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Intrathecal methotrexate prophylaxis and central nervous system relapse in diffuse large B-cell lymphoma patients following R-CHOP Naoto Tomita, Hirotaka Takasaki, Yasufumi Ishiyama, Kumiko Kishimoto, Daisuke Ishibashi, Satoshi Koyama, Yoshimi Ishii, Hiroyuki Takahashi, Ayumi Numata, Reina Watanabe, Takayoshi Tachibana, Rika Ohshima, Maki Hagihara, Chizuko Hashimoto, Sachiya Takemura, Jun Taguchi, Katsumichi Fujimaki, Rika Sakai, Shigeki Motomura, and Yoshiaki Ishigatsubo doi: 10.3109/10428194.2014.931953 Abstract This study evaluated the efficacy of central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX) in patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively studied 322 patients who achieved first complete remission (CR) after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The CNS prophylaxis consisted of 4 doses of IT-MTX (15 mg) with hydrocortisone (25 mg) administered after CR was achieved. Forty patients (12%) received CNS prophylaxis (group A) and 282 patients (88%) did not (group B). Three patients in group A (8%) and 8 in group B (3%) experienced isolated CNS relapse during the first CR, although this difference was not statistically significant (P = 0.14). Ten of 11 CNS relapses occurred in the brain parenchyma with (n = 3) or without (n = 7) leptomeningeal involvement, the remaining patient had exclusive leptomeningeal involvement. In DLBCL patients attaining CR after R-CHOP, IT-MTX administration was insufficient to prevent CNS relapse.
© 2014 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Original Article
D
Intrathecal methotrexate prophylaxis and central nervous system
PT E
R-CHOP
Naoto Tomita,1 Hirotaka Takasaki,2 Yasufumi Ishiyama,1 Kumiko Kishimoto,3
CE
Daisuke Ishibashi,4 Satoshi Koyama,5 Yoshimi Ishii,1 Hiroyuki Takahashi,2
Ayumi Numata,3 Reina Watanabe,2 Takayoshi Tachibana,3 Rika Ohshima,6
AC
Maki Hagihara,1 Chizuko Hashimoto,7 Sachiya Takemura,6 Jun Taguchi,5
Katsumichi Fujimaki,6 Rika Sakai,2 Shigeki Motomura,2 and Yoshiaki Ishigatsubo1
1
Department of Internal Medicine and Clinical Immunology, Yokohama City University
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
relapse in diffuse large B-cell lymphoma patients following
Graduate School of Medicine; 2Department of Medical Oncology, Kanagawa Cancer
Center; 3Department of Hematology, Yokohama City University Medical Center;
4
Department of Hematology, Yokosuka City Hospital; 5Department of Hematology,
Shizuoka Red Cross Hospital; 6Department of Hematology/Immunology, Fujisawa City
Hospital; 7Department of Hematology, Yamato City Hospital, Japan
Correspondence to: Naoto Tomita, Department of Internal Medicine and Clinical
D
Immunology, Yokohama City University Graduate School of Medicine, 3-9
PT E
Fax: 81-45-786-3444. E-mail: [email protected]
Short title: IT-MTX in DLBCL
CE
Abstract
This study evaluated the efficacy of central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX) in patients with diffuse large
first
AC
B-cell lymphoma (DLBCL). We retrospectively studied 322 patients who achieved complete
remission
(CR)
after
rituximab
plus cyclophosphamide,
doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The CNS prophylaxis consisted of 4 doses of IT-MTX (15 mg) with hydrocortisone (25 mg) administered after CR was achieved. Forty patients (12%) received CNS
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Phone: 81-45-787-2800,
prophylaxis (group A) and 282 patients (88%) did not (group B). Three patients in group A (8%) and 8 in group B (3%) experienced isolated CNS relapse during the first CR, although this difference was not statistically significant (P = 0.14). Ten of 11 CNS relapses occurred in the brain parenchyma with (n = 3) or without (n = 7) leptomeningeal involvement, the remaining patient had exclusive leptomeningeal
involvement. In DLBCL patients attaining CR after R-CHOP, IT-MTX administration was insufficient to prevent CNS relapse.
