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Complete response in a patient with adult T-cell leukemia (ATL) treated with combination of alemtuzumab and pentostatin
Leukemia Research 30 (2006) 103–105
Case report
Complete response in a patient with adult T-cell leukemia (ATL) treated with combination of alemtuzumab and pentostatin Farhad Ravandi ∗ , Stefan Faderl Department of Leukemia, Box 428, University of Texas–M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA Received 6 May 2005; received in revised form 9 May 2005; accepted 15 May 2005 Available online 24 June 2005
Abstract Treatment of adult T-cell leukemia (ATL) remains difficult. Alemtuzumab with or without nucleoside analogs such as pentostatin may provide a role in this setting. However, the associated immunosuppression is a concern in patients with viral-mediated disease. © 2005 Elsevier Ltd. All rights reserved. Keywords: ATL; Alemtuzumab; Pentostatin; HTLV-I
1. Introduction The association of ATL with human T-cell leukemia virus type I (HTLV-I), the first oncogenic retrovirus discovered in man, is well described [1]. The virus is the pathogenic factor for ATL and a number of other disorders including tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM), and HTLV-I associated uveitis. HTLV-1 is endemic in southwest Japan, the Caribbean basin, Southeastern United States, and Central and South America as well as in parts of Europe and the Middle East [2]. The majority of patients with ATL present with the acute form of the disease, although chronic, lymphoma, and smoldering forms have also been described [3]. Treatment of patients with aggressive forms of ATL has been difficult. The leukemic cells from patients with ATL are generally resistant to conventional chemotherapeutic agents possibly related to their over-expression of the multi-drug resistance (MDR) gene as well as mutations of the p53 gene [4]. Response rates to single agent chemotherapy such as the nucleoside analogs fludarabine, pentostatin and cladribine are low. Combination regimens achieve higher responses but response duration and overall survival remain short [5]. ∗
Corresponding author. Tel.: +713 745 0394; fax: +713 745 4612. E-mail address: [email protected] (F. Ravandi).
0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2005.05.008
Autologous and allogeneic transplant remain investigational and the few reported patients have not fared well. The combination of the antiretroviral drugs zidovudine (AZT) and interferon-␣ (IFN-␣) demonstrated activity in several studies [6]. New investigational approaches to the treatment of patients with ATL include the combination of arsenic trioxide and IFN-␣, the proteasome inhibitor bortezomib (Velcade), and the humanized anti-Tac antibody (daclizumab) [7,8].
2. Materials and methods We describe our experience in a patient with refractory ATL with the combination of alemtuzumab and pentostatin.
3. Case report The patient, a 55-year old woman from the Southeastern United States, with a known history of perineal herpes simplex virus (HSV) infection, initially presented to her local physician with an asymptomatic elevation of her white blood cell (WBC) count and adenopathy. The diagnosis of ATL was determined based on marrow examination and demonstration of HTLV-I infection by PCR. She was initiated on therapy with the combination of prednisone and chlorambu-
104
F. Ravandi, S. Faderl / Leukemia Research 30 (2006) 103–105
showed no morphological or immunophenotypic evidence of ATL. At this time, due to asymptomatic reactivation of cytomegalovirus (CMV) infection, the treatment was discontinued and therapy with intravenous gancyclovir was initiated with a good response. Due to her excellent clinical response and reactivation of a prior perineal HSV infection, it was decided not to reinitiate the combination therapy.
4. Discussion
Fig. 1. Peripheral blood smear demonstrating the polylobulated nucleus of the leukemic lymphocyte.
