Thalidomide-Induced Leukopenia in Japanese Patients with Refractory Multiple Myeloma.
Authors: Murakami Hirokazu , Handa Hiroshi , Abe Masahiro , Iida Shinsuke , Ishii Akihiro , Ishikawa Takayuki , Ishida Tadao , Oota Masatsugu , Ozaki Shuji , Kosaka Masaaki , Sakai Akira , Sawamura Morio , Shimizu Kazuaki , Takagi Toshiyuki , Hata Hiroyuki , Fukuhara Takashi , Fujii Hiroshi , Miyata Akira , Wakayama Toshio , Takatsuki Kiyoshi 
Published: April 2020

Background: Thalidomide is effective for treating refractory multiple myeloma; however, it induces many adverse events, including peripheral neuropathy, deep vein thrombosis, constipation, and neuropsychological symptoms. Hematological adverse events have rarely been reported in the United States and Europe. Some Japanese cases have been reported to reveal leucopenia during thalidomide therapy. We report here severe leucopenia, which has been observed in the JMSG phase II study “Low-dose thalidomide plus low-dose dexamethasone therapy for refractory myeloma”, and analyze the factors related to leucopenia.

Patients and Methods: Patients with refractory myeloma were eligible. Thalidomide at 100 mg/day was administered on Days 1–7 and increased to 200 mg/day without severe adverse events, and continued until disease progression. Dexamethasone at 4 mg/day was administered on Days 1–28, decreased to 1 mg/day, and maintained at 1 mg/day. The response was assessed by the finding of a decline in paraprotein in serum or urine on two occasions at least 4 weeks apart.

Results: Sixty-six patients (male/female ratio: 0.7; median age, 64.5 years; range, 40–74 years) were enrolled in the study. The myeloma subtypes were 48 IgG, 6 IgA, 1 IgD, and 11 light chain only. Forty-nine patients were refractory for conventional chemotherapy and 17 patients had relapsed disease after autologous stem cell transplantation. Responses were observed in 30 patients (4 near complete response, 9 partial response, and 17 minimal response) (45.5%). Median progression-free and overall survivals were 6.2 months and 23.3 months. The incidence rates of grade 2 or higher events were: peripheral neuropathy, 7.5%; hyperglycemia, 1.5%; skin rash, 4.5%; constipation, 4.5%; and deep vein thrombosis, 4.8%. Grade 1–2 incidence of leukopenia was 41% and of thrombocytopenia was 27%; Grade 3 or higher leucopenia was observed in 12%. One patient died from sepsis caused by severe leucopenia. Thalidomide-induced leucopenia was closely related to pre-treatment white blood cell count (p&lt;0.02) and platelet count (p&lt;0.001). Thrombocytopenia was related to pre-treatment platelet count (p&lt;0.01). In addition, the incidence of leucopenia was significantly higher in patients with a pretreatment platelet count &lt;100×109/L (p&lt;0.001). There was no relationship between hematological adverse events and disease period.

Conclusion: Low-dose thalidomide plus low-dose dexamethasone therapy was as effective as low-dose thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. The incidence of adverse events including deep vein thrombosis and hyperglycemia was lower than the data reported in the United States and Europe. However, leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with low pretreatment white blood cell and platelet counts.