Search

We recently treated a chronic myeloid leukemia (CML) patient with liver and renal dysfunction, who was undergoing hemodialysis (HD). He was treated with 50 mg dasatinib (DAS) once daily just before HD. The maximum plasma concentration of DAS was 227 ng/mL on a non-HD day and 46.9 ng/mL on a HD day. He was subsequently treated with 200 mg bosutinib (BOS) once daily. The plasma concentration of BOS changed from 74.5 ng/mL before HD to 58.8 ng/mL after HD. Our results indicate that close monitoring of the plasma tyrosine kinase inhibitor concentrations should be considered in CML patients with organ impairment.

We previously examined the utility of rituximab-bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to two-cycles of R-CHOP. The aim of this study was to identify molecular biomarkers that can predict prognosis in the RB-treated patients in the context of the prospective cohort. We first analyzed mutational status of 410 genes in diagnostic tumor specimens by target capture and sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however, none of which was predictive for progression-free survival (PFS) in the RB-treated patients (n=34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or immune response showed that expressions of CD8+ T-cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within 24 months (POD24)-group (n=8) than in noPOD24-group (n=31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS by using principal component analysis, which dichotomized the RB-treated patients into immune IIShigh (n=19) and IISlow (n=20) groups. The 3-year PFS rate was significantly lower in the IISlow group than in the IIShigh group (50.0% [95% CI: 27.1-69.2%] vs. 84.2% [95% CI: 58.7-94.6%], p=0.0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r=0.460, p=0.00355). These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL patients. (UMIN:000013795, jRCT:051180181).

Background: Several clinical risk stratification models have been proposed to predict the clinical outcomes of follicular lymphoma (FL) cases, however, few reports are available to predict prognosis of FL cases receiving bendamustine-based regimens. We previously examined the utility of rituximab-bendamustine (RB) treatment for newly diagnosed advanced FL, who showed non-optimal responses to two cycles of R-CHOP therapy. Methods: In this study, we explored the biomarkers that could influence outcomes for the RB-treated FL cases in the context of the prospective cohort by target capture and sanger sequencing, and gene-expression profiling analyses using 50 diagnostic biopsies.Results: We first examined the mutational status of 410 genes in tumor specimens derived from RB-treated cases. As reported before, CREBBP, KMT2D, MEF2B, BCL2, EZH2, CARD11, TNFRSF14, EP300, and APC were recurrently mutated, however, none of which was predictive for progression-free survival (PFS) in RB-treated cases. Similarly, the m7-FLIPI did not correlate with PFS or progression of disease within 24 months (POD24). A gene expression analysis using a panel of 770 genes associated with carcinogenesis and/or immune response showed that the expression of CD8+ T-cell markers (GZMM, FLT3LG, CD8A, CD8B, GZMK) and half of the genes regulating Th1 and Th2 responses were significantly lower in the POD24 group than in the noPOD24 group. Finally, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and dichotomized RB-treated cases into immune infiltrationhigh (infilhigh) and infiltrationlow (infillow) clusters. The 3-years PFS rate was lower in the infillow cluster than in the infilhigh cluster (50.0% [95% CI: 27.1–69.2%] vs. 84.2% [95% CI: 58.7–94.6%], p=0.0237). Of note, the proportion of cases with peripheral lymphopenia (low cluster than in the infilhigh cluster (38.5% vs. 9.09%, OR: 6.25 [95%CI, 1.20-32.7], p=0.0235). Conclusion: These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL cases.Trial registration: This trial was retrospectively registered in UMIN on April. 24, 2014 (UMIN000013795; http://www.umin.ac.jp/icdr/index-j.html).

Acute myeloid leukemia (AML) is a heterogeneous disease often associated with poor prognosis. We previously showed that the localization of KIT-D816V at endolysosomes is critical to activate aberrant Akt signaling and Chlorpromazine (CPZ) perturbs the intracellular localization, leading to cell death in AML cells with KIT-D816V. We report that daily administration of CPZ, prescribed for controlling anxiety disorder in patient with AML harboring KIT-D816V, led to a dramatic reduction in AML cells. In vitro and in vivo experiments showed that CPZ inhibited the growth and survival of the patient-derived AML cells, implying potent efficacy of CPZ in AML with KIT-D816V.

Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML). Clathrin assembly lymphoid myeloid leukemia protein (CALM) regulates intracellular transport of RTKs, however, the precise role for MT-RTKs remains elusive. We here show that CALM knock down leads to severely impaired FLT3 ITD- or KIT D814V-dependent cell growth compared to marginal influence on wild-type FLT3- or KIT-mediated cell growth. An antipsychotic drug chlorpromazine (CPZ) suppresses the growth of primary AML samples, and human CD34+CD38- AML cells including AML initiating cells with MT-RTKs in vitro and in vivo. Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ., Receptor tyrosine kinase mutations are frequent and associated with poor prognosis in acute myeloid leukemia (AML). Here the authors show that the antipsychotic drug chlorpromazine reduces AML cells viability by perturbing the intracellular localization of FLT3-ITD and KIT-D816V.