Key words: central nervous system, diffuse large B-cell lymphoma, intrathecal
D
methotrexate, R-CHOP
PT E
Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant
lymphoma, accounting for 30—40% of all non-Hodgkin lymphomas [1]. The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy provides long-term first remission in two-thirds of DLBCL patients [2]. The main cause of
CE
failure with the R-CHOP treatment is primary refractoriness and relapse after complete remission (CR) [3]. Even in such cases, salvage chemotherapy followed by autologous stem cell transplantation has been reported to produce prolonged event-free survival and improved
AC
overall survival (OS) in a clinical study setting [3]. However, patients with central nervous system (CNS) relapse sometimes might not be candidates for such treatments and are a frequently missed, poor prognosis subgroup. CNS relapse is an extremely severe complication for DLBCL patients, and in our experience, the 5-year OS rate after the relapse is approximately 20% [4]. The agents included in R-CHOP chemotherapy cannot adequately
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
Introduction
penetrate the CNS at standard doses, and a prophylactic strategy is needed for DLBCL patients at a high-risk for CNS relapse. In the pre-rituximab era, a high rate of CNS relapse was reported, despite intrathecal prophylactic therapy [5]. Whether the frequency of CNS relapses changed between the rituximab and pre-rituximab eras also remains controversial [6-10]. A recent meta-analysis indicates that rituximab treatment moderately reduces, but does not eliminate, the risk of CNS relapse in DLBCL patients [11].
Although various strategies have been used for CNS prophylaxis [12-15], the most popular is intrathecal administration of methotrexate (IT-MTX). In a cohort of elderly DLBCL patients, IT-MTX did not help prevent CNS relapse, with the possible exception of patients with testicular involvement [7 8]. Evaluating the efficacy of CNS prophylaxis is difficult because
D
the profiles of the patients receiving prophylaxis in different studies varies and the methods of
PT E
prophylaxis only in DLBCL patients achieving first CR after the initial R-CHOP chemotherapy. Patients and Methods Patient Selection
CE
Between 2003 and 2009, 362 patients with newly diagnosed DLBCL each received 6 cycles (maximum 8 cycles) of full-dose R-CHOP chemotherapy at 7 institutions associated with the Yokohama City University Hematology Group (YCUHG). Patients were identified from the
AC
YCUHG lymphoma database, which includes only the patients who received full-dose (>80%) R-CHOP treatment. Among those, the 322 patients who achieved the first CR were the subjects of this retrospective study. Patients who did not achieve a CR after R-CHOP did not receive IT-MTX, according to YCUHG guidelines. Patients with an HIV-positive status were not included in this study. Patients aged >70 years with an Eastern Cooperative
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
prophylaxis are mismatched, even within a single study. This study evaluated IT-MTX
Oncology Group performance status (PS) of >2 were excluded if they were treated with a reduced dose of R-CHOP chemotherapy, but were included if they received full-dose R-CHOP chemotherapy, at the discretion of the attending physician. A reduction of the initial therapy dose by >20% because of a major comorbidity was also an exclusion criterion. IT-MTX
CNS prophylaxis consisted of 4 doses of IT-MTX (15 mg) with hydrocortisone (25 mg) after CR was achieved; the administration interval of IT-MTX did not exceed twice per week. In
general, CNS prophylaxis was administered to patients with at least one of the following risk factors at the time of presentation: a lactate dehydrogenase (LDH) level more than or equal to twice the upper normal limit; the presence of a bulky mass of at least 10 cm in diameter; a PS of >2; or involvement of the bone marrow, skin, testis, nasal/paranasal tissue, bone, or
D
breasts. CNS prophylaxis was recommended for patients aged 70 years received prophylaxis at the discretion of their attending physician. A written
date of death or last contact, whichever occurred first. Statistical Analysis
