Two patients with the myelodysplastic syndrome (MDS) presented with symptoms associated with familial Mediterranean fever. Sweet's syndrome also developed in the two patients, who were found to have ...mutations in the gene associated with familial Mediterranean fever.
To the Editor:
We report the finding of
MEFV
mutations in two Japanese patients with the myelodysplastic syndrome (MDS) and skin lesions that are consistent with Sweet's syndrome (acute febrile neutrophilic dermatosis). Both patients had heterozygous mutations in
MEFV,
which are known to cause familial Mediterranean fever.
1
,
2
Patient 1, a 63-year-old man with an 8-month history of MDS, was admitted with high fever (temperature, 39.2°C), leukocytosis, and transfusion-dependent anemia. Patient 2, a 63-year-old woman with a 3-month history of MDS, had general malaise on admission, along with anemia and thrombocytopenia. Patient 1 had an MDS subtype that included refractory . . .
The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody. Progression‐free survival ...(PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T‐cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1‐year PFS was 26%, whereas median OS was 14.4 months, and 3‐year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1‐year PFS was zero, with a median OS of 6.0 months, and 3‐year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1‐year PFS was 50%, with a median OS of 25.6 months, and 3‐year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune‐related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.
Mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune‐related adverse event.
This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI‐8000) in patients with relapsed or refractory (R/R) adult T‐cell leukemia/lymphoma (ATLL) was ...undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty‐three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end‐point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval CI, 13.2, 52.9. Median progression‐free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.
Tucidinostat is an oral novel benzamide HDACi of HDAC isoenzymes 1, 2, 3 and 10 selectively. 23 patients with relapsed/refractory ATLL were treated with tucidinostat 40mg orally twice a week. Out of 23 patients, 7 showed objective responses including 1 CR, and ORR was 30.4%.
The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index ...(PI) for acute- and lymphoma-type ATL (ATL-PI).
In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model.
Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor sIL-2R) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test).
The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.
Patients with indolent non-Hodgkin lymphoma (iNHL) typically respond to first-line immunochemotherapy, but relapse is common. Treatment options for relapsed iNHL include chemotherapy ± rituximab and ...rituximab monotherapy. Lenalidomide plus rituximab (
R
2
) is an immunomodulatory regimen that enhances rituximab-mediated cytotoxicity and improves clinical activity in iNHL. AUGMENT was a double-blind phase III randomized trial of
R
2
vs. rituximab + placebo (R-placebo) in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma who were not refractory to rituximab. The primary endpoint was progression-free survival (PFS). Data reported here focus on Japanese patients from AUGMENT and reflect 36 patients (
n
= 18, each group). PFS was superior in the
R
2
group, HR = 0.32 (95% CI 0.11–0.96). Median PFS was not reached (95% CI 19.7–NE) in the
R
2
group vs. 16.5 months (95% CI 11.3–30.6) in the R-placebo group. Grade 3/4 adverse events were more frequent in patients treated with
R
2
(67%) than with R-placebo (22%), primarily attributable to increased neutropenia (50% vs 17%).
R
2
resulted in significantly longer median PFS than R-placebo in Japanese patients with R/R iNHL, and the efficacy and the safety profile of
R
2
were similar to those reported in the global population.
Purpose
Adult T‐cell leukemia/lymphoma (ATLL) is a relatively refractory peripheral T‐cell lymphoma caused by human T‐cell lymphotropic virus type 1 (HTLV‐1). The objective of this study was to ...investigate the characteristics of long‐term survivors with ATLL.
Methods
We conducted an observational study of 75 aggressive‐type ATLL patients. Flow cytometry was conducted to analyze HTLV‐1 Tax‐specific cytotoxic T‐lymphocytes (CTLs) and T‐cell receptor Vβ gene repertoire.
Results
We first evaluated six long‐term survