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Peripheral T cell lymphoma not otherwise specified induced by fingolimod treatment for multiple sclerosis
abstracts
Annals of Oncology
P1
088
Relative adrenal insufficiency post-discontinuation of topical steroids in a patient with acute lymphoblastic leukemia
Sakiko Uho1, Hideaki Goto2, Ako Higashime2, Koji Kawaguchi2, Yoko Ishikawa2, Taiji Koyama2, Keiji Kurata2, Yoshiharu Miyata2, Kimikazu Yakushijin2, Hiroshi Matsuoka2, Hironobu Minami2 1 Integrated Clinical Education Center Kobe University Hospital, 2Division of Medical Oncology/Hematology, Kobe University Hospital Accelerated cortisol production is observed in patients with severe infections, trauma, burns, illness, and surgery. The cortisol levels observed in relative adrenal insufficiency are insufficient for controlling the inflammatory response. Sudden discontinuation of glucocorticoid therapy is one of the causes of relative adrenal insufficiency. A 63-year-old-man who had undergone cord blood transplantation for T-cell acute lymphoblastic leukemia (T-ALL) and had shown complete remission for 2 years was admitted to our hospital because of high fever, general fatigue, lowering blood pressure, and tachycardia. Physical, laboratory, and imaging examinations revealed T-ALL relapse and pneumonia. Although administration of antibacterial drugs and vasopressors relieved his symptoms and temporarily resolved his fever, he showed prolonged fatigue and mild fever; thus, we could not stop administering vasopressors. He had been using the following three types of topical steroids for chronic eczema for several years: betamethasone butyrate propionate, prednisolone valerate acetate, and hydrocortisone acetate. Thereafter, he had himself discontinued topical steroids because of general fatigue. We suspected his symptoms were caused by relative adrenal insufficiency due to sudden discontinuation of topical steroids; thus, we administered 100 mg of hydrocortisone intravenously. His fever resolved remarkably, and he resumed application of topical steroids and started oral steroid supplementation. His temperature was maintained in the normal range. He successfully achieved complete remission with salvage chemotherapy followed by a second transplantation; with the use of low-dose oral steroids, he did not develop relative adrenal insufficiency. Adrenal insufficiency is known to be caused by sudden discontinuation of oral steroids. Furthermore, we should pay attention to sudden discontinuation of topical steroids, which could cause relative adrenal insufficiency.
P1
091
Clinical feature of very elderly malignant lymphoma patients unfit for chemotherapy
Takenori Takahata1, Kensuke Saito1, Yu Chen1, Kengo Hasui1, Emiko Abo2, Akemi Awatsu2, Atsushi Sato1 1 Department of Medical Oncology, Hirosaki University Graduate school of Medicine, 2 Nursing Department, Hirosaki University Hospital Introduction: Malignant lymphoma is a curable disease by chemotherapy, and therefore very elderly patients with good condition can undergo reduced-dose chemotherapy and achieve longer survival. But there are few studies about those who are frail and cannot undergo chemotherapy. We studied about the outcome of palliative treatment for such patients. Methods: From April 2011 to December 2018, 529 malignant lymphoma patients have visited our department. Eighty-five patients were aged more than 80. Among them, 61 patients underwent reduced standard chemotherapy, course observation was selected in 8 for indolent lymphoma, and palliative treatment in 9 and best supportive care (BSC) in 7 patients. In this study, we focused on 16 patients (9 palliative treatments and 7 BSCs). Results: Histological type contained 9 diffuse large B-cell lymphomas (DLBCLs), 2 Tcell lymphomas and 5 other types. Clinical stage was divided into 6 limited and 8 advanced stages and 2 no data. The reasons of unfitness for chemotherapy were 7 performance status>2, 5 dementia, 4 combinations with other malignancy and 3 latent tuberculosis infections. Treatments were performed as 2 radiotherapies (RT), 6 oral steroids (contained 2 rituximab) and 1 surgical resection. Mean survival time was 452 days, but the distribution was clearly divided into very short group (<120 days) and
Volume 30 | Supplement 6 | October 2019
very long (>1000 days). Causes of death were 10 lymphomas, 1 lung cancer 1 abdominal aneurysm rapture and 1 senility. Final treatment institutes were 2 university hospitals, 7 local hospitals, 5 clinics and 2 palliative care hospitals. A DLBCL case who achieved complete remission with RT and oral etoposide is presented. Conclusion: The most patients without standard chemotherapy lived only for 3 months but one quarter lived for 3 years. Palliative therapies as possible might have some advantages in malignant lymphoma patients unfit for chemotherapy.
