulio Demontea, Tiziana Tallaricoa, Serena Polidoroa, ⁎ Aldo Quattronea,d, Paola Valentinoa, Institute of Neurology, Department of Medical and Surgical Sciences, University “Magna Graecia”, Catanzaro, Italy Unit of Infectious and Tropical Diseases, Department of Medical and Surgical Sciences, University "Magna Graecia", Catanzaro, Italy c Radiology Unit, Department of Experimental and Clinical Medicine, University “Magna Graecia", Catanzaro, Italy d Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Catanzaro, Italy a
b
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple sclerosis Cytomegalovirus Alemtuzumab CMV reactivation Opportunistic CMV infection Hepatic microabscesses
The anti-CD52 monoclonal antibody alemtuzumab is a highly active treatment for multiple sclerosis (MS) causing rapid depletion of B and T lymphocytes with nadir one month after last infusion. Opportunistic Cytomegalovirus (CMV) infections have been reported in MS patients treated with this drug. We report one patient who developed a CMV reactivation with hepatic involvement three weeks after the first cycle of alemtuzumab. This patient, promptly diagnosed and treated, achieved a complete recovery with valganciclovir. The possibility of this treatable opportunistic infection should be considered by neurologists in febrile patients with hepatic markers alteration after treatment with alemtuzumab.
1. Introduction
2. Case report
The latent infection with human cytomegalovirus (CMV) is common in the general population. Functional immunity effectively contains such latent infections; however, CMV reactivation risk increases in immunocompromised patients and rarely can lead to severe organ complications (Piukovics et al., 2017). In some instance, CMV could be the cause of hepatic involvement in either immunocompromised hosts or in liver transplant recipients (Kanj et al., 1996). Alemtuzumab (Lemtrada®) is a humanized monoclonal antibody targeting the CD52 antigen, a protein present on the surface of mature lymphocytes and less on natural killer cells, monocytes and dendritic cells. Alemtuzumab was first indicated for use in chronic lymphocytic leukemia (CLL) and then recently approved for the treatment of patients with relapsingremitting multiple sclerosis (RRMS) (Rai et al., 2002). Each treatment course of alemtuzumab induces a rapid depletion of circulating B and T lymphocytes, with the lowest observed values occurring one month after a course of treatment (Hartung et al., 2015). Although the CMV reactivation is present in 4–29% of patients treated with alemtuzumab for CLL (O'Brien et al., 2006), this event was also recently described in MS patients treated with this drug (Clerico et al., 2017). In this report, we describe a case of CMV reactivation with hepatic involvement in a RRMS patient treated with alemtuzumab.
A previously healthy, 45-year-old caucasian woman presented in 1999 with left optic neuritis. She was diagnosed in 2006 with multiple sclerosis based on McDonald criteria with compatible brain and spinal cord lesions in the magnetic resonance imaging and cerebrospinal fluid findings. After the diagnosis, she started interferon beta-1a sub-cutaneously, which she discontinued because of poor efficacy and increased of transaminases. Therefore, in October 2010, she switched to natalizumab 300 mg/month intravenously (i.v.). The patient was negative for anti-JC virus (JCV) antibodies but, natalizumab was interrupted in November 2012 due to hypertransaminasemia and one additional pyramidal relapse. Until May 2014, she did not receive disease modifying treatments (DMTs) and showed two sensorimotor relapses with complete recovery after steroid treatment, then she started fingolimod 0.5 mg/day which was stopped in March 2015 because of severe lymphopenia (lymphocytes count < 0.2 × 10^3/uL) and increment of transaminases. During the 2016, in absence of DMTs, she had three sensorimotor relapses with partial recovery after steroid treatment. In September 2016, she began alemtuzumab (12 mg/day i.v. for 5 consecutive days). On the first day of infusion, she started oral prophylaxis for herpes infection with acyclovir 200 mg/twice a day. In the last day of infusion, she developed hypotension (90/45 mmHg) and bradycardia
⁎
Correspondence to: Clinica Neurologica, Università degli Studi “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy. E-mail address: [email protected] (P. Valentino).
https://doi.org/10.1016/j.msard.2017.12.009 Received 1 June 2017; Received in revised form 11 December 2017; Accepted 15 December 2017 2211-0348/ © 2017 Published by Elsevier B.V.
