Leukemia & Lymphoma, July 2014; 55(7): 1691–1693 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.853300
LETTER TO THE EDITOR
Lenalidomide-induced cytokine release syndrome in a patient with multiple myeloma Nobuhiko Nakamura, Nobuhiro Kanemura, Yuhei Shibata, Takuro Matsumoto, Ryoko Mabuchi, Hiroshi Nakamura, Junichi Kitagawa, Naoe Goto, Takeshi Hara, Hisashi Tsurumi & Hisataka Moriwaki First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow, and is associated with an increased level of monoclonal protein in the blood and/or urine [1]. Although the disease remains incurable, outcomes have improved substantially over recent years as a result of advances in therapy. During the last decade, thalidomide, the parent compound of a new class of anticancer drugs referred to as immunomodulating agents, has demonstrated impressive antitumor activity in diverse malignant disorders [2–4]. Lenalidomide was designed to enhance immunologic and anti-cancer properties while potentially decreasing neurotoxic adverse effects of the parent compound thalidomide. Currently, it is one of the most potent immunomodulatory drugs, and has shown an anti-tumor effect in patients with multiple myeloma [5–7]. Lenalidomide stimulates T and natural killer (NK) cells to produce T cell helper Th1-type cytokines such as interleukin (IL)-2 and interferon-γ (IFN-γ), whereas it inhibits the production of Th2-type cytokines and pro-inflammatory cytokines such as IL-4, IL-6 and tumor necrosis factor α (TNF-α) in vitro [8]. Here we describe the case of a patient with multiple myeloma who developed a high-grade fever with high plasma levels of IL-6 and TNF-α after the initiation of lenalidomide therapy. A 76-year-old man with multiple myeloma was admitted to our hospital. Four years prior to admission, he had been diagnosed with multiple myeloma at stage IIIA according to the Durie and Salmon staging system and at stage II according to the international staging system. His serum immunoglobulin G (IgG) level was 6468 mg/dL, and bone marrow aspiration revealed 56% plasma cells. He was treated with melphalan and prednisolone and subsequently obtained a partial response according to the International Myeloma Working Group (IMWG) criteria. Two years prior to admission, melphalan and prednisolone combination therapy was discontinued due to grade 2 thrombocytopenia. The patient then received bortezomib and dexamethasone; however, this therapy was discontinued after two cycles due to grade 3
peripheral neuropathy. Seven months before admission, the patient’s serum IgG level had gradually increased, and he had developed progressive disease. Hence, he was treated with vincristine, doxorubicin and dexamethasone. Although this therapy was effective, it was discontinued after two cycles due to severe pneumonia. Four months later, the patient’s serum IgG level was increased again, and he was admitted to our hospital. Table I summarizes the laboratory findings at admission. The serum M-spike was 5.4 g/dL. The serum free kappa chain level was 11 700 mg/L, and the serum free lambda chain level was less than 0.6 mg/L. Bone marrow aspiration revealed 21.3% of plasma cells. Salvage therapy consisting of lenalidomide (25 mg on days 1–21) with low-dose dexamethasone (20 mg once a week) was started. The dosage of dexamethasone was reduced due to the development of hyperglycemia. On day 4 of treatment, the patient developed a high-grade fever with elevation of the C-reactive protein (CRP) level. Two sets of blood cultures and a urine culture were negative. A chest and abdominal computed tomography (CT) scan was performed, but no abnormal findings suggesting the presence of infection were revealed. After lenalidomide was discontinued on day 6, the patient’s fever improved. Before the administration of lenalidomide, plasma IL-6 and TNF-α levels were 4.5 pg/mL and 1.2 pg/mL, respectively, and after the initiation of