P1
097
Peripheral T cell lymphoma not otherwise specified induced by fingolimod treatment for multiple sclerosis
Hidetsugu Kawai1, Hiromichi Matsushita2, Hibiki Akashi1, Shohei Kawakami1, Daisuke Furuya1, Rikio Suzuki1, Yoshiaki Ogawa1, Hiroshi Kawada1, Naoya Nakamura3, Kiyoshi Ando1 1 Department of Hematology / Oncology, Tokai University School of Medicine, 2Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 3Department of Pathology, Tokai University School of Medicine Introduction: Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator that prevents B and T lymphocyte egress from the lymph nodes, and reduces peripheral lymphocyte counts and entry of lymphocytes into the central nervous system. In 2010, the Food and Drug Administration (FDA) approved it for the treatment of relapsingremitting multiple sclerosis (MS). It has been reported that Fingolimod treatment causes cutaneous side-effects such as opportunistic skin infections and cutaneous malignancies. We herein report the first case of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) induced by Fingolimod. Case report: A 63-year-old man was diagnosed with MS at 33 years of age. Due to repeated MS relapses, the administration of Fingolimod was started at 61 years of age. After 2 years, skin rash appeared in the abdominal and right femoral regions. Computed tomography showed swelling of the left cervical, mesenteric and bilateral inguinal lymph nodes and cutaneous tumors in the abdominal and right femoral regions. He was diagnosed with PTCL-NOS based on biopsies of the skin in right femoral region and right inguinal lymph nodes. Immunohistochemistry was positive for CD3, CD4, CD5, CD7, and negative for CD8, CD25 and CD30. He was treated with methylprednisolone (500 mg/day) for 3 days followed by prednisolone. His skin tumors and lymph node swelling did not progress. Discussion: Among 10 reported cases of malignant lymphoma induced by fingolimod, 7 had a T-cell lineage and 8 cases occurred in the cutaneous region. Fingolimod should be stopped if lymphomatous lesions are found. However, the treatment of the MS patients with lymphoma is very troublesome. There are few alternatives to fingolimod for the treatment of relapsing MS. Additionally, the performance status of the patients with relapsing MS is not usually good enough to undergo standard therapies. Further analyses are required to reveal the lymphomagenesis in patients undergoing fingolimod treatment.
P1
100
Impact of Charlson comorbidity index on survival in patients with diffuse large B-cell lymphoma who received R-CHOP
Atsushi Inagaki1, Shigeru Kusumoto2, Ayako Masaki3, Yoshiaki Marumo1, Takaki Kikuchi1,2, Shiori Kinoshita2, Fumiko Mori1, Hirokazu Komatsu2, Hiroshi Inagaki3, Shinsuke Iida2 1 Department of Hematology and Oncology, Nagoya City West Medical Center, 2 Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, 3Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences Introduction: There is limited evidence regarding the impact of updated Charlson comorbidity index (CCI) on survival in patients with newly diagnosed diffuse large Bcell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. Methods: We retrospectively reviewed 125 patients with newly diagnosed DLBCL receiving R-CHOP as a first-line immunochemotherapy who were admitted to Nagoya City West Medical Center between May 2011 and December 2018. We evaluated the association between their survival and the 5 following baseline indexes: CCI, ageadjusted CCI, updated CCI, Barthel index and mini-nutritional assessment (MNA-SF). Result: Baseline characteristics of the 125 patients with newly diagnosed DLBCL were as follows: median age was 75 years; 84% was >60 years; 70% had high LDH (> upper limit of normal); 33% had ECOG-PS 2; Ann Arbor stage of I, II, III, IV was 14%, 21%, 18% and 48%, respectively; 39% had extranodal site 2; 11% had high BNP levels (BNP100 pg/mL). None of CCI, age-adjusted CCI and updated CCI was associated with the survival, although both a lower Barthel index and malnutrition were significantly associated with shorter overall survival. The patients with high BNP levels had worse prognosis compared to those with low levels. Multivariate analysis revealed that age >60 years, extranodal site 2 and malnutrition (MNA-SF 7) were independent risk factors for survival (adjusted hazard ratios, 2.9, 2.2 and 2.0, respectively; p < 0.05). Conclusion: In our cohort, none of CCI, age-adjusted CCI and updated CCI had impact on survival in patient with DLBCL receiving R-CHOP treatment, whereas malnutrition (MNA-SF 7) had negative impact on survival in those patients. Well-