Multiple Sclerosis and Related Disorders 20 (2018) 6–8
S. Barone et al.
3. Discussion
(45 bpm) with spontaneous recovery after one hour of infusion interruption. Three weeks after last alemtuzumab infusion, she was hospitalised for fever (38 °C). The laboratory tests showed a modest increase in transaminases with alanine aminotransferase (ALT) 46 UI/l, aspartate aminotransferase (AST) 41 UI/l, gamma-glutamil transpetidase (GGT) 63 UI/l and a considerable increase in inflammation index with C-reactive Protein 75.5 mg/l. White Blood Cells (WBC) and lymphocytes counts were 2.8 × 10^3/uL and 0.08 × 10^3/uL respectively. The following comprehensive infective and autoimmune panel of tests has been performed with negative results: blood and urine cultures, procalcitonin, acute hepatitis (A/B/C) markers, human immunodeficiency virus (HIV) antibodies, Epstein-Barr virus (EBV) immunoglobulin M (IgM) antibodies, Varicella Zoster (VZV) IgM antibodies, Syphilis tests (rapid plasma reagin – RPR; Treponema Pallidum Hemagglutination Assay – TPHA), QuantiFERON®-Tuberculosis (TB) Test, Widal-Wright reaction, Immunoglobulin G (IgG) and IgM antibodies against Bartonella, Brucella, Borrelia, Treponema and Toxoplasma, anti-double strand deoxyribonucleic acid (ds-DNA) antibodies, antinuclear antibodies (ANA), Waaler-Rose reaction, anti-mitochondrial antibodies (AMA), anti-Liver Kidney Microsomal Antibodies (LKM), anti-smooth muscle antibody (ASMA). The CMV viral DNA polymerase chain reaction (PCR) was positive with 17.318 copies/ml, anti CMV IgG antibodies were positive at 48 U/ ml and anti CMV IgM antibodies were negative indicating a CMV reactivation. The liver ultrasonography, made because of the transaminase increase, demonstrated multiple small hypoechoic lesions (maximum size 1 cm) diffusely scattered in the hepatic lobes suggesting multiple hepatic microabscesses (Fig. 1(A–B)), not detected in previous hepatic ultrasonography. Oral valganciclovir was administered at dose of 450 mg twice daily for 4 weeks. The CMV viral load became undetectable 13 days after the beginning of antiviral treatment. Fever, inflammation indexes and hypertransaminasemia resolved in two weeks. At the follow-up two months later, liver ultrasonography showed regression of the microabscesses (Fig. 1(C–D)).
The data so far available about CMV reactivation in patients treated with alemtuzumab concern its use in lymphoproliferative disorders (Ferrajoli et al., 2003). The guidelines on the management of CMV reactivation in patient with CLL treated with alemtuzumab recommend: 1) performing the CMV DNA assay in all patients that develop fever soon after the treatment and, 2) treating all symptomatic patients with positive CMV DNA using valganciclovir or ganciclovir (O'Brien et al., 2006). The increasing use of alemtuzumab in MS treatment makes relevant the topic of opportunistic infections (Brownlee and Chataway, 2017). The reported case has several similarities with those recently described (Clerico et al., 2017), especially the fever as initial symptom of CMV reactivation, the onset within one month after alemtuzumab infusion and the complete recovery achieved with specific antiviral therapy (valganciclovir). In addition, in our case the liver was involved with microabscesses that resolved after therapy with valganciclovir. Hepatic microabscesses during CMV reactivation have been described in immunosuppressed patients, especially in liver transplant recipients, where the hepatic involvement by CMV tends to be focal (MacDonald et al., 1997). Liver microabscesses and parenchymal alterations are also common in CMV hepatitis (Minemura et al., 2014). However, there has been no previous report concerning hepatic microabscesses in RRMS patients after alemtuzumab treatment. Because the acyclovir prophylaxis could be ineffective against the CMV reactivations (Hartung et al., 2015), all patients that develop fever and increase in transaminases after alemtuzumab should undergo CMV PCR assay and, in our opinion, also liver ultrasonography to demonstrate hepatic involvement like in this case. Furthermore, we suggest performing baseline CMV status before starting alemtuzumab in all MS patients and implementing a weekly monitoring with CMV PCR assay during the first month after infusion, such as indicated in the guidelines for CLL (O'Brien et al., 2006). This surveillance would allow a prompt switch from acyclovir to a more specific antiviral treatment (ganciclovir or valganciclovir) in case of CMV reactivation. It is important to note that during the treatment with beta-interferon, natalizumab and fingolimod this patient developed alteration in the liver function tests (LFTs); in these cases, the Fig. 1. (A, B) small hypoechoic lesions in the liver, suggestive of multiple microabscesses and (C, D) no evidence of residual hypoechoic lesions after treatment with valganciclovir.
