Severe and/or Prolonged COVID-19 in Hematologic Diseases: Clinical Implications Before and During the Omicron Era

Akinao Okamoto^1*Masahiro Yoshida²Senji Kasahara³Takahide Ara⁴Kazutaka Ozeki⁵Takanobu Morishita^1,6Daisuke Ikeda⁷Minoru Kanaya⁸Tomohiro Kajiguchi⁹Yasuhiro Suzuki¹⁰Shingo Kurahashi¹¹Tomohiro Horio¹²Yoshiaki Marumo¹³Tatsuo Oyake¹⁴Shigeki Saito⁶Hitomi Sawa¹⁵Shun-ichi Kimura¹⁶Takahiro Nishiyama¹⁷Eisei Kondo¹⁸Junji Hiraga¹⁹Hiroki Hosoi²⁰Yasufumi Masaki²¹Yoshiko Atsuta²²Hideyuki Yamamoto¹Takahiko Miyama¹Naoe Goto¹Chisako Iriyama¹Keichiro Mihara¹Yoshihiro Inamoto¹Akihiro Tomita^1,23

• ¹Fujita Health University Hospital, Toyoake, Japan
• ²Osaka City General Hospital, Osaka, Japan
• ³Gifu Municipal Hospital, Gidu, Japan
• ⁴Hokkaido Daigaku, Sapporo, Japan
• ⁵Aichi Konan Kosei Hospital, Konan, Japan
• ⁶Nihon Sekijujisha Aichi Iryo Center Nagoya Daiichi Byoin Ketsueki Naika, Nagoya, Japan
• ⁷Kameda Medical Center, Kamogawa, Japan
• ⁸Aiiku Byoin, Sapporo, Japan
• ⁹Koritsu Tosei Byoin, Seto, Japan
• ¹⁰Nagoya Medical Center, Nagoya, Japan
• ¹¹Toyohashi Shimin Byoin, Toyohashi, Japan
• ¹²Aichi Ika Daigaku Daigakuin Igaku Kenkyuka Igakubu, Nagakute, Japan
• ¹³Nagoya Shiritsu Daigaku, Nagoya, Japan
• ¹⁴Iwate Ika Daigaku Igakubu Daigakuin Igaku Kenkyuka, Shiwa District, Japan
• ¹⁵Anjo Kosei Byoin, Anjo, Japan
• ¹⁶Jichi Ika Daigaku Fuzoku Saitama Iryo Center Ketsuekika, Saitama, Japan
• ¹⁷Ichinomiya Shiritsu Shimin Byoin, Ichinomiya, Japan
• ¹⁸Kawasaki Ika Daigaku, Kurashiki, Japan
• ¹⁹Toyota Kosei Byoin, Toyota, Japan
• ²⁰Wakayama Kenritsu Ika Daigaku, Wakayama, Japan
• ²¹Kanazawa Ika Daigaku, Kahoku District, Japan
• ²²Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
• ²³Fujita Ika Daigaku, Toyoake, Japan

Background: Although the Omicron variant has been reported to reduce COVID-19 severity in the general population, its impact on patients with hematologic malignancies remains uncertain, and epidemiological investigation is warranted. Methods: We conducted a multicenter retrospective cohort study of 1,023 patients with hematologic diseases diagnosed with COVID-19 at 22 centers in Japan between January 2020 and January 2023. Outcomes within 60 days after diagnosis including severe and/or prolonged disease, COVID-19–related mortality, and overall survival (OS) were compared between the pre-Omicron and Omicron periods. Multivariable analysis was performed to identify independent adverse prognostic factors. Results: Severe and/or prolonged disease occurred in 27.5% of patients, COVID-19–related mortality was 6.3%, and OS was 91.4%. Compared with the pre-Omicron period, the Omicron period was associated with significantly lower rates of severe/prolonged disease (26.0% vs. 48.0%, P < 0.01) and COVID-19–related mortality (5.0% vs. 15.0%, P < 0.01), but no significant difference in OS (92.0% vs. 84.0%, P = 0.62). Age ≥60 years was the strongest predictor of severe/prolonged disease (sHR 3.08, P < 0.01) and mortality (HR 8.94, P < 0.01). Male sex (sHR 1.38; HR 1.82, both P < 0.01) and prior bendamustine exposure (sHR 1.83; HR 1.87, both P < 0.01) were also associated with both outcomes, whereas anti-CD38 antibody therapy was linked only to mortality (HR 3.65, P < 0.01). Conclusion: In patients with hematologic diseases, the Omicron period was associated with reduced severity and COVID-19–related mortality but no improvement in OS. Older age and prior bendamustine exposure were strongly associated with adverse outcomes, highlighting the need for strict infection prevention and prompt, aggressive COVID-19 management in these high-risk populations.