doi:10.1093/annonc/mdz343 | vi121
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz343.016/5583011 by La Trobe University user on 16 November 2019
assay. Protein expression was detected by Western blot and apoptosis antibody array chip. Immunofluorescence staining detected necroptosis effect. Results: Ardisianone inhibited cell viability in HL-60, a promyelocytic leukemia cell line, with IC50 value of 1.87 m M in a 24h exposure. Further detection showed that ardisianone induced time- and concentration-dependent apoptosis. JC-1 staining demonstrated that ardisianone caused a profound loss of mitochondrial membrane potential. Western blot also confirmed the decrease of pro-survival Bcl-2 family protein and the downregulation of necroptosis relatives (e.g., RIPK1 and RIPK3). The caspase cascade was profoundly activated by ardisianone. Notably, the specific pan-caspase inhibitor Q-VD-OPh significantly blunted ardisianone induced loss of membrane potential and apoptosis, suggesting that caspase cascade activation may further amplify mitochondrial damage and apoptotic signaling cascade. The expression of RIPK1/RIPK3/MIKL as significantly reduced by pre-treatment of necroptosis inhibitor (Necrostatin-1, Nec1), suggesting that Nec-1 attenuates ardisianone-induced necroptosis. Conclusion: The data suggest that ardisianone induces mitochondrial dysfunction and apoptosis in leukemia cells through modification of Bcl-2 family members and causes necrotic cell death.
Annals of Oncology
P1
088
Relative adrenal insufficiency post-discontinuation of topical steroids in a patient with acute lymphoblastic leukemia
Sakiko Uho1, Hideaki Goto2, Ako Higashime2, Koji Kawaguchi2, Yoko Ishikawa2, Taiji Koyama2, Keiji Kurata2, Yoshiharu Miyata2, Kimikazu Yakushijin2, Hiroshi Matsuoka2, Hironobu Minami2 1 Integrated Clinical Education Center Kobe University Hospital, 2Division of Medical Oncology/Hematology, Kobe University Hospital Accelerated cortisol production is observed in patients with severe infections, trauma, burns, illness, and surgery. The cortisol levels observed in relative adrenal insufficiency are insufficient for controlling the inflammatory response. Sudden discontinuation of glucocorticoid therapy is one of the causes of relative adrenal insufficiency. A 63-year-old-man who had undergone cord blood transplantation for T-cell acute lymphoblastic leukemia (T-ALL) and had shown complete remission for 2 years was admitted to our hospital because of high fever, general fatigue, lowering blood pressure, and tachycardia. Physical, laboratory, and imaging examinations revealed T-ALL relapse and pneumonia. Although administration of antibacterial drugs and vasopressors relieved his symptoms and temporarily resolved his fever, he showed prolonged fatigue and mild fever; thus, we could not stop administering vasopressors. He had been using the following three types of topical steroids for chronic eczema for several years: betamethasone butyrate propionate, prednisolone valerate acetate, and hydrocortisone acetate. Thereafter, he had himself discontinued topical steroids because of general fatigue. We suspected his symptoms were caused by relative adrenal insufficiency due to sudden discontinuation of topical steroids; thus, we administered 100 mg of hydrocortisone intravenously. His fever resolved remarkably, and he resumed application of topical steroids and started oral steroid supplementation. His temperature was maintained in the normal range. He successfully achieved complete remission with salvage chemotherapy followed by a second transplantation; with the use of low-dose oral steroids, he did not develop relative adrenal insufficiency. Adrenal insufficiency is known to be caused by sudden discontinuation of oral steroids. Furthermore, we should pay attention to sudden discontinuation of topical steroids, which could cause relative adrenal insufficiency.