7
Multiple Sclerosis and Related Disorders 20 (2018) 6–8
S. Barone et al.
References
hypertransaminasaemia was modest and occurred without any clinical symptom suggestive of CMV reactivation (e.g. fever or lymphadenopathy). Furthermore, LFTs returned to normal range few days after discontinuation of each drug without need for any pharmacological therapy. Moreover, the liver ultrasonography performed after LFT elevations with previous treatments were always unremarkable. Although the hypertransaminasaemia is a common side effect reported with beta-interferon, natalizumab and fingolimod, we could speculate that in this patient there was a strong susceptibility to druginduced liver injury (Abboud and Kaplowitz, 2007). This report highlights the risk of CMV reactivation in the first month following alemtuzumab infusion and suggests that an appropriate surveillance is needed to manage this potential and treatable opportunistic infection.
Abboud, G., Kaplowitz, N., 2007. Drug-induced liver injury. Drug Saf. 30 (4), 277–294. Brownlee, W.J., Chataway, J., 2017. Opportunistic infections after alemtuzumab: new cases of norcardial infection and cytomegalovirus syndrome. Mult. Scler. 23 (6), 876–877. http://dx.doi.org/10.1177/1352458517693440. (Epub 2017 Feb 1). Clerico, M., De Mercanti, S., Artusi, C.A., et al., 2017. Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab. Mult. Scler. 23 (6), 874–876. http://dx.doi.org/10.1177/1352458516688350. (Epub 2017 Feb 1). Ferrajoli, A., O'Brien, S.M., Cortes, J.E., et al., 2003. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 98 (4), 773–778. Hartung, H.P., Aktas, O., Boyko, A.N., 2015. Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult. Scler. 21 (1), 22–34. Kanj, S.S., Sharara, A., Clavien, P.A., et al., 1996. Cytomegalovirus infection following liver transplantation: review of the literature. Clin. Infect. Dis. 22 (3), 537–549. MacDonald, G.A., Greenson, J.K., DelBuono, E.A., et al., 1997. Mini-microabscess syndrome in liver transplant recipients. Hepatology 26 (1), 192–197. Minemura, M., Tajiri, K., Shimizu, Y., 2014. Liver involvement in systemic infection. World J. Hepatol. 6 (9), 632–642. O'Brien, S.M., Keating, M.J., Mocarski, E.S., 2006. Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. Clin. Lymphoma Myeloma 7 (2), 125–130. Piukovics, K., Terhes, G., Gurbity-Pálfi, T., et al., 2017. Cytomegalovirus infection in patients with haematological diseases and after autologous stem cell transplantation as consolidation: a single-centre study. Ann. Hematol. 96 (1), 125–131. Rai, K.R., Freter, C.E., Mercier, R.J., et al., 2002. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J. Clin. Oncol. 20 (18), 3891–3897.
Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
8
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Case report
Hepatic microabscesses during CMV reactivation in a multiple sclerosis patient after alemtuzumab treatment
T
Stefania Baronea, Sara Scannapiecoa, Carlo Tortib, Enrica Filippellia, Vincenzo Pisanib, Alfredo Granataa, Domenico Consolec, Giulio Demontea, Tiziana Tallaricoa, Serena Polidoroa, ⁎ Aldo Quattronea,d, Paola Valentinoa, Institute of Neurology, Department of Medical and Surgical Sciences, University “Magna Graecia”, Catanzaro, Italy Unit of Infectious and Tropical Diseases, Department of Medical and Surgical Sciences, University "Magna Graecia", Catanzaro, Italy c Radiology Unit, Department of Experimental and Clinical Medicine, University “Magna Graecia", Catanzaro, Italy d Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Catanzaro, Italy a
b
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple sclerosis Cytomegalovirus Alemtuzumab CMV reactivation Opportunistic CMV infection Hepatic microabscesses
The anti-CD52 monoclonal antibody alemtuzumab is a highly active treatment for multiple sclerosis (MS) causing rapid depletion of B and T lymphocytes with nadir one month after last infusion. Opportunistic Cytomegalovirus (CMV) infections have been reported in MS patients treated with this drug. We report one patient who developed a CMV reactivation with hepatic involvement three weeks after the first cycle of alemtuzumab. This patient, promptly diagnosed and treated, achieved a complete recovery with valganciclovir. The possibility of this treatable opportunistic infection should be considered by neurologists in febrile patients with hepatic markers alteration after treatment with alemtuzumab.
1. Introduction
2. Case report
The latent infection with human cytomegalovirus (CMV) is common in the general population. Functional immunity effectively contains such latent infections; however, CMV reactivation risk increases in immunocompromised patients and rarely can lead to severe organ complications (Piukovics et al., 2017). In some instance, CMV could be the cause of hepatic involvement in either immunocompromised hosts or in liver transplant recipients (Kanj et al., 1996). Alemtuzumab (Lemtrada®) is a humanized monoclonal antibody targeting the CD52 antigen, a protein present on the surface of mature lymphocytes and less on natural killer cells, monocytes and dendritic cells. Alemtuzumab was first indicated for use in chronic lymphocytic leukemia (CLL) and then recently approved for the treatment of patients with relapsingremitting multiple sclerosis (RRMS) (Rai et al., 2002). Each treatment course of alemtuzumab induces a rapid depletion of circulating B and T lymphocytes, with the lowest observed values occurring one month after a course of treatment (Hartung et al., 2015). Although the CMV reactivation is present in 4–29% of patients treated with alemtuzumab for CLL (O'Brien et al., 2006), this event was also recently described in MS patients treated with this drug (Clerico et al., 2017). In this report, we describe a case of CMV reactivation with hepatic involvement in a RRMS patient treated with alemtuzumab.
A previously healthy, 45-year-old caucasian woman presented in 1999 with left optic neuritis. She was diagnosed in 2006 with multiple sclerosis based on McDonald criteria with compatible brain and spinal cord lesions in the magnetic resonance imaging and cerebrospinal fluid findings. After the diagnosis, she started interferon beta-1a sub-cutaneously, which she discontinued because of poor efficacy and increased of transaminases. Therefore, in October 2010, she switched to natalizumab 300 mg/month intravenously (i.v.). The patient was negative for anti-JC virus (JCV) antibodies but, natalizumab was interrupted in November 2012 due to hypertransaminasemia and one additional pyramidal relapse. Until May 2014, she did not receive disease modifying treatments (DMTs) and showed two sensorimotor relapses with complete recovery after steroid treatment, then she started fingolimod 0.5 mg/day which was stopped in March 2015 because of severe lymphopenia (lymphocytes count < 0.2 × 10^3/uL) and increment of transaminases. During the 2016, in absence of DMTs, she had three sensorimotor relapses with partial recovery after steroid treatment. In September 2016, she began alemtuzumab (12 mg/day i.v. for 5 consecutive days). On the first day of infusion, she started oral prophylaxis for herpes infection with acyclovir 200 mg/twice a day. In the last day of infusion, she developed hypotension (90/45 mmHg) and bradycardia
⁎
Correspondence to: Clinica Neurologica, Università degli Studi “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy. E-mail address: [email protected] (P. Valentino).
https://doi.org/10.1016/j.msard.2017.12.009 Received 1 June 2017; Received in revised form 11 December 2017; Accepted 15 December 2017 2211-0348/ © 2017 Published by Elsevier B.V.
