Vincristine (VCR) is an important drug used in the treatment of acute lymphoblastic leukemia (ALL). VCR-induced neurotoxicity can manifest as peripheral neuropathy, constipation, or paralytic ileus. While there are some case reports describing VCR-induced paralytic ileus (VIPI) in pediatric ALL, there are fewer publication on adult ALL patients. Therefore, we retrospectively investigated VIPI during induction therapy of treatment protocols for ALL in 19 adult patients. The incidence of VIPI was 32%. VIPI was significantly increased in patients receiving concomitant itraconazole (ITCZ) (p = 0.04). We recommend avoidance of the combination of VCR and ITCZ.
Despite the emergence of monoclonal antibodies, the prognosis of patients with multiple myeloma (MM) with extramedullary disease remains poor. The present report describes a rare case of daratumumab‑refractory MM that was successfully treated with elotuzumab, pomalidomide and dexamethasone. A 66‑year‑old male patient diagnosed with MM was treated with bortezomib, lenalidomide and dexamethasone, followed by high‑dose chemotherapy and autologous stem cell transplantation. Thereafter, the patient was treated with lenalidomide and dexamethasone as maintenance therapy. This was changed to daratumumab, bortezomib and dexamethasone when new paraskeletal lesions were identified, resulting in marked tumor shrinkage. After 15 months, an increase in serum monoclonal protein levels, development of a skeletal lesion in the right second rib and extramedullary disease of the right thoracic mediastinal lymph nodes were noted. Treatment with elotuzumab, pomalidomide and dexamethasone (EPd) resulted in expeditious symptomatic improvement and regression of the lesions. Notably, during daratumumab, bortezomib and dexamethasone treatment, lymphocyte counts gradually increased to a level at which elotuzumab was sufficiently effective. EPd might be a promising strategy for the treatment of patients with relapsed extramedullary MM while on daratumumab treatment.
Four semi-synthetic and fourteen quassinoids were tested for their antifeedant and insecticidal activity against 3rd instar larvae of the diamondback moth (Plutella xylostella). In this quassinoid series, isobrucein-B was the most potent compound in both assays. Chemical conversion of the methoxy and/or methylenedioxy groups in the A and C rings to hydroxy groups among these quassinoids resulted in decreased activity.
Adult T-cell leukaemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm caused by human T-cell leukaemia virus type I infection. Most cases of aggressive ATL (acute, lymphoma, or unfavourable chronic type) are resistant to conventional chemotherapeutic agents, and, thus, it has a poor prognosis (Shimoyama, 1991; Tsukasaki et al, 2007). Therefore, development of alternative treatment strategies is an urgent issue. CC chemokine receptor 4 (CCR4) is expressed on most ATL cells and has been shown to be a new molecular target of immunotherapy in vivo (Ito et al, 2009). Mogamulizumab, a novel molecular targeting agent, is a humanized anti-CCR4 immunoglobulin G1 monoclonal antibody with a defucosylated Fc region, and 50% efficacy has been shown as a single agent in a phase II study for relapsed and refractory ATL (Ishida et al, 2012). We have little experience with this agent, as large-scale clinical studies have not been conducted. Here, we report an acute ATL case whose tumour cells lost CCR4 expression after administration of mogamulizumab. A 63-year-old female was admitted to our hospital for fatigue, fever, skin eruption and hypercalcaemia, and was diagnosed with acute-type ATL. We started a dose-intensified chemotherapy of VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, and prednisone; doxorubicin, ranimustine, and prednisone; and vindesine, etoposide, carboplatin, and prednisone) immediately. Six cycles were carried out, and partial remission was obtained, but the ATL cells remained in peripheral blood and skin lesions. ATL recurred with skin lesions immediately while myelosuppression was prolonged. Therefore, we started administration of mogamulizumab as a single agent, once per week for 8 weeks at a dose of 1·0 mg/kg. By the end of the treatment, complete remission was obtained with disappearance of ATL cells in peripheral blood, skin lesions, and normalization of lactate dehydrogenase levels. Unfortunately, a similar eruption developed approximately 3 months later, and the ATL relapsed. The patient again underwent mogamulizumab therapy, as she did not want further chemotherapy. However, the second administration had no effect, and the patient died due to disease progression. We analysed CCR4 expression on patient ATL cells using multi-colour flow cytometry analysis, as described previously (Tian et al, 2011) to reveal the resistance mechanism. After dead cells (propidium iodide positive) and monocytes (CD4dim CD14+) were gated out, a CD3 vs. CD7 plot of CD4+ T cells was constructed, and CCR4 expression on the CD3dim/CD7low subpopulation, in which ATL cells were highly enriched, was analysed. This analysis clearly revealed loss of CCR4 expression on ATL tumour cells after mogamulizumab therapy (Fig 1). Furthermore, we conducted clonal analysis by inverse long polymerase chain reaction (PCR) using the same sample. Genomic DNA extracted from peripheral blood mononuclear cells was digested with PstI. The purified DNA was self-ligated with T4 DNA ligase (Takara Bio, Otsu, Japan) and inverse long PCR was performed using Tks Gflex DNA Polymerase (Takara Bio) (Kobayashi et al, 2013). The PCRs were performed in duplicate. The band of the major clone was of identical size before and after mogamulizumab therapy (Fig 2), suggesting that the relapsed CCR4− ATL cells belonged to the same clone as the original CCR4+ ATL cells. To the best of our knowledge, this is the first report of loss of the CCR4 antigen by clonal analysis after mogamulizumab therapy. The resistance mechanism to mogamulizumab has not been elucidated to date. Mogamulizumab exerts its activity on CCR4-expressing T cells through an indirect effector mechanism, antibody-dependent cell-mediated cytotoxicity (ADCC) (Ishii et al, 2010). Thus, the CCR4 molecule itself could be involved in the resistance to mogamulizumab by loss of expression. It is believed that target molecular loss is not a rare phenomenon during monoclonal antibody therapy. For example, several reports are available regarding the loss of CD20 expression after the administration of rituximab, which is an anti-CD20 monoclonal antibody (Duman et al, 2012). Several mechanisms ranging from the gene to the protein level have been proposed to explain loss of CD20; a similar mechanism might cause loss of CCR4 expression. We demonstrated loss of CCR4 expression on the same ATL clone, which excluded the possibility of a clonal change by CCR4− ATL cells after mogamulizumab treatment. We have experienced another patient who became resistant to a second mogamulizumab administration but whose ATL cells maintained CCR4 expression. Loss of CCR4 expression is one of the resistance mechanisms to mogamulizumab; others include mutation or deletion within epitope-coding regions for mogamulizumab, increase in soluble CCR4, and reduced ADCC. The anti-CCR4 antibody used in this study, clone 1G1, recognizes a distinct epitope from mogamulizumab (Ishii et al, 2010), which excluded the possibility of epitope masking by mogamulizumab. Our results indicate that CCR4 expression by ATL cells should be re-evaluated when relapsed patients with ATL are treated after mogamulizumab therapy even if their tumour cells express CCR4 at the initial evaluation. We thank Ms. Eri Watanabe (Institute of Medical Science, The University of Tokyo) for technical assistance with flow cytometry. We are grateful to the hospital staff who are committed to providing high-quality care for all of our patients. NO and KU wrote the manuscript. SK and TI performed the experiments using patient samples. KY, MK, and KS provided patient care and clinical information. NW supervized the flow cytometry. NO, AT, and KU supervized the research; and all authors approved the final manuscript. The authors declare no financial conflict of interest.
