Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy.

BACKGROUND: Wilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis. METHODS: 33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed. RESULTS: The median age was 73 years (range 39-87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210-482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse. CONCLUSION: This study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

[Primary breast diffuse large B-cell lymphoma in an elderly man maintaining long-term complete response].

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin's lymphoma that mostly affects women. Here, we report a case of primary breast DLBCL that affected an older man without any autoimmune disease or drug-related female hormones. The patient was a 65-year-old man whose chief complaints were gradually-increasing lump in the right chest and swelling of the right axillary lymph nodes. He was diagnosed with malignant lymphoma through a needle biopsy on suspicion of right breast cancer with right axillary lymph node metastasis. Since the histological type could not be confirmed, right breast mass resection was performed. The patient was referred to our department for treatment because of the diagnoses of primary breast DLBCL, germinal center B-cell type (Hans classification), and clinical stage IIA. In addition to the six courses of R-CHOP therapy, intrathecal injections were used in combination to prevent CNS infiltration. He has been in complete remission for 5 years. Although rare, breast lymphoma can also occur in men; therefore, early histological diagnosis and response to CNS recurrence prevention are important.

Safety and efficacy of low-dose liposomal amphotericin B as empirical antifungal therapy for patients with prolonged neutropenia.

BACKGROUND: Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia. METHODS: High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy. RESULTS: Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %. CONCLUSION: This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.

Ovarian Follicular Lymphoma Diagnosed Due to Hydronephrosis.

A 74-year-old woman presented with left lateral abdominal pain. Abdominal echography revealed left hydronephrosis and a pelvic mass. The patient underwent left adnexal resection of a suspected left ovarian tumor and was diagnosed with follicular lymphoma (FL) of clinical stage IIIA, grade 2. The patient was treated with rituximab-combined chemotherapy and achieved complete remission. The most common histological types of ovarian lymphoma are diffuse large B-cell lymphoma and Burkitt lymphoma, with FL being an extremely rare variant. We herein report a case of ovarian FL diagnosed as hydronephrosis.

[Adult T-cell leukemia-lymphoma developed from an HTLV-1 carrier during treatment of B-cell lymphoma-associated hemophagocytic syndrome].

A 63-year-old woman was admitted to our hospital with high-grade fever, liver dysfunction, and pancytopenia. Computed tomography of the whole body revealed hepatosplenomegaly but no lymphoadenopaties. Bone marrow aspiration showed infiltrations of CD20-positive large atypical B-lymphocytes with severe hemophagocytosis. Although she was a human T-cell leukemia virus type 1 carrier, the atypical lymphocyte in bone marrow had IgH rearrangement but not TCR rearrangement. From these clinical and laboratory data, the patient was diagnosed as having B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) and treated with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). After 4 cycles of R-CHOP, she had achieved complete remission. However, increased numbers of CD4+CD25+ flower cells were observed in peripheral blood and HTLV-1 provirus DNA was detected after 5 cycle of R-CHOP. The patient was diagnosed as adult T-cell leukemia-lymphoma (ATL) complicated by B-LAHS. Our observations suggest that continuous immunosuppressive statement for B-cell lymphoma or the chemotherapy against B-LAHS may induce the development of ATL in an HTLV-1 carrier.

[Cost benefit analysis for prophylactic use of itraconazole versus fluconazole after hematopoietic stem cell transplantation].

Systemic fungal infection (SFI) is now one of the main causes of death from infective complications after hematopoietic stem cell transplantation (HSCT) and the role of prophylaxis of fungal infection has been established. However, there is no evidence evaluating the cost-benefit ratio of SFI management in Japan. To estimate the medical costs on prophylaxis and treatment of SFI in HSCT, we embarked on a randomized control prospective study of the medical cost-benefit ratio comparing fluconazole with itraconazole for antifungal prophylaxis in 40 patients who received HSCT in our hospital. Despite the similarity of efficacy for prophylaxis, the median cost of itraconazole prophylaxis between Day-10 and Day+28 was significantly less than that of fluconazole. There are many patients who require an i.v. formulation because of non-compliance with oral administration after HSCT and these cases cause increased medical costs. Therefore, further investigation is needed not only regarding differences among prophylactic agents but also regarding differences in administration routes focusing on the cost-effectiveness of treatment.

Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells.

This report addresses whether small molecules can deplete FoxP3-expressing regulatory T (T reg) cells, thereby augmenting antitumor immunity. Imatinib, a tyrosine kinase inhibitor of oncogenic BCR-ABL protein expressed by chronic myelogenous leukemia (CML) cells, possesses off-targets including LCK expressed in T cells. We showed that imatinib-treated CML patients in complete molecular remission (CMR) exhibited selective depletion of effector T reg (eT reg) cells and significant increase in effector/memory CD8+ T cells while non-CMR patients did not. Imatinib at CML-therapeutic concentrations indeed induced apoptosis specifically in eT reg cells and expanded tumor antigen-specific CD8+ T cells in vitro in healthy individuals and melanoma patients, and suppressed colon tumor growth in vivo in mice. Mechanistically, because of FoxP3-dependent much lower expression of LCK and ZAP-70 in T reg cells compared with other T cells, imatinib inhibition of LCK further reduced their TCR signal intensity, rendering them selectively susceptible to signal-deprived apoptotis. Taken together, eT reg cell depletion by imatinib is instrumental in evoking effective immune responses to various cancers.

Switching to nilotinib is associated with deeper molecular responses in chronic myeloid leukemia chronic phase with major molecular responses to imatinib: STAT1 trial in Japan.

The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR4.5, BCR-ABL1IS ≤ 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1IS ≤ 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study. The median age was 55.0 years. The median duration of IM treatment was 69.0 months. All patients showed MMR at the time of entry into the study; the median time to MMR on IM therapy was 20.4 months. The proportion of patients who achieved MR4.5 increased over time. The rates of MR4.5 in the 74 evaluable patients were 27.0% [90% confidence interval (CI) (18.7-36.8%)] and 44.6% [90% CI (34.7-54.8%)] at 12 and 24 months, respectively. The frequency of ABCG2 421C/A + A/A was an independent predictive biomarker for achieving a 24-month MR4.5. Switching to NIL led to safer, deeper molecular responses in patients with MMR on long-term IM therapy for future treatment-free remission.

Dasatinib-responsive chronic lymphocytic leukemia in a patient treated for coexisting chronic myeloid leukemia.

We herein present a case of concurrent chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Two different clones, a Philadelphia (Ph) clone and a CLL clone with a 13q deletion, were identified using fluorescent in situ hybridization. Dasatinib was administered to inhibit Bcr-Abl and Lyn kinase. The patient exhibited a molecular response for CML and a partial response for CLL. To our knowledge, this is the first report to describe the occurrence of a gradual increase in the Bcr-Abl transcript level prior to the diagnosis of Ph-positive CML in an individual with CLL who was successfully treated with dasatinib as the first-line therapy.

Repeated donor lymphocyte infusions overcome a myeloid sarcoma of the stomach resulting from a relapse of acute myeloid leukemia after allogeneic cell transplantation in long-term survival of more than 10 years.

A patient with acute myeloid leukemia had a relapse with a myeloid sarcoma of the stomach 32 months after allogeneic bone marrow transplantation. The patient was treated with the first donor lymphocyte infusion (DLI) and one course of induction chemotherapy. Due to severe infectious complication after chemotherapy, the patient could not continue chemotherapy. Subsequently, the patient was treated with a total of 13 cycles of DLI at 1-2 month intervals. Complete remission was achieved and neither relapse nor graft versus host disease has occurred during a follow-up of more than 10 years.

Diffuse large B-cell lymphoma with massive portal vein tumor thrombosis in a patient with alcoholic cirrhosis: a case report and literature review.

We describe a case of diffuse large B-cell lymphoma with massive portal vein tumor thrombosis in a patient with alcoholic cirrhosis. The tumor was detected only in the intrahepatic portal vein and the spermatic cord by FDG-PET/CT. Percutaneous liver biopsy and orchiectomy were performed and histological examination revealed diffuse large B-cell lymphoma. The tumor showed complete response after six courses of the combination chemotherapy. Portal vein tumor thrombosis of malignant lymphoma is extremely rare; moreover, it is possible that this is the first case of malignant lymphoma originating from the spermatic cord producing portal vein tumor thrombosis.