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Abstract Background Although roxadustat has been reported to cause central hypothyroidism, the details of the mechanisms and clinical characteristics of patients who are prone to developing hypothyroidism with roxadustat are uncertain. Case presentation A 53-year-old man with a 3-year history of hemodialysis due to diabetic kidney disease who had been treated with roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, for 2 years was admitted to the hospital because of worsening gait disturbance and impaired consciousness. He had also acquired pure red cell aplasia associated with T-cell large granular lymphocytic leukemia and received multiple blood transfusions. Because his serum concentration of thyroid hormones was low, we diagnosed him with hypothyroidism, and his consciousness level recovered to normal with thyroid hormone replacement therapy. Computed tomography revealed a high-intensity atrophic thyroid gland, and magnetic resonance imaging showed diffusely reduced T2 and T1 signals of the pituitary anterior gland. These findings confirmed the accumulation of iron in the pituitary and thyroid glands. Combined pituitary stimulation tests with thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, and corticotropin-releasing hormone revealed that the patient had pan-hypopituitarism. After discontinuation of roxadustat, the patient was treated with another hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat. One month after switching medication, a stimulation test with thyrotropin-releasing hormone showed normal responses to thyroid-stimulating hormone. The patient was treated with levothyroxine 50 μg daily without any significant symptoms and is currently under follow-up observation as an outpatient. Conclusions We encountered a dialysis patient with roxadustat-induced hypothyroidism associated with transfusion iron overload. To our knowledge, this is the first case to clearly show that roxadustat can impair thyroid-stimulating hormone secretion in repeated thyrotropin-releasing hormone stimulation tests. Because the present patient had received roxadustat for more than 2 years before hypothyroidism became apparent, regular monitoring of the thyroid function may be needed in patients with renal anemia who have been treated with roxadustat, especially those at high risk of thyroid dysfunction.

Wild-type Wilms' tumor gene WT1 is expressed at a high level in hematopoietic malignancies including acute leukemia, chronic myelogenous leukemia, and myelodysplastic syndromes, as well as in various kinds of solid cancers. Human cytotoxic T lymphocytes (CTLs), which could specifically lyse WT1-expressing tumor cells with HLA class I restriction, were generated in vitro. It was also demonstrated that mice immunized with the WT1 peptide rejected challenges by WT1-expressing cancer cells and survived with no signs of autoaggression to normal organs that physiologically expressed WT1. Furthermore, we and others detected IgM and IgG WT1 antibodies in patients with hematopoietic malignancies, indicating that the WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing, WT1-specific, cellular immune responses were elicited in these patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of these findings, we performed a phase I clinical trial of a WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that the WT1 peptide cancer vaccine had efficacy in the clinical setting because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of a tumor-associated-antigen (TAA)-derived cancer vaccine may be enhanced in combination with stronger adjuvants, helper peptide, molecular-target-based drugs, or some chemotherapy drugs, such as gemcitabine, which has been revealed to suppress regulartory T-cell function. In contrast, reduction of WT1 peptide dose may be needed for the treatment of patients with hematological stem cell diseases, because rapid and strong destruction of malignant cell-sustained hematopoiesis before recovery of normal hematopoiesis may lead to pancytopenia in these patients.

Although tyrosine kinase inhibitors is effective for dramatically reducing CML cells, it might be difficult to eradicate completely the CML stem cells. We aimed to clarify the safety and effects of WT1 peptide vaccination in combination with imatinib therapy for a CML patient. A 51 year-old male with CML in CP, who showed a resistance against imatinib therapy for 2.5 years, began to be treated with 9mer modified-type WT1 peptides in combination with standard dose of imatinib. Although every 2-week-administration of WT1 peptides for 22 weeks did not show definite effects on the quantification of bcr-abl transcripts, by changing the administration from every 2 weeks to 4 weeks bcr-abl transcripts decreased remarkably. After 11 months of every 4-week-administration of the peptides and 12 months post cessation of the peptides bcr-abl transcripts achieved to the level below detection by RQ/RT-PCR (complete molecular response). WT1/MHC tetramer+CD8+ CTLs, which appeared after the second administration of WT1 peptides and remained more than 15 in number among 106 CD8+ T cells throughout the administration of WT1 peptides, are still present in the blood on 14th month post cessation of the peptides. An in vitro study as to the cytotoxicity of lymphocytes induced by mixed lymphocyte peptide culture demonstrated that cultured lymphocytes possessed cytotoxicity against WT1 expressing leukemia cells and the cytotoxicity was WT1-specific and MHC class I restricted. The present study showed that WT1 peptide vaccination in combination with TKI is feasible and effective in the therapy for imatinib-resistant CML.