cil, which she received for approximately 6 months without any response. Her treatment was then changed to the combination of pentostatin and cyclophosphamide, which was administered for a total of four cycles. With disease progression, therapy with IFN-␣ and zidovudine was commenced. Three months later, she presented to our institution. On presentation she had evidence of extensive disease with palpable splenomegaly 3 cm below the left costal margin and 2 cm lymph nodes in the neck, axillary and inguinal areas. Laboratory studies revealed a WBC of 56.3 × 109 /L, hemoglobin of 8.7 g/dL, and platelet count of 123 × 109 /L. Differential count showed 97% lymphocytes with the typical “flower cell” morphology (Fig. 1). Bone marrow examination showed extensive involvement by leukemic cells, which were positive for CD2, CD3, CD5, CD25, CD45Ro, CD52 and CD8 (dim) and negative for CD4 and B-lymphoid markers. The majority of cells (99%) expressed T-cell receptor (TCR)␣ and molecular studies for the TCR gene rearrangements demonstrated the presence of a monoclonal population of T-cells. Infection with HTLV-I was confirmed by the presence of antibodies, a positive western blot for the viral protein, and a positive PCR for viral DNA. Imaging studies revealed extensive adenopathy in the mediastinal, hilar, abdominal, and pelvic areas as well as splenomegaly. After signing an informed consent form, the patient was initiated on therapy with alemtuzumab intravenously 30 mg three times a week and pentostatin 4 mg/m2 weekly for 4 weeks then every other week, on an ongoing clinical trial. The patient tolerated this regimen very well and after 2 months of therapy had complete resolution of her palpable disease, normalization of her blood counts with CT scans showing only persistent subcentimeter nodes in the abdomen and chest. Repeat bone marrow examination
The immunosuppressive effects of alemtuzumab are of concern when treating patients with HTLV-related diseases. We have previously reported administration of alemtuzumab to a patient with chronic lymphocytic leukemia (CLL) and known human immunodeficiency virus (HIV) infection [9]. We demonstrated a response in this patients which was associated with a significant decline in the HIV viral load [9]. More recently, Porcu et al. have described a case of ATL treated with alemtuzumab given as a single agent for 3 months, and reported a sustained response with a reduction in the HTLV-I viral load [10]. These reports suggest the significant activity of alemtuzumab in ATL, a disease prevalent worldwide where only limited therapeutic options are currently available. The decline in the viral load reported in the patient with concurrent CLL and HIV infection and in the patient reported by Porcu et al. is an interesting observation that may be related to the depletion of the available host cells for viral replication [9]. We did not quantitatively measure the HTLV-I viral load in this patient with ATL. Formal studies of alemtuzumab for treating patients with ATL should be considered in endemic areas.
Acknowledgements Authors disclosure: F. Ravandi reports: research grantBerlex, research grant-Supergen, research grant-Genzyme, research grant-BioCryst. S. Faderl reports: research grant and speakers bureauBerlex, research grant and speakers bureau-Genetech. Contributions. F. Ravandi—concept, writing, patient management, revisions, S. Faderl—critical review.
References [1] Uchiyama T. Human T cell leukemia virus type I (HTLV-I) and human diseases. Annu Rev Immunol 1997;15:15–37. [2] Bazarbachi A, Hermine O. Treatment of adult T-cell leukaemia/lymphoma: current strategy and future perspectives. Virus Res 2001;78:79–92. [3] Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group. Br J Haematol 1991;79:428–37. [4] Sakashita A, Hattori T, Miller CW, et al. Mutations of the p53 gene in adult T-cell leukemia. Blood 1992;79:477–80.
F. Ravandi, S. Faderl / Leukemia Research 30 (2006) 103–105 [5] Yamada Y, Tomonaga M, Fukuda H, et al. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemialymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol 2001;113:375–82. [6] Gill PS, Harrington Jr W, Kaplan MH, et al. Treatment of adult Tcell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 1995;332:1744–8. [7] Bazarbachi A, Ghez D, Lepelletier Y, et al. New therapeutic approaches for adult T-cell leukaemia. Lancet Oncol 2004;5:664–72. [8] Waldmann TA, White JD, Goldman CK, et al. The interleukin2 receptor: a target for monoclonal antibody treatment of human
105
T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood 1993;82:1701–2. [9] Ravandi F, Verma A, Ridgeway J, Pursell K. Chronic lymphocytic leukemia (B-CLL) occurring with human immunodeficiency virus (HIV) infection: implications. Leuk Res 2003;27: 853–7. [10] Porcu P, Mone A, Puhalla S, et al. Durable complete response (CR) and suppression of the human T-cell leukemia (HTLV-I) viral load with alemtuzumab in refractory adult T-cell leukemia (ATL). J Clin Oncol 2005;23:594s.