Fisher’s exact test was used to determine statistically significant differences between the characteristics of the groups. CNS relapse rates were compared by the presence or absence of each risk factor using the log-rank test in time to CNS relapse analysis. A survival curve was constructed using the Kaplan-Meier method, and the groups were compared using the log-rank test. P-values
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
Intrathecal methotrexate prophylaxis and central nervous system relapse in diffuse large B-cell lymphoma patients following R-CHOP Naoto Tomita, Hirotaka Takasaki, Yasufumi Ishiyama, Kumiko Kishimoto, Daisuke Ishibashi, Satoshi Koyama, Yoshimi Ishii, Hiroyuki Takahashi, Ayumi Numata, Reina Watanabe, Takayoshi Tachibana, Rika Ohshima, Maki Hagihara, Chizuko Hashimoto, Sachiya Takemura, Jun Taguchi, Katsumichi Fujimaki, Rika Sakai, Shigeki Motomura, and Yoshiaki Ishigatsubo doi: 10.3109/10428194.2014.931953 Abstract This study evaluated the efficacy of central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX) in patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively studied 322 patients who achieved first complete remission (CR) after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The CNS prophylaxis consisted of 4 doses of IT-MTX (15 mg) with hydrocortisone (25 mg) administered after CR was achieved. Forty patients (12%) received CNS prophylaxis (group A) and 282 patients (88%) did not (group B). Three patients in group A (8%) and 8 in group B (3%) experienced isolated CNS relapse during the first CR, although this difference was not statistically significant (P = 0.14). Ten of 11 CNS relapses occurred in the brain parenchyma with (n = 3) or without (n = 7) leptomeningeal involvement, the remaining patient had exclusive leptomeningeal involvement. In DLBCL patients attaining CR after R-CHOP, IT-MTX administration was insufficient to prevent CNS relapse.
© 2014 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Original Article
D
Intrathecal methotrexate prophylaxis and central nervous system
PT E
R-CHOP
Naoto Tomita,1 Hirotaka Takasaki,2 Yasufumi Ishiyama,1 Kumiko Kishimoto,3
CE
Daisuke Ishibashi,4 Satoshi Koyama,5 Yoshimi Ishii,1 Hiroyuki Takahashi,2
Ayumi Numata,3 Reina Watanabe,2 Takayoshi Tachibana,3 Rika Ohshima,6
AC
Maki Hagihara,1 Chizuko Hashimoto,7 Sachiya Takemura,6 Jun Taguchi,5
Katsumichi Fujimaki,6 Rika Sakai,2 Shigeki Motomura,2 and Yoshiaki Ishigatsubo1
1
Department of Internal Medicine and Clinical Immunology, Yokohama City University
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
relapse in diffuse large B-cell lymphoma patients following
Graduate School of Medicine; 2Department of Medical Oncology, Kanagawa Cancer
Center; 3Department of Hematology, Yokohama City University Medical Center;
4
Department of Hematology, Yokosuka City Hospital; 5Department of Hematology,
Shizuoka Red Cross Hospital; 6Department of Hematology/Immunology, Fujisawa City
Hospital; 7Department of Hematology, Yamato City Hospital, Japan
Correspondence to: Naoto Tomita, Department of Internal Medicine and Clinical
D
Immunology, Yokohama City University Graduate School of Medicine, 3-9
PT E
Fax: 81-45-786-3444. E-mail: [email protected]
Short title: IT-MTX in DLBCL
CE
Abstract
This study evaluated the efficacy of central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX) in patients with diffuse large
first
AC
B-cell lymphoma (DLBCL). We retrospectively studied 322 patients who achieved complete
remission
(CR)
after
rituximab
plus cyclophosphamide,
doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The CNS prophylaxis consisted of 4 doses of IT-MTX (15 mg) with hydrocortisone (25 mg) administered after CR was achieved. Forty patients (12%) received CNS
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Phone: 81-45-787-2800,
prophylaxis (group A) and 282 patients (88%) did not (group B). Three patients in group A (8%) and 8 in group B (3%) experienced isolated CNS relapse during the first CR, although this difference was not statistically significant (P = 0.14). Ten of 11 CNS relapses occurred in the brain parenchyma with (n = 3) or without (n = 7) leptomeningeal involvement, the remaining patient had exclusive leptomeningeal
involvement. In DLBCL patients attaining CR after R-CHOP, IT-MTX administration was insufficient to prevent CNS relapse.