P1
091
Clinical feature of very elderly malignant lymphoma patients unfit for chemotherapy
Takenori Takahata1, Kensuke Saito1, Yu Chen1, Kengo Hasui1, Emiko Abo2, Akemi Awatsu2, Atsushi Sato1 1 Department of Medical Oncology, Hirosaki University Graduate school of Medicine, 2 Nursing Department, Hirosaki University Hospital Introduction: Malignant lymphoma is a curable disease by chemotherapy, and therefore very elderly patients with good condition can undergo reduced-dose chemotherapy and achieve longer survival. But there are few studies about those who are frail and cannot undergo chemotherapy. We studied about the outcome of palliative treatment for such patients. Methods: From April 2011 to December 2018, 529 malignant lymphoma patients have visited our department. Eighty-five patients were aged more than 80. Among them, 61 patients underwent reduced standard chemotherapy, course observation was selected in 8 for indolent lymphoma, and palliative treatment in 9 and best supportive care (BSC) in 7 patients. In this study, we focused on 16 patients (9 palliative treatments and 7 BSCs). Results: Histological type contained 9 diffuse large B-cell lymphomas (DLBCLs), 2 Tcell lymphomas and 5 other types. Clinical stage was divided into 6 limited and 8 advanced stages and 2 no data. The reasons of unfitness for chemotherapy were 7 performance status>2, 5 dementia, 4 combinations with other malignancy and 3 latent tuberculosis infections. Treatments were performed as 2 radiotherapies (RT), 6 oral steroids (contained 2 rituximab) and 1 surgical resection. Mean survival time was 452 days, but the distribution was clearly divided into very short group (<120 days) and
Volume 30 | Supplement 6 | October 2019
very long (>1000 days). Causes of death were 10 lymphomas, 1 lung cancer 1 abdominal aneurysm rapture and 1 senility. Final treatment institutes were 2 university hospitals, 7 local hospitals, 5 clinics and 2 palliative care hospitals. A DLBCL case who achieved complete remission with RT and oral etoposide is presented. Conclusion: The most patients without standard chemotherapy lived only for 3 months but one quarter lived for 3 years. Palliative therapies as possible might have some advantages in malignant lymphoma patients unfit for chemotherapy.
P1
097
Peripheral T cell lymphoma not otherwise specified induced by fingolimod treatment for multiple sclerosis
Hidetsugu Kawai1, Hiromichi Matsushita2, Hibiki Akashi1, Shohei Kawakami1, Daisuke Furuya1, Rikio Suzuki1, Yoshiaki Ogawa1, Hiroshi Kawada1, Naoya Nakamura3, Kiyoshi Ando1 1 Department of Hematology / Oncology, Tokai University School of Medicine, 2Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 3Department of Pathology, Tokai University School of Medicine Introduction: Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator that prevents B and T lymphocyte egress from the lymph nodes, and reduces peripheral lymphocyte counts and entry of lymphocytes into the central nervous system. In 2010, the Food and Drug Administration (FDA) approved it for the treatment of relapsingremitting multiple sclerosis (MS). It has been reported that Fingolimod treatment causes cutaneous side-effects such as opportunistic skin infections and cutaneous malignancies. We herein report the first case of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) induced by Fingolimod. Case report: A 63-year-old man was diagnosed with MS at 33 years of age. Due to repeated MS relapses, the administration of Fingolimod was started at 61 years of age. After 2 years, skin rash appeared in the abdominal and right femoral regions. Computed tomography showed swelling of the left cervical, mesenteric and bilateral inguinal lymph nodes and cutaneous tumors in the abdominal and right femoral regions. He was diagnosed with PTCL-NOS based on biopsies of the skin in right femoral region and right inguinal lymph nodes. Immunohistochemistry was positive for CD3, CD4, CD5, CD7, and negative for CD8, CD25 and CD30. He was treated with methylprednisolone (500 mg/day) for 3 days followed by prednisolone. His skin tumors and lymph node swelling did not progress. Discussion: Among 10 reported cases of malignant lymphoma induced by fingolimod, 7 had a T-cell lineage and 8 cases occurred in the cutaneous region. Fingolimod should be stopped if lymphomatous lesions are found. However, the treatment of the MS patients with lymphoma is very troublesome. There are few alternatives to fingolimod for the treatment of relapsing MS. Additionally, the performance status of the patients with relapsing MS is not usually good enough to undergo standard therapies. Further analyses are required to reveal the lymphomagenesis in patients undergoing fingolimod treatment.