Case report
Complete response in a patient with adult T-cell leukemia (ATL) treated with combination of alemtuzumab and pentostatin Farhad Ravandi ∗ , Stefan Faderl Department of Leukemia, Box 428, University of Texas–M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA Received 6 May 2005; received in revised form 9 May 2005; accepted 15 May 2005 Available online 24 June 2005
Abstract Treatment of adult T-cell leukemia (ATL) remains difficult. Alemtuzumab with or without nucleoside analogs such as pentostatin may provide a role in this setting. However, the associated immunosuppression is a concern in patients with viral-mediated disease. © 2005 Elsevier Ltd. All rights reserved. Keywords: ATL; Alemtuzumab; Pentostatin; HTLV-I
1. Introduction The association of ATL with human T-cell leukemia virus type I (HTLV-I), the first oncogenic retrovirus discovered in man, is well described [1]. The virus is the pathogenic factor for ATL and a number of other disorders including tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM), and HTLV-I associated uveitis. HTLV-1 is endemic in southwest Japan, the Caribbean basin, Southeastern United States, and Central and South America as well as in parts of Europe and the Middle East [2]. The majority of patients with ATL present with the acute form of the disease, although chronic, lymphoma, and smoldering forms have also been described [3]. Treatment of patients with aggressive forms of ATL has been difficult. The leukemic cells from patients with ATL are generally resistant to conventional chemotherapeutic agents possibly related to their over-expression of the multi-drug resistance (MDR) gene as well as mutations of the p53 gene [4]. Response rates to single agent chemotherapy such as the nucleoside analogs fludarabine, pentostatin and cladribine are low. Combination regimens achieve higher responses but response duration and overall survival remain short [5]. ∗
Corresponding author. Tel.: +713 745 0394; fax: +713 745 4612. E-mail address: [email protected] (F. Ravandi).
0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2005.05.008
Autologous and allogeneic transplant remain investigational and the few reported patients have not fared well. The combination of the antiretroviral drugs zidovudine (AZT) and interferon-␣ (IFN-␣) demonstrated activity in several studies [6]. New investigational approaches to the treatment of patients with ATL include the combination of arsenic trioxide and IFN-␣, the proteasome inhibitor bortezomib (Velcade), and the humanized anti-Tac antibody (daclizumab) [7,8].
2. Materials and methods We describe our experience in a patient with refractory ATL with the combination of alemtuzumab and pentostatin.
3. Case report The patient, a 55-year old woman from the Southeastern United States, with a known history of perineal herpes simplex virus (HSV) infection, initially presented to her local physician with an asymptomatic elevation of her white blood cell (WBC) count and adenopathy. The diagnosis of ATL was determined based on marrow examination and demonstration of HTLV-I infection by PCR. She was initiated on therapy with the combination of prednisone and chlorambu-
104
F. Ravandi, S. Faderl / Leukemia Research 30 (2006) 103–105
showed no morphological or immunophenotypic evidence of ATL. At this time, due to asymptomatic reactivation of cytomegalovirus (CMV) infection, the treatment was discontinued and therapy with intravenous gancyclovir was initiated with a good response. Due to her excellent clinical response and reactivation of a prior perineal HSV infection, it was decided not to reinitiate the combination therapy.
4. Discussion
Fig. 1. Peripheral blood smear demonstrating the polylobulated nucleus of the leukemic lymphocyte.