We report a case with extramedullary tumors affecting the supraclavicular region that presented as a relapse of acute myeloid leukemia (AML) with FLT3-ITD mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Treatment with gilteritinib resulted in remarkable response with disappearance of both the medullary and extramedullary tumors. Subsequently, a 2nd allo-HSCT was performed in an attempt to cure his AML and complete molecular response has been sustained with gilteritinib resumption without worsening GVHD. Targeted therapy with gilteritinib for medullary and extramedullary relapse of FLT3-ITD AML could be effective and suitable as a bridging therapy for allo-HSCT.

A 62-year-old male was diagnosed with chronic lymphocytic leukemia (CLL) and treated with a fludarabine-containing regimen which maintained the disease in a partial response. Nine years after diagnosis, a rapidly growing systemic lymphadenopathy was observed, and a biopsy specimen revealed the presence of typical Hodgkin/Reed-Sternberg (HRS) cells, surrounded by T-lymphocytes and CLL cells. Sequencing analysis of the germline complementary determining region 3 (CDR3) region of the immunoglobulin heavy chain (IGH) gene showed that the Hodgkin/Reed-Sternberg cells were clonally unrelated to the preexisting CLL cells and the HRS cells were composed of five different clones, leading to the molecular diagnosis of de novo lymphocyte-rich classic Hodgkin lymphoproliferative diseases (LPDs) with small lymphocytic lymphoma (SLL). As the initial treatment was neither effective for classic Hodgkin LPDs nor for SLL, Bendamustine, Rituximab (BR) was started and complete remission was achieved, which has continued for more than one year so far. BR may be a good therapeutic option for both entities without causing hematological toxicity.

A 70-year-old man with diffuse large B cell lymphoma, who had been in complete remission without treatment, presented with a visual disorder in the right eye. Vitreous biopsy was performed, although the results were not typically suggestive of lymphoma. The concentration of interleukin-10 (IL-10) in the vitreous humor was markedly elevated, suggesting intraocular lymphoma (IOL). Weekly intravitreal injections of methotrexate (MTX) resulted in remission of the visual disorder. During this remission, 10 months after the last intravitreal MTX treatment, a cerebral tumor was observed in the corpus callosum and atypical lymphocytes were detected in the cerebrospinal fluid. The concentration of IL-10 in the CSF was markedly elevated and the IL-6 level was slightly elevated, suggesting central nervous system (CNS) involvement. The patient was treated with intrathecal MTX, systemic rituximab, high-dose cytarabine, and high-dose methotrexate. After this therapy, the cerebral tumor disappeared, atypical lymphocytes were undetectable in the CSF, and the CSF IL-10 level was significantly reduced. IL-10 and IL-6 concentrations in the vitreous humor and CSF are important for diagnosis of IOL with CNS involvement and for monitoring the efficacy of therapy.

Background Hemophagocytic lymphohistiocytosis associated with autoimmune diseases is seen in patients with systemic juvenile idiopathic arthritis, adult-onset Still’s disease, and systemic lupus erythematosus, whereas it is rarely seen in patients with dermatomyositis. In addition, central nervous system involvement with dermatomyositis is rare. To the best of our knowledge, this is the first case of hemophagocytic lymphohistiocytosis complicated by leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma. Case presentation A 17-year-old Asian male adolescent with dermatomyositis and hemophagocytic lymphohistiocytosis that were controlled with corticosteroid therapy presented to our hospital with high fever and altered consciousness. Brain magnetic resonance imaging revealed multiple cerebral lesions. We diagnosed the central nervous system lesions as leukoencephalopathy secondary to dermatomyositis and hemophagocytic lymphohistiocytosis. Because corticosteroid and cyclophosphamide pulse therapy was ineffective, he was treated with a modified hemophagocytic lymphohistiocytosis-2004 protocol, which resulted in the disappearance of the lesions of his central nervous system. Conclusions Our findings suggest that the hemophagocytic lymphohistiocytosis-2004 protocol including etoposide should be initiated immediately in patients with hemophagocytic lymphohistiocytosis who respond poorly to treatment for the underlying disease. Moreover, irrespective of the underlying disease, patients with hemophagocytic lymphohistiocytosis with central nervous system lesions might require bone marrow transplantation.

The CC-chemokine receptor 4 (CCR4) is expressed in almost ATLL cells. Thus, anti-CCR4 antibodies can be used as a treatment strategy for ATLL. Mogamulizumab (MOG), which is a defucosylated anti-CCR4 monoclonal antibody, showed good results even in patients with recurrent ATLL in phase I or II studies. We treated 8 elderly patients with ATL who were resistant to chemotherapy using MOG monotherapy. All patients received 1.0 mg/kg of mogamulizumab (MOG) once per week for 8 weeks by intravenous infusion. In the present study, we observed CCR4-specific ADCC against CCR4-positive ATL cells. All patients showed CR with a marked decrease in the number of ATL cells. However, 2 patients contracted viral infection because of severe lymphopenia. One patient died because of severe cytomegalovirus infection despite adequate treatment. One patient had Stevens’ Johnson syndrome. These results suggested that MOG was effective in chemotherapy-resistant ATL patients. However, CCR4 is not only on ATL cells but also on endogenous Treg. The decrease in the number of Treg after MOG monotherapy has been expected to boost the antitumor activity and to be involved in the development of immune disorders, including autoimmune diseases. Furthermore, a decrease in CD4+ T cells led to viral infection. In conclusion, several treatments for prophylaxis of opportunistic infection, including CMV infection, should be recommended.