A novel anticancer quinolone, (R)-WAC-224, has anti-leukemia activities against acute myeloid leukemia.

Approximately 60%-80% of patients who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances of novel anticancer agents. Continuing development of more effective novel treatments for acute myeloid leukemia (AML) is necessary. We developed (R)-WAC-224 (R-WAC), which is an anticancer quinolone, targeting topoisomerase II. This study evaluated the anti-leukemia potential of R-WAC or racemic WAC-224 (WAC) in vitro and in vivo. R-WAC significantly inhibited the human AML cell line proliferation (MV4-11, HL60, and KG1a), which was comparable to daunorubicin and cytarabine, not affected by P-glycoprotein overexpression. WAC did neither increase serum troponin-T nor decrease the crypt numbers in the small intestine, indicating WAC was less toxic than doxorubicin. R-WAC monotherapy demonstrated prolonged survival in the AML mice model and inhibited tumor growth in the MV4-11 xenograft mice model. Moreover, the combination of R-WAC and cytarabine demonstrated more active anti-leukemia effects than daunorubicin and cytarabine. Finally, R-WAC inhibited the colony-forming abilities using primary AML cells. These results indicate that R-WAC is a promising therapeutic agent for AML.

Progressive Multifocal Leukoencephalopathy in Relapsed Ph+ Acute Lymphoblastic Leukemia after Cord Blood Transplantation and Blinatumomab Treatment: A Case Report and Literature Review.

Progressive multifocal leukoencephalopathy (PML) is a rare neurological disease caused by the reactivation of latent John Cunningham polyomavirus. Hematological disorders associated with immunomodulatory monoclonal antibodies and hematopoietic stem cell transplantation (HSCT) are risk factors for PML. Blinatumomab is a novel antileukemic immunomodulatory agent and more effective for relapsed and refractory acute lymphoblastic leukemia (ALL) than conventional chemotherapy. But, blinatumomab suppresses humoral immunity due to long-lasting B-cell depletion during and after the treatment. The development of PML involves cellular immunity and impairment of humoral immunity. Although few cases of blinatumomab-related PML have been reported, the use of blinatumomab after allogeneic HSCT may increase the risk of developing PML. The current case report presents a patient of Philadelphia chromosome-positive ALL wherein PML developed after cord blood stem cell transplantation and administrating blinatumomab.

Successful Pre- and Post-transplant Administration of Gilteritinib in a Patient with Relapsed and Refractory Acute Myeloid Leukemia Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation.

Patients with acute myeloid leukemia (AML) harboring FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication mutation are associated with a poor survival outcome, even those receiving allogeneic stem cell transplantation (Allo-SCT). An additional treatment strategy with allo-SCT is therefore required to reduce relapse in these patients. Gilteritinib is a specific FLT3 inhibitor that has shown clinical benefit for patients with relapsed and refractory (R/R) AML harboring FLT3 mutation. We herein report a 49-year-old woman with R/R AML who was successfully treated with pre- and post-transplant gilteritinib. Post-transplant gilteritnib yielded a durable response with possible exacerbation of graft-versus-host disease.

Successful combination treatment with azacitidine and venetoclax as a bridging therapy for third allogenic stem cell transplantation in a patient with 11q23/MLL-rearranged complex karyotype acute myeloid leukemia.

Translocation t(6;11) occurs in approximately 5% of patients with acute myeloid leukemia (AML) corresponding to 11q23/mixed lineage leukemia (MLL) rearrangement. The AF6 gene on chromosome 6q27 is the fusion partner of the MLL gene on 11q23 in t(6;11), which results in a poor prognosis. The case of a patient with 11q23/MLL-rearranged AML who successfully underwent a third allogeneic stem cell transplantation after treatment with azacitidine (AZA) and venetoclax (VEN) is presented in this article. This report suggests that a combination of AZA and VEN is an effective therapeutic approach for relapsed and refractory MLL-rearranged AML.

[Successful treatment with bortezomib for a patient with plasma cell leukemia accompanied by severe hyperbilirubinemia].

A 59-year-old woman was admitted to our hospital with jaundice, renal dysfunction, anemia and hypercalcemia. Primary plasma cell leukemia (PCL) was diagnosed based on findings of IgA-λ type M-protein, 22% plasma cells in the bone marrow and 23.1% plasma cells of WBC in the peripheral blood. Because the total bilirubin (T.Bil) level increased even after the administration of prednisolone (PSL), dexamethasone and methylprednisolone, the patient was started on bortezomib (0.7 mg/m(2) on days 1, 4, 8 and 11 for 3 weeks) combined with PSL (40 mg/day). The level of T.Bil decreased and the patient's condition remarkably improved. We then increased the dose of bortezomib to 1.0 mg/m(2) in the second course, but discontinued treatment just after starting the third course because NCI-CTCAE Grade 3 peripheral neuropathy developed. According to the criteria of the International Myeloma Working Group, the response category was VGPR (=very good partial response) at 1 month after pausing treatment. We recommend these novel agents for PCL, which is an aggressive form of extramedullary plasma cell cancer.