lenalidomide therapy, they increased to 105 pg/mL and 1.9 pg/mL, respectively. The serum M-spike decreased from 5.4 g/dL to 3.7 g/dL, and the serum free light chain ratio decreased from more than 19 500 to 9 500. The clinical course and change in plasma cytokine levels are shown in Figure 1. A treatment consisting of lenalidomide (20 mg on days 1–21, 28-day interval) and dexamethasone (4 mg on days 1–4, 8–11 and 15–18) was restarted 12 days after the first salvage therapy was discontinued. With this dosemodified treatment, the patient did not develop a fever. The patient was treated with four courses of lenalidomide– dexamethasone therapy and achieved a very good partial
Correspondence: Hisashi Tsurumi, MD, PhD, First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. Tel: ⫹ 81-58-230-6308. Fax: ⫹ 81-58-230-6310. E-mail: [email protected] Received 13 August 2013; revised 26 September 2013; accepted 3 October 2013
1691
1692 N. Nakamura et al. Table I. Laboratory data on admission. Biochemistry test
Complete blood count White blood cells Red blood cells Hemoglobin Hematocrit Platelets
5.73 ⫻ 109/L 3.24 ⫻ 1012/L 10.1 g/dL 30.4% 139 ⫻ 109/L
Hemogram Basophils Eosinophils Neutrophils Lymphocytes Monocytes
0.2% 1.2% 53.9% 37.5% 7.2%
TP M-spike Alb T-Bil AST ALT ALP γGTP LDH BUN Cre Ca P FBS CRP
10.3 g/dL 5.4 g/dL 2.8 g/dL 0.5 mg/dL 17 IU/L 10 IU/L 186 IU/L 22 IU/L 127 IU/L 14.8 mg/dL 0.72 mg/dL 8.3 mg/dL 3.7 mg/dL 143 mg/dL 0.7 mg/dL
Coagulation test PT APTT Fibrinogen AT-III FDP D-dimer
84% 38 s 261 mg/dL 83% 9.2 μg/mL 6.8 ng/mL
Immunological test IgG 5560 mg/dL IgA 5 mg/dL IgM 6 mg/dL 11 700 mg/L FLC κ FLC γ ⬍ 0.6 mg/L
TP, total protein; Alb, albumin; T-Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine transaminase; ALP, alkaline phosphatase; γGTP, γ-glutamyltranspeptidase; LDH, lactate dehydrogenase; BUN, blood urea nitrogen; Cre, creatinine; Ca, calcium; P, phosphate; FBS, fasting blood sugar; CRP, C-reactive protein; PT, prothrombin time; APTT, activated partial thromboplastin time; AT-III, antithrombin III; FDP, fibrin degradation products; IgG, immunoglobulin G; FLC, free light chain.
response according to IMWG criteria. Treatment was discontinued due to repeated infections, but the patient maintained the plateau phase for 8 months. An important pharmacological effect of lenalidomide is its ability to modulate the production of various cytokines in the tumor microenvironment. Lenalidomide down-regulates key pro-survival cytokines such as TNF-α, IL-6, IL-8 and vascular endothelial growth factor (VEGF) [9]. Lenalidomide may also affect other components of the tumor microenvironment such as the immune cellular compartment. Preclinical observations demonstrate its activation of immune effector cells (T and NK cells), which in turn stimulates T-cell proliferation and increased production of IL-2 and IFN-γ through T-cell receptor activation. Lenalidomide monotherapy has been reported to elevate serum CRP levels in patients with chronic lymphocytic
leukemia through the production of pro-inflammatory cytokines such as IL-6 and TNF-α [10,11]. The present case suggests that lenalidomide can induce different types of immune activation, including inflammatory reactions, in patients with multiple myeloma, especially when combined with reduced-dose dexamethasone. In such cases, lenalidomide therapy should be postponed until infectious complications are excluded and symptoms of cytokine release syndrome improve. Then, therapeutic cycles could be continued safely with an increased dose of dexamethasone. Inflammatory cytokines such as IL-6 are crucial growth factors for myeloma cells, and elevated CRP levels protect myeloma cells from apoptosis induced by chemotherapeutic drugs and stimulate myeloma cells to secrete more IL-6, which creates a positive feedback loop in multiple myeloma [12]. In the present case, lenalidomide induced a very good
Figure 1. Clinical course.