Multiple Sclerosis and Related Disorders 20 (2018) 6–8
S. Barone et al.
3. Discussion
(45 bpm) with spontaneous recovery after one hour of infusion interruption. Three weeks after last alemtuzumab infusion, she was hospitalised for fever (38 °C). The laboratory tests showed a modest increase in transaminases with alanine aminotransferase (ALT) 46 UI/l, aspartate aminotransferase (AST) 41 UI/l, gamma-glutamil transpetidase (GGT) 63 UI/l and a considerable increase in inflammation index with C-reactive Protein 75.5 mg/l. White Blood Cells (WBC) and lymphocytes counts were 2.8 × 10^3/uL and 0.08 × 10^3/uL respectively. The following comprehensive infective and autoimmune panel of tests has been performed with negative results: blood and urine cultures, procalcitonin, acute hepatitis (A/B/C) markers, human immunodeficiency virus (HIV) antibodies, Epstein-Barr virus (EBV) immunoglobulin M (IgM) antibodies, Varicella Zoster (VZV) IgM antibodies, Syphilis tests (rapid plasma reagin – RPR; Treponema Pallidum Hemagglutination Assay – TPHA), QuantiFERON®-Tuberculosis (TB) Test, Widal-Wright reaction, Immunoglobulin G (IgG) and IgM antibodies against Bartonella, Brucella, Borrelia, Treponema and Toxoplasma, anti-double strand deoxyribonucleic acid (ds-DNA) antibodies, antinuclear antibodies (ANA), Waaler-Rose reaction, anti-mitochondrial antibodies (AMA), anti-Liver Kidney Microsomal Antibodies (LKM), anti-smooth muscle antibody (ASMA). The CMV viral DNA polymerase chain reaction (PCR) was positive with 17.318 copies/ml, anti CMV IgG antibodies were positive at 48 U/ ml and anti CMV IgM antibodies were negative indicating a CMV reactivation. The liver ultrasonography, made because of the transaminase increase, demonstrated multiple small hypoechoic lesions (maximum size 1 cm) diffusely scattered in the hepatic lobes suggesting multiple hepatic microabscesses (Fig. 1(A–B)), not detected in previous hepatic ultrasonography. Oral valganciclovir was administered at dose of 450 mg twice daily for 4 weeks. The CMV viral load became undetectable 13 days after the beginning of antiviral treatment. Fever, inflammation indexes and hypertransaminasemia resolved in two weeks. At the follow-up two months later, liver ultrasonography showed regression of the microabscesses (Fig. 1(C–D)).
