Mycophenolate Mofetil after Rituximab for Childhood-Onset... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome

Iijima, Kazumoto1,2; Sako, Mayumi3; Oba, Mari4; Tanaka, Seiji5; Hamada, Riku6; Sakai, Tomoyuki7; Ohwada, Yoko8; Ninchoji, Takeshi1; Yamamura, Tomohiko1; Machida, Hiroyuki9; Shima, Yuko10; Tanaka, Ryojiro11; Kaito, Hiroshi1,11; Araki, Yoshinori12; Morohashi, Tamaki13; Kumagai, Naonori14; Gotoh, Yoshimitsu15; Ikezumi, Yohei16; Kubota, Takuo17; Kamei, Koichi18; Fujita, Naoya19; Ohtsuka, Yasufumi20; Okamoto, Takayuki21; Yamada, Takeshi22; Tanaka, Eriko23; Shimizu, Masaki24; Horinochi, Tomoko1; Konishi, Akihide25; Omori, Takashi25; Nakanishi, Koichi26; Ishikura, Kenji27; Ito, Shuichi9; Nakamura, Hidefumi28; Nozu, Kandai1; on behalf of Japanese Study Group of Kidney Disease in Children

1Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan

2Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan

3Department of Clinical Research Promotion, National Center for Child Health and Development, Tokyo, Japan

4Department of Medical Statistics, Toho University, Tokyo, Japan

5Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan

6Department of Nephrology, Tokyo Metropolitan Children’s Medical Center, Fuchu, Japan

7Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan

8Department of Pediatrics, Dokkyo Medical University School of Medicine, Mibu, Japan

9Department of Pediatrics, Yokohama City University, Yokohama, Japan

10Department of Pediatrics, Wakayama Medical University, Wakayama City, Japan

11Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan

12Department of Pediatrics, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan

13Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan

14Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan

15Department of Pediatrics, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan

16Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan

17Department of Pediatrics, Osaka University, Suita, Japan

18Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan

19Department of Nephrology, Aichi Children's Health and Medical Center, Obu, Japan

20Department of Pediatrics, Saga University, Saga City, Japan

21Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan

22Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata City, Japan

23Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan

24Department of Pediatrics, Kanazawa University, Kanazawa, Japan

25Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan

26Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

27Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan

28Department of Research and Development Supervision, Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan

*The members of the Japanese Study Group of Kidney Disease in Children are Takayuki Okamoto, Yasuyuki Sato, Asako Hayashi, Toshiyuki Takahashi, Yoshinori Araki, Yoshinobu Nagaoka, Azusa Kawaguchi, Masayoshi Nagao, Naonori Kumagai, Noriko Sugawara, Takeshi Yamada, Yoko Ohwada, Shori Takahashi, Tamaki Morohashi, Hiroshi Saito, Koichi Kamei, Mayumi Sako, Hidefumi Nakamura, Riku Hamada, Hiroshi Hataya, Ryoko Harada, Naoaki Mikami, Tomohiro Inoguchi, Eriko Tanaka, Shuichi Ito, Hiroyuki Machida, Aya Inaba, Naoya Fujita, Satoshi Hibino, Kazuki Tanaka, Yoshimitsu Gotoh, Katsuaki Kasahara, Hisakazu Majima, Yohei Ikezumi, Masaki Shimizu, Tadafumi Yokoyama, Tomoyuki Sakai, Toshihiro Sawai, Yusuke Okuda, Toshiki Masuda, Takuo Kubota, Taichi Kitaoka, Hirofumi Nakayama, Rika Fujimaru, Katsusuke Yamamoto, Takahisa Kimata, Kazumoto Iijima, Kandai Nozu, Takeshi Ninchoji, Tomohiko Yamamura, Tomoko Horinochi, China Nagano, Nana Sakakibara, Ryojiro Tanaka, Hiroshi Kaito, Yosuke Inaguma, Yuko Shima, Kunihiko Aya, Toshiyuki Ohta, Yoshitsugu Kaku, Seiji Tanaka, Takuya Esaki, Satoko Kurata, Yasufumi Ohtsuka, Kenji Ishikura, and Koichi Nakanishi.

Present address: Naonori Kumagai, Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

Present address: Eriko Tanaka, Department of Pediatrics, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

Present address: Masaki Shimizu, Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

K.I., M.S., and K.N. contributed equally to this study.

Correspondence: Prof. Kazumoto Iijima, Hyogo Prefectural Kobe Children's Hospital, Minatojimaminami-machi 1-6-7, Chuo-ku, Kobe 650-0047, Japan. Email: [email protected], [email protected]

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Abstract

Significance Statement

Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. This multicenter, randomized, double-blind, placebo-controlled trial was conducted to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab) in these patients. MMF after rituximab decreased the risk of treatment failure during the MMF administration period by 80% and was well tolerated. However, after MMF discontinuation, the relapse-preventing effect disappeared, and most patients in the MMF group presented with treatment failure. In conclusion, MMF maintenance therapy after rituximab may be an option for sustaining remission in children with complicated FRNS/SDNS.

Background

Methods

We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient).

Results

TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: _P_=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups.

Conclusions

Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.

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Erratum

Kazumoto Iijima, Mayumi Sako, Mari Oba, Seiji Tanaka, Riku Hamada, Tomoyuki Sakai, Yoko Ohwada, Takeshi Ninchoji, Tomohiko Yamamura, Hiroyuki Machida, Yuko Shima, Ryojiro Tanaka, Hiroshi Kaito, Yoshinori Araki, Tamaki Morohashi, Naonori Kumagai, Yoshimitsu Gotoh, Yohei Ikezumi, Takuo Kubota, Koichi Kamei, Naoya Fujita, Yasufumi Ohtsuka, Takayuki Okamoto, Takeshi Yamada, Eriko Tanaka, Masaki Shimizu, Tomoko Horinouchi, Akihide Konishi, Takashi Omori, Koichi Nakanishi, Kenji Ishikura, Shuichi Ito, Hidefumi Nakamura, Kandai Nozu and on behalf of Japanese Study Group of Kidney Disease in Children: Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome. J Am Soc Nephrol 33: , 2022; DOI: https://doi.org/10.1681/ASN.2021050643.

Due to author error, in the Results section of this article, Table 4 did not provide information on the placebo group. The number of patients and Mean (SD) of the placebo group were 39 and 1.99 (2.73), respectively. The correct Table 4 is as follows:

We apologize for the errors and for any inconvenience this may have caused.

Journal of the American Society of Nephrology. 33(5):1050, May 2022.