Cooccurrence of CD10-Positive and CD10-Negative Mantle Cell Lymphoma Complicated With Central Nervous System Involvement Solely by CD10-Positive Population.

The neoplastic cells of mantle cell lymphoma (MCL) usually express CD5 and not CD10. However, cases of MCL with aberrant expression of CD10 have been seldom reported. A 71-year-old man presented multiple lymphadenopathies with a bulky tumor of the abdomen. He received the biopsies from the left cervical lymph node and the duodenum. The former specimen showed MCL with CD5-positive and CD10-negative, but the latter showed MCL with CD5-positive and CD10-positive. After receiving induction therapy, he developed convulsions, and lymphoma cells expressing CD5-positive and CD10-positive were detected in cerebrospinal fluid (CSF). CD10-positive MCL has some significant clinical characteristics. And it shows worse overall survival compared with CD10-negative MCL when it has aggressive features such as blastoid and pleomorphic morphology, high-Ki-67 index, and high mantle cell lymphoma international prognostic index (MIPI). Therefore, physicians and pathologists must carefully discriminate against cases having this aberrant expression.

Allogeneic hematopoietic cell transplantation using fludarabine plus myeloablative busulfan and melphalan confers promising survival in high-risk hematopoietic neoplasms: a single-center retrospective analysis.

OBJECTIVES: Optimal selection of pretransplant conditioning is crucially vital for improving survival and quality-of-life of patients who receive allogeneic hematopoietic cell transplantation (allo-HCT), particularly in those with high-risk diseases. In this study, we evaluated the efficacy and safety of recently-developed reduced-toxicity myeloablative regimen that combines fludarabine, intravenous busulfan, and melphalan (FBM). METHODS: We conducted a single-center retrospective analysis of 39 patients (23 with myeloid neoplasms and 16 with lymphoid neoplasms), with a median age of 50 (range, 17-68) years, who underwent their first allo-HCT using the FBM regimen. Graft types were bone marrow in 11, peripheral blood in 11, and cord blood in 17 patients. Cyclosporine- or tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was administered. The primary end point of the study was the overall survival rate at 2-year after transplantation. RESULTS: After a median follow-up of 910 days for the surviving patients, 2-year overall survival was 62% for the entire cohort; 73% in the low-to-intermediate-risk group and 44% in the high-to-very high-risk group classified by the refined CIBMTR Disease Risk Index. Cumulative incidences of engraftment, grade II-IV acute GVHD, chronic GVHD, relapse, and non-relapse mortality were 95%, 56%, 56%, 31%, and 17%, respectively. CONCLUSION: These results suggest that our FBM regimen can be applied to allo-HCT using various graft types and yields acceptable outcomes with relatively low non-relapse mortality in both myeloid and lymphoid neoplasms. Also, we observed a promising survival in the group of patients with high-risk diseases, warranting more accumulation of patients and longer follow-up.

All-trans retinoic acid enhances cytotoxic effect of T cells with an anti-CD38 chimeric antigen receptor in acute myeloid leukemia.

We reported that T cells with anti-CD38-chimeric antigen receptors (CAR) eliminated B-cell lymphoma cells expressing CD38. To employ anti-CD38-CAR against acute myeloid leukemia (AML) blasts not expressing CD38, it is necessary to induce or increase the intensity of CD38 expression. A lactate dehydrogenase (LDH)-releasing assay and flow cytometry showed that anti-CD38-CAR T cells were cytotoxic against AML lines (THP-1 and CMK) expressing high CD38 levels (>99%), in time- and number of effector-dependent manners. In other AML lines (KG1, U937 and HL60) partially expressing CD38, CD38+ AML cells were killed by CD38-specific T cells, but CD38- AML cells remained survived. Intriguingly, 10 nM all-trans retinoic acid (ATRA) augmented CD38 expression in KG1, U937 and HL60 cells and primary leukemic cells from AML patients. Moreover, the withdrawal of ATRA from the medium decreased CD38 expression in AML cells. Killing effects of anti-CD38-CAR T cells against AML lines and AML cells were limited without ATRA, whereas CD38-specific T cells enhanced cytotoxicity on AML cells by ATRA in association with enhanced CD38 expression. These results indicate that anti-CD38-CAR T cells eliminate AML cells through CD38 expression induced by ATRA.