The data so far available about CMV reactivation in patients treated with alemtuzumab concern its use in lymphoproliferative disorders (Ferrajoli et al., 2003). The guidelines on the management of CMV reactivation in patient with CLL treated with alemtuzumab recommend: 1) performing the CMV DNA assay in all patients that develop fever soon after the treatment and, 2) treating all symptomatic patients with positive CMV DNA using valganciclovir or ganciclovir (O'Brien et al., 2006). The increasing use of alemtuzumab in MS treatment makes relevant the topic of opportunistic infections (Brownlee and Chataway, 2017). The reported case has several similarities with those recently described (Clerico et al., 2017), especially the fever as initial symptom of CMV reactivation, the onset within one month after alemtuzumab infusion and the complete recovery achieved with specific antiviral therapy (valganciclovir). In addition, in our case the liver was involved with microabscesses that resolved after therapy with valganciclovir. Hepatic microabscesses during CMV reactivation have been described in immunosuppressed patients, especially in liver transplant recipients, where the hepatic involvement by CMV tends to be focal (MacDonald et al., 1997). Liver microabscesses and parenchymal alterations are also common in CMV hepatitis (Minemura et al., 2014). However, there has been no previous report concerning hepatic microabscesses in RRMS patients after alemtuzumab treatment. Because the acyclovir prophylaxis could be ineffective against the CMV reactivations (Hartung et al., 2015), all patients that develop fever and increase in transaminases after alemtuzumab should undergo CMV PCR assay and, in our opinion, also liver ultrasonography to demonstrate hepatic involvement like in this case. Furthermore, we suggest performing baseline CMV status before starting alemtuzumab in all MS patients and implementing a weekly monitoring with CMV PCR assay during the first month after infusion, such as indicated in the guidelines for CLL (O'Brien et al., 2006). This surveillance would allow a prompt switch from acyclovir to a more specific antiviral treatment (ganciclovir or valganciclovir) in case of CMV reactivation. It is important to note that during the treatment with beta-interferon, natalizumab and fingolimod this patient developed alteration in the liver function tests (LFTs); in these cases, the Fig. 1. (A, B) small hypoechoic lesions in the liver, suggestive of multiple microabscesses and (C, D) no evidence of residual hypoechoic lesions after treatment with valganciclovir.
7
Multiple Sclerosis and Related Disorders 20 (2018) 6–8
S. Barone et al.
References
hypertransaminasaemia was modest and occurred without any clinical symptom suggestive of CMV reactivation (e.g. fever or lymphadenopathy). Furthermore, LFTs returned to normal range few days after discontinuation of each drug without need for any pharmacological therapy. Moreover, the liver ultrasonography performed after LFT elevations with previous treatments were always unremarkable. Although the hypertransaminasaemia is a common side effect reported with beta-interferon, natalizumab and fingolimod, we could speculate that in this patient there was a strong susceptibility to druginduced liver injury (Abboud and Kaplowitz, 2007). This report highlights the risk of CMV reactivation in the first month following alemtuzumab infusion and suggests that an appropriate surveillance is needed to manage this potential and treatable opportunistic infection.
Abboud, G., Kaplowitz, N., 2007. Drug-induced liver injury. Drug Saf. 30 (4), 277–294. Brownlee, W.J., Chataway, J., 2017. Opportunistic infections after alemtuzumab: new cases of norcardial infection and cytomegalovirus syndrome. Mult. Scler. 23 (6), 876–877. http://dx.doi.org/10.1177/1352458517693440. (Epub 2017 Feb 1). Clerico, M., De Mercanti, S., Artusi, C.A., et al., 2017. Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab. Mult. Scler. 23 (6), 874–876. http://dx.doi.org/10.1177/1352458516688350. (Epub 2017 Feb 1). Ferrajoli, A., O'Brien, S.M., Cortes, J.E., et al., 2003. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 98 (4), 773–778. Hartung, H.P., Aktas, O., Boyko, A.N., 2015. Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult. Scler. 21 (1), 22–34. Kanj, S.S., Sharara, A., Clavien, P.A., et al., 1996. Cytomegalovirus infection following liver transplantation: review of the literature. Clin. Infect. Dis. 22 (3), 537–549. MacDonald, G.A., Greenson, J.K., DelBuono, E.A., et al., 1997. Mini-microabscess syndrome in liver transplant recipients. Hepatology 26 (1), 192–197. Minemura, M., Tajiri, K., Shimizu, Y., 2014. Liver involvement in systemic infection. World J. Hepatol. 6 (9), 632–642. O'Brien, S.M., Keating, M.J., Mocarski, E.S., 2006. Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. Clin. Lymphoma Myeloma 7 (2), 125–130. Piukovics, K., Terhes, G., Gurbity-Pálfi, T., et al., 2017. Cytomegalovirus infection in patients with haematological diseases and after autologous stem cell transplantation as consolidation: a single-centre study. Ann. Hematol. 96 (1), 125–131. Rai, K.R., Freter, C.E., Mercier, R.J., et al., 2002. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J. Clin. Oncol. 20 (18), 3891–3897.
Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
8