Dasatinib-Triggered Severe Hypocalcemia in a Patient with Chronic Kidney Disease and Osteoporosis.

Given the increasing prevalence of chronic myeloid leukemia (CML) in older individuals, careful selection of tyrosine kinase inhibitors (TKIs) is required. The case of an 84-year-old woman with chronic-phase CML and chronic kidney disease undergoing osteoporosis, in whom dasatinib triggered severe hypocalcemia, is reported. She was intolerant to both imatinib and nilotinib. Initiation of low-dose dasatinib treatment led to severe hypocalcemia and long QT syndrome, compounded by vitamin D deficiency and denosumab use. We stopped dasatinib, and her hypocalcemia was improved after calcium administration. This case highlights the potential of TKIs in triggering hypocalcemia, emphasizing the need to assess mineral disorders before initiating TKI therapy.

The Impact of Pretransplant Use of Tyrosine Kinase Inhibitors on Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia-A Single-institution Retrospective Study.

Objective Chronic myeloid leukemia (CML) is a malignant hematological disorder, and allogeneic stem cell transplantation (allo-SCT) was its only curative treatment until the introduction of tyrosine kinase inhibitors (TKIs). Allo-SCT is still considered for CML patients who are resistant to TKIs and in an advanced phase. Currently, second- and third-generation (2/3 G) TKIs are typically incorporated into the first-line treatment of CML. However, the impact of 2/3 G TKIs on subsequent allo-SCT remains unclear. We therefore evaluated the effect of 2/3 G TKIs on allo-SCT. Methods We retrospectively evaluated the effect of pretransplant therapy with TKIs on the outcome of allo-SCT for CML using clinical data at our institution. Patients or Materials Thirty-two CML patients who received their first allo-SCT procedure at our institute from 2001 to 2020 were included. We divided the patients into three subgroups based on TKI treatment before allo-SCT. Patients receiving no TKIs, only imatinib (IM), and 2/3 G TKIs were classified into the Non-TKI, IM, and 2/3 G TKI groups, respectively. Results In a univariate analysis, the pretransplant use of 2/3 G TKIs was significantly associated with a higher 5-year overall survival (91.7%) and relapse-free survival (75.0%) than the use of IM (37.5% and 12.5%) in patients presenting with or progressing to the advanced phase. In addition, pretransplant use of 2/3 G TKIs did not increase the incidence of graft-versus-host disease (GVHD). Conclusions We demonstrated that the pretransplant use of 2/3 G TKIs was safe and improved the outcome of CML patients who presented with or progressed to the advanced phase without increasing the frequency of GVHD.

Thromboembolism Early After Glucocorticoid Administration in Patients with Autoimmune Hemolytic Anemia.

Pulmonary embolism and deep venous thrombosis (PE/DVT) are well-known lethal complications in autoimmune hemolytic anemia (AIHA). However, the impact of their treatment is unclear. Here, we describe three elderly Japanese patients with AIHA who developed PE/DVT early after glucocorticoid administration. All patients presented with active hemolysis and high D-dimer levels upon admission. Thromboembolism was confirmed within 2 weeks after starting glucocorticoid, suggesting that both active hemolysis and glucocorticoid administration synergistically contributed to the development of PE/DVT. Clinicians should consider that such synergism may increase the risk of thromboembolism in patients with AIHA, and prophylactic anticoagulation is worth considering in patients after starting glucocorticoid.

GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c-MET tyrosine kinase.

OBJECTIVE: Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. METHODS: ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS. RESULTS: Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity. CONCLUSION: Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.

Efficacy of ondansetron against emesis induced by a multiple-day cisplatin-based chemotherapy regimen for malignant lymphoma.

OBJECTIVES: This study aimed to evaluate the antiemetic efficacy of a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), ondansetron, in patients with malignant lymphoma receiving multi-day cisplatin-based combination chemotherapy. METHODS: We conducted a single-institution retrospective analysis of patients receiving the first course of an ESHAP (etoposide, cisplatin, methylprednisolone, cytarabine) regimen including 4-day continuous infusion of cisplatin (25 mg/m2/day). All patients received ondansetron 4 mg intravenously during 5-day administration of ESHAP. The primary endpoint was complete response (CR) for emesis, which was defined as absence of both emesis and rescue medications. Total control (TC) was defined as an absence of emetic episodes, including nausea and emesis, and complete protection (CP) was defined as an absence of emesis with addition of rescue antiemetics. Nausea and vomiting were assessed and graded daily by medical staff. RESULTS: Eighty-two patients were analyzed. Nausea and vomiting were generally well controlled, with the CR rates of emesis being 79% in the overall phase, 82% in the early phase (days 1-6), and 89% in the delayed phase (days 7-10). TC and CP were achieved in 51 patients (62%) and 77 patients (94%) in the overall phase. DISCUSSION: Most of the chemotherapy regimens for lymphoid malignancies include high-dose corticosteroid which may be also effective as antiemetics. Although NK1 receptor antagonist (NK1RA) is generally recommended for cisplatin-containing chemotherapy, it can interact with variety drugs. CONCLUSION: Although NK1RA is generally recommended for cisplatin-containing regimen, our results suggest that ondansetron effectively controlled emesis in patients receiving ESHAP therapy which includes high-dose corticosteroid.