Key words: central nervous system, diffuse large B-cell lymphoma, intrathecal
D
methotrexate, R-CHOP
PT E
Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant
lymphoma, accounting for 30—40% of all non-Hodgkin lymphomas [1]. The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy provides long-term first remission in two-thirds of DLBCL patients [2]. The main cause of
CE
failure with the R-CHOP treatment is primary refractoriness and relapse after complete remission (CR) [3]. Even in such cases, salvage chemotherapy followed by autologous stem cell transplantation has been reported to produce prolonged event-free survival and improved
AC
overall survival (OS) in a clinical study setting [3]. However, patients with central nervous system (CNS) relapse sometimes might not be candidates for such treatments and are a frequently missed, poor prognosis subgroup. CNS relapse is an extremely severe complication for DLBCL patients, and in our experience, the 5-year OS rate after the relapse is approximately 20% [4]. The agents included in R-CHOP chemotherapy cannot adequately
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
Introduction
penetrate the CNS at standard doses, and a prophylactic strategy is needed for DLBCL patients at a high-risk for CNS relapse. In the pre-rituximab era, a high rate of CNS relapse was reported, despite intrathecal prophylactic therapy [5]. Whether the frequency of CNS relapses changed between the rituximab and pre-rituximab eras also remains controversial [6-10]. A recent meta-analysis indicates that rituximab treatment moderately reduces, but does not eliminate, the risk of CNS relapse in DLBCL patients [11].
Although various strategies have been used for CNS prophylaxis [12-15], the most popular is intrathecal administration of methotrexate (IT-MTX). In a cohort of elderly DLBCL patients, IT-MTX did not help prevent CNS relapse, with the possible exception of patients with testicular involvement [7 8]. Evaluating the efficacy of CNS prophylaxis is difficult because
D
the profiles of the patients receiving prophylaxis in different studies varies and the methods of
PT E
prophylaxis only in DLBCL patients achieving first CR after the initial R-CHOP chemotherapy. Patients and Methods Patient Selection
CE
Between 2003 and 2009, 362 patients with newly diagnosed DLBCL each received 6 cycles (maximum 8 cycles) of full-dose R-CHOP chemotherapy at 7 institutions associated with the Yokohama City University Hematology Group (YCUHG). Patients were identified from the
AC
YCUHG lymphoma database, which includes only the patients who received full-dose (>80%) R-CHOP treatment. Among those, the 322 patients who achieved the first CR were the subjects of this retrospective study. Patients who did not achieve a CR after R-CHOP did not receive IT-MTX, according to YCUHG guidelines. Patients with an HIV-positive status were not included in this study. Patients aged >70 years with an Eastern Cooperative
JU ST
Leuk Lymphoma Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/25/14 For personal use only.
prophylaxis are mismatched, even within a single study. This study evaluated IT-MTX
Oncology Group performance status (PS) of >2 were excluded if they were treated with a reduced dose of R-CHOP chemotherapy, but were included if they received full-dose R-CHOP chemotherapy, at the discretion of the attending physician. A reduction of the initial therapy dose by >20% because of a major comorbidity was also an exclusion criterion. IT-MTX
CNS prophylaxis consisted of 4 doses of IT-MTX (15 mg) with hydrocortisone (25 mg) after CR was achieved; the administration interval of IT-MTX did not exceed twice per week. In
general, CNS prophylaxis was administered to patients with at least one of the following risk factors at the time of presentation: a lactate dehydrogenase (LDH) level more than or equal to twice the upper normal limit; the presence of a bulky mass of at least 10 cm in diameter; a PS of >2; or involvement of the bone marrow, skin, testis, nasal/paranasal tissue, bone, or
D
breasts. CNS prophylaxis was recommended for patients aged 70 years received prophylaxis at the discretion of their attending physician. A written
date of death or last contact, whichever occurred first. Statistical Analysis
Fisher’s exact test was used to determine statistically significant differences between the characteristics of the groups. CNS relapse rates were compared by the presence or absence of each risk factor using the log-rank test in time to CNS relapse analysis. A survival curve was constructed using the Kaplan-Meier method, and the groups were compared using the log-rank test. P-values