P1
100
Impact of Charlson comorbidity index on survival in patients with diffuse large B-cell lymphoma who received R-CHOP
Atsushi Inagaki1, Shigeru Kusumoto2, Ayako Masaki3, Yoshiaki Marumo1, Takaki Kikuchi1,2, Shiori Kinoshita2, Fumiko Mori1, Hirokazu Komatsu2, Hiroshi Inagaki3, Shinsuke Iida2 1 Department of Hematology and Oncology, Nagoya City West Medical Center, 2 Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, 3Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences Introduction: There is limited evidence regarding the impact of updated Charlson comorbidity index (CCI) on survival in patients with newly diagnosed diffuse large Bcell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. Methods: We retrospectively reviewed 125 patients with newly diagnosed DLBCL receiving R-CHOP as a first-line immunochemotherapy who were admitted to Nagoya City West Medical Center between May 2011 and December 2018. We evaluated the association between their survival and the 5 following baseline indexes: CCI, ageadjusted CCI, updated CCI, Barthel index and mini-nutritional assessment (MNA-SF). Result: Baseline characteristics of the 125 patients with newly diagnosed DLBCL were as follows: median age was 75 years; 84% was >60 years; 70% had high LDH (> upper limit of normal); 33% had ECOG-PS 2; Ann Arbor stage of I, II, III, IV was 14%, 21%, 18% and 48%, respectively; 39% had extranodal site 2; 11% had high BNP levels (BNP100 pg/mL). None of CCI, age-adjusted CCI and updated CCI was associated with the survival, although both a lower Barthel index and malnutrition were significantly associated with shorter overall survival. The patients with high BNP levels had worse prognosis compared to those with low levels. Multivariate analysis revealed that age >60 years, extranodal site 2 and malnutrition (MNA-SF 7) were independent risk factors for survival (adjusted hazard ratios, 2.9, 2.2 and 2.0, respectively; p < 0.05). Conclusion: In our cohort, none of CCI, age-adjusted CCI and updated CCI had impact on survival in patient with DLBCL receiving R-CHOP treatment, whereas malnutrition (MNA-SF 7) had negative impact on survival in those patients. Well-
doi:10.1093/annonc/mdz343 | vi121
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz343.016/5583011 by La Trobe University user on 16 November 2019
assay. Protein expression was detected by Western blot and apoptosis antibody array chip. Immunofluorescence staining detected necroptosis effect. Results: Ardisianone inhibited cell viability in HL-60, a promyelocytic leukemia cell line, with IC50 value of 1.87 m M in a 24h exposure. Further detection showed that ardisianone induced time- and concentration-dependent apoptosis. JC-1 staining demonstrated that ardisianone caused a profound loss of mitochondrial membrane potential. Western blot also confirmed the decrease of pro-survival Bcl-2 family protein and the downregulation of necroptosis relatives (e.g., RIPK1 and RIPK3). The caspase cascade was profoundly activated by ardisianone. Notably, the specific pan-caspase inhibitor Q-VD-OPh significantly blunted ardisianone induced loss of membrane potential and apoptosis, suggesting that caspase cascade activation may further amplify mitochondrial damage and apoptotic signaling cascade. The expression of RIPK1/RIPK3/MIKL as significantly reduced by pre-treatment of necroptosis inhibitor (Necrostatin-1, Nec1), suggesting that Nec-1 attenuates ardisianone-induced necroptosis. Conclusion: The data suggest that ardisianone induces mitochondrial dysfunction and apoptosis in leukemia cells through modification of Bcl-2 family members and causes necrotic cell death.