Letter to the Editor 1693 partial response; hence, cytokine release syndrome might predict a good clinical response as well as a tumor flare reaction. Further studies are needed to address the incidence of this inflammatory reaction and to clarify whether this phenomenon influences the clinical outcome in patients with multiple myeloma. 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] Palumbo A , Anderson K . Multiple myeloma. N Engl J Med 2011;364:1046–1060. [2] Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341: 1565–1571. [3] Weber D, Rankin K , Gavino M, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003;21:16–19. [4] Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial
coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431–436. [5] Dimopoulos M, Spencer A , Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132. [6] Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142. [7] Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29–37. [8] Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 2010;24:22–32. [9] Chanan-Khan AA , Cheson BD. Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol 2008;26:1544–1552. [10] Ferrajoli A , Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;111:5291–5297. [11] Aue G, Njuguna N, Tian X, et al. Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia. Haematologica 2009; 94:1266–1273. [12] Yang J, Wezeman M, Zhang X, et al. Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis. Cancer Cell 2007;12:252–265.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTER TO THE EDITOR
Lenalidomide-induced cytokine release syndrome in a patient with multiple myeloma Nobuhiko Nakamura, Nobuhiro Kanemura, Yuhei Shibata, Takuro Matsumoto, Ryoko Mabuchi, Hiroshi Nakamura, Junichi Kitagawa, Naoe Goto, Takeshi Hara, Hisashi Tsurumi & Hisataka Moriwaki First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow, and is associated with an increased level of monoclonal protein in the blood and/or urine [1]. Although the disease remains incurable, outcomes have improved substantially over recent years as a result of advances in therapy. During the last decade, thalidomide, the parent compound of a new class of anticancer drugs referred to as immunomodulating agents, has demonstrated impressive antitumor activity in diverse malignant disorders [2–4]. Lenalidomide was designed to enhance immunologic and anti-cancer properties while potentially decreasing neurotoxic adverse effects of the parent compound thalidomide. Currently, it is one of the most potent immunomodulatory drugs, and has shown an anti-tumor effect in patients with multiple myeloma [5–7]. Lenalidomide stimulates T and natural killer (NK) cells to produce T cell helper Th1-type cytokines such as interleukin (IL)-2 and interferon-γ (IFN-γ), whereas it inhibits the production of Th2-type cytokines and pro-inflammatory cytokines such as IL-4, IL-6 and tumor necrosis factor α (TNF-α) in vitro [8]. Here we describe the case of a patient with multiple myeloma who developed a high-grade fever with high plasma levels of IL-6 and TNF-α after the initiation of lenalidomide therapy. A 76-year-old man with multiple myeloma was admitted to our hospital. Four years prior to admission, he had been diagnosed with multiple myeloma at stage IIIA according to the Durie and Salmon staging system and at stage II according to the international staging system. His serum immunoglobulin G (IgG) level was 6468 mg/dL, and bone marrow aspiration revealed 56% plasma cells. He was treated with melphalan and prednisolone and subsequently obtained a partial response according to the International Myeloma Working Group (IMWG) criteria. Two years prior to admission, melphalan and prednisolone combination therapy was discontinued due to grade 2 thrombocytopenia. The patient then received bortezomib and dexamethasone; however, this therapy was discontinued after two cycles due to grade 3
peripheral neuropathy. Seven months before admission, the patient’s serum IgG level had gradually increased, and he had developed progressive disease. Hence, he was treated with vincristine, doxorubicin and dexamethasone. Although this therapy was effective, it was discontinued after two cycles due to severe pneumonia. Four months later, the patient’s serum IgG level was increased again, and he was admitted to our hospital. Table I summarizes the laboratory findings at admission. The serum M-spike was 5.4 g/dL. The serum free kappa chain level was 11 700 mg/L, and the serum free lambda chain level was less than 0.6 mg/L. Bone marrow aspiration revealed 21.3% of plasma cells. Salvage therapy consisting of lenalidomide (25 mg on days 1–21) with low-dose dexamethasone (20 mg once a week) was started. The dosage of dexamethasone was reduced due to the development of hyperglycemia. On day 4 of treatment, the patient developed a high-grade fever with elevation of the C-reactive protein (CRP) level. Two sets of blood cultures and a urine culture were negative. A chest and abdominal computed tomography (CT) scan was performed, but no abnormal findings suggesting the presence of infection were revealed. After lenalidomide was discontinued on day 6, the patient’s fever improved. Before the administration of lenalidomide, plasma IL-6 and TNF-α levels were 4.5 pg/mL and 1.2 pg/mL, respectively, and after the initiation of lenalidomide therapy, they increased to 105 pg/mL and 1.9 pg/mL, respectively. The serum M-spike decreased from 5.4 g/dL to 3.7 g/dL, and the serum free light chain ratio decreased from more than 19 500 to 9 500. The clinical course and change in plasma cytokine levels are shown in Figure 1. A treatment consisting of lenalidomide (20 mg on days 1–21, 28-day interval) and dexamethasone (4 mg on days 1–4, 8–11 and 15–18) was restarted 12 days after the first salvage therapy was discontinued. With this dosemodified treatment, the patient did not develop a fever. The patient was treated with four courses of lenalidomide– dexamethasone therapy and achieved a very good partial