[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.

Interleukin-6-producing Intravascular Large B-cell Lymphoma with Lymphadenopathy Mimicking the Histology of Multicentric Castleman Disease.

An inguinal lymph node biopsy of a woman with a one-month history of a progressive fever, fatigue, dyspnea, skin rash, and lymphadenopathy revealed a well-preserved basic structure, hyperplastic germinal centers, and an interfollicular region containing polyclonal plasma cell sheets, suggesting plasma cell-type multicentric Castleman disease (MCD). We initiated prednisolone and anti-interleukin (IL)-6 antibody (tocilizumab), without success. A biopsy specimen re-evaluation detected CD20-positive atypical large B cells infiltrating the small vessels within and around the lymph node and its capsule. We diagnosed her with intravascular large B-cell lymphoma (IVLBCL). Lymphoma cells were weakly positive for IL-6 by immunohistochemical staining. IL-6 from lymphoma cells may have caused the MCD-like presentation as a paraneoplastic etiology. Malignant lymphoma should be excluded before diagnosing MCD.

Successful Treatment of End-stage Renal Disease in a Patient With Chronic Myeloid Leukemia by Kidney Transplantation and Tyrosine Kinase Inhibitors: A Case Report.

Consensus regarding kidney transplantation feasibility in patients with chronic myeloid leukemia (CML) well controlled by tyrosine kinase inhibitors has not yet been achieved. Here, we report a patient with CML well controlled by tyrosine kinase inhibitors who developed end-stage renal disease during treatment and underwent kidney transplantation. CML activity has been carefully and successfully controlled for 4 years post-transplant. Very cautious dose adjustment and temporary cessation of nilotinib were required because kidney function fluctuated in reference to the doses of nilotinib.

Impact of immunoglobulin G2 subclass level on late-onset bacterial infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Immunoglobulin (Ig) G2 subclass deficiency is known to be associated with recurrent bacterial respiratory infections caused by capsulated bacteria and is found mostly in pediatric patients. However, its impact after allogeneic hematopoietic stem cell transplantation (HSCT) has not been fully assessed. METHODS: We retrospectively evaluated the relationship between IgG2 subclass levels and bacterial pneumonia in 74 adult patients who survived longer than 2 years after allogeneic HSCT. RESULTS: During the evaluation period, nine patients developed bacterial pneumonia. The median IgG2 level was significantly lower in patients with an infectious episode than in those without (143 mg/dL vs 287 mg/dL; P < 0.01). In multivariate analysis, a history of rituximab therapy and cord blood as a stem cell source were significantly associated with decreased levels of both IgG2 and IgG2/IgG ratios (P < 0.05). CONCLUSIONS: Suboptimal serum IgG2 levels could increase susceptibility to late-onset bacterial pneumonia after allogeneic HSCT. IgG2 levels should be considered carefully, especially in patients receiving cord blood transplantation and/or rituximab treatment.

A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress.

New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas' disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20 mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.

Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma.

Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development.

Allogeneic hematopoietic stem cell transplantation following treatment with brentuximab vedotin for refractory Hodgkin lymphoma.

Brentuximab vedotin (BV) is a novel agent used for the treatment of relapsed or refractory Hodgkin lymphoma. We have described two patients with refractory Hodgkin lymphoma, who were successfully treated with BV followed by allogeneic hematopoietic stem cell transplantation (HSCT). Although both patients were resistant to conventional chemotherapies, they responded to four or five doses of BV given every 3 weeks. Then, the patients underwent bone marrow transplantation from unrelated donors after reduced-intensity conditioning consisting of fludarabine and melphalan. They remained progression-free for more than 3 years after the transplantation. These findings suggest that BV could be a promising bridging therapy to curative allogeneic HSCT for relapsed or refractory Hodgkin lymphoma. Further accumulation of such cases is warranted to evaluate the efficacy and safety of BV therapy prior to allogeneic HSCT.

[Cellulitis due to Achromobacter xylosoxidans during bortezomib therapy for multiple myeloma].

Achromobacter xylosoxidans (A. xylosoxidans) is a non-fermentative gram-negative rod. This organism is reportedly a causative pathogen of bacteremia mainly in patients with hematological disorders. However, only one case of cellulitis due to A. xylosoxidans associated with hematological malignancy has been reported. An 80-year-old man developed cellulitis and subsequent bacteremia due to A. xylosoxidans during bortezomib therapy for multiple myeloma. Although his condition was serious enough to require intensive care, he fully recovered with appropriate antimicrobial agents and supportive care. The isolate was broadly resistant to antimicrobial agents, including cefepime, amikacin, and ciprofloxacin. Therefore, the identification and selection of appropriate antimicrobial agents were considered to have contributed to the successful outcome in this case. Physicians should recognize A. xylosoxidans as a possible pathogen causing cellulitis and secondary bacteremia, as well as being aware of its broad resistance to antimicrobial agents.