cil, which she received for approximately 6 months without any response. Her treatment was then changed to the combination of pentostatin and cyclophosphamide, which was administered for a total of four cycles. With disease progression, therapy with IFN-␣ and zidovudine was commenced. Three months later, she presented to our institution. On presentation she had evidence of extensive disease with palpable splenomegaly 3 cm below the left costal margin and 2 cm lymph nodes in the neck, axillary and inguinal areas. Laboratory studies revealed a WBC of 56.3 × 109 /L, hemoglobin of 8.7 g/dL, and platelet count of 123 × 109 /L. Differential count showed 97% lymphocytes with the typical “flower cell” morphology (Fig. 1). Bone marrow examination showed extensive involvement by leukemic cells, which were positive for CD2, CD3, CD5, CD25, CD45Ro, CD52 and CD8 (dim) and negative for CD4 and B-lymphoid markers. The majority of cells (99%) expressed T-cell receptor (TCR)␣ and molecular studies for the TCR gene rearrangements demonstrated the presence of a monoclonal population of T-cells. Infection with HTLV-I was confirmed by the presence of antibodies, a positive western blot for the viral protein, and a positive PCR for viral DNA. Imaging studies revealed extensive adenopathy in the mediastinal, hilar, abdominal, and pelvic areas as well as splenomegaly. After signing an informed consent form, the patient was initiated on therapy with alemtuzumab intravenously 30 mg three times a week and pentostatin 4 mg/m2 weekly for 4 weeks then every other week, on an ongoing clinical trial. The patient tolerated this regimen very well and after 2 months of therapy had complete resolution of her palpable disease, normalization of her blood counts with CT scans showing only persistent subcentimeter nodes in the abdomen and chest. Repeat bone marrow examination
The immunosuppressive effects of alemtuzumab are of concern when treating patients with HTLV-related diseases. We have previously reported administration of alemtuzumab to a patient with chronic lymphocytic leukemia (CLL) and known human immunodeficiency virus (HIV) infection [9]. We demonstrated a response in this patients which was associated with a significant decline in the HIV viral load [9]. More recently, Porcu et al. have described a case of ATL treated with alemtuzumab given as a single agent for 3 months, and reported a sustained response with a reduction in the HTLV-I viral load [10]. These reports suggest the significant activity of alemtuzumab in ATL, a disease prevalent worldwide where only limited therapeutic options are currently available. The decline in the viral load reported in the patient with concurrent CLL and HIV infection and in the patient reported by Porcu et al. is an interesting observation that may be related to the depletion of the available host cells for viral replication [9]. We did not quantitatively measure the HTLV-I viral load in this patient with ATL. Formal studies of alemtuzumab for treating patients with ATL should be considered in endemic areas.
Acknowledgements Authors disclosure: F. Ravandi reports: research grantBerlex, research grant-Supergen, research grant-Genzyme, research grant-BioCryst. S. Faderl reports: research grant and speakers bureauBerlex, research grant and speakers bureau-Genetech. Contributions. F. Ravandi—concept, writing, patient management, revisions, S. Faderl—critical review.
References [1] Uchiyama T. Human T cell leukemia virus type I (HTLV-I) and human diseases. Annu Rev Immunol 1997;15:15–37. [2] Bazarbachi A, Hermine O. Treatment of adult T-cell leukaemia/lymphoma: current strategy and future perspectives. Virus Res 2001;78:79–92. [3] Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group. Br J Haematol 1991;79:428–37. [4] Sakashita A, Hattori T, Miller CW, et al. Mutations of the p53 gene in adult T-cell leukemia. Blood 1992;79:477–80.
F. Ravandi, S. Faderl / Leukemia Research 30 (2006) 103–105 [5] Yamada Y, Tomonaga M, Fukuda H, et al. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemialymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol 2001;113:375–82. [6] Gill PS, Harrington Jr W, Kaplan MH, et al. Treatment of adult Tcell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 1995;332:1744–8. [7] Bazarbachi A, Ghez D, Lepelletier Y, et al. New therapeutic approaches for adult T-cell leukaemia. Lancet Oncol 2004;5:664–72. [8] Waldmann TA, White JD, Goldman CK, et al. The interleukin2 receptor: a target for monoclonal antibody treatment of human
105
T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood 1993;82:1701–2. [9] Ravandi F, Verma A, Ridgeway J, Pursell K. Chronic lymphocytic leukemia (B-CLL) occurring with human immunodeficiency virus (HIV) infection: implications. Leuk Res 2003;27: 853–7. [10] Porcu P, Mone A, Puhalla S, et al. Durable complete response (CR) and suppression of the human T-cell leukemia (HTLV-I) viral load with alemtuzumab in refractory adult T-cell leukemia (ATL). J Clin Oncol 2005;23:594s.