Correspondence: Hisashi Tsurumi, MD, PhD, First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. Tel: ⫹ 81-58-230-6308. Fax: ⫹ 81-58-230-6310. E-mail: [email protected] Received 13 August 2013; revised 26 September 2013; accepted 3 October 2013
1691
1692 N. Nakamura et al. Table I. Laboratory data on admission. Biochemistry test
Complete blood count White blood cells Red blood cells Hemoglobin Hematocrit Platelets
5.73 ⫻ 109/L 3.24 ⫻ 1012/L 10.1 g/dL 30.4% 139 ⫻ 109/L
Hemogram Basophils Eosinophils Neutrophils Lymphocytes Monocytes
0.2% 1.2% 53.9% 37.5% 7.2%
TP M-spike Alb T-Bil AST ALT ALP γGTP LDH BUN Cre Ca P FBS CRP
10.3 g/dL 5.4 g/dL 2.8 g/dL 0.5 mg/dL 17 IU/L 10 IU/L 186 IU/L 22 IU/L 127 IU/L 14.8 mg/dL 0.72 mg/dL 8.3 mg/dL 3.7 mg/dL 143 mg/dL 0.7 mg/dL
Coagulation test PT APTT Fibrinogen AT-III FDP D-dimer
84% 38 s 261 mg/dL 83% 9.2 μg/mL 6.8 ng/mL
Immunological test IgG 5560 mg/dL IgA 5 mg/dL IgM 6 mg/dL 11 700 mg/L FLC κ FLC γ ⬍ 0.6 mg/L
TP, total protein; Alb, albumin; T-Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine transaminase; ALP, alkaline phosphatase; γGTP, γ-glutamyltranspeptidase; LDH, lactate dehydrogenase; BUN, blood urea nitrogen; Cre, creatinine; Ca, calcium; P, phosphate; FBS, fasting blood sugar; CRP, C-reactive protein; PT, prothrombin time; APTT, activated partial thromboplastin time; AT-III, antithrombin III; FDP, fibrin degradation products; IgG, immunoglobulin G; FLC, free light chain.
response according to IMWG criteria. Treatment was discontinued due to repeated infections, but the patient maintained the plateau phase for 8 months. An important pharmacological effect of lenalidomide is its ability to modulate the production of various cytokines in the tumor microenvironment. Lenalidomide down-regulates key pro-survival cytokines such as TNF-α, IL-6, IL-8 and vascular endothelial growth factor (VEGF) [9]. Lenalidomide may also affect other components of the tumor microenvironment such as the immune cellular compartment. Preclinical observations demonstrate its activation of immune effector cells (T and NK cells), which in turn stimulates T-cell proliferation and increased production of IL-2 and IFN-γ through T-cell receptor activation. Lenalidomide monotherapy has been reported to elevate serum CRP levels in patients with chronic lymphocytic
leukemia through the production of pro-inflammatory cytokines such as IL-6 and TNF-α [10,11]. The present case suggests that lenalidomide can induce different types of immune activation, including inflammatory reactions, in patients with multiple myeloma, especially when combined with reduced-dose dexamethasone. In such cases, lenalidomide therapy should be postponed until infectious complications are excluded and symptoms of cytokine release syndrome improve. Then, therapeutic cycles could be continued safely with an increased dose of dexamethasone. Inflammatory cytokines such as IL-6 are crucial growth factors for myeloma cells, and elevated CRP levels protect myeloma cells from apoptosis induced by chemotherapeutic drugs and stimulate myeloma cells to secrete more IL-6, which creates a positive feedback loop in multiple myeloma [12]. In the present case, lenalidomide induced a very good
Figure 1. Clinical course.
Letter to the Editor 1693 partial response; hence, cytokine release syndrome might predict a good clinical response as well as a tumor flare reaction. Further studies are needed to address the incidence of this inflammatory reaction and to clarify whether this phenomenon influences the clinical outcome in patients with multiple myeloma. 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] Palumbo A , Anderson K . Multiple myeloma. N Engl J Med 2011;364:1046–1060. [2] Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341: 1565–1571. [3] Weber D, Rankin K , Gavino M, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003;21:16–19. [4] Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial
coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431–436. [5] Dimopoulos M, Spencer A , Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132. [6] Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142. [7] Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29–37. [8] Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 2010;24:22–32. [9] Chanan-Khan AA , Cheson BD. Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol 2008;26:1544–1552. [10] Ferrajoli A , Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;111:5291–5297. [11] Aue G, Njuguna N, Tian X, et al. Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia. Haematologica 2009; 94:1266–1273. [12] Yang J, Wezeman M, Zhang X, et al. Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis. Cancer Cell 2007;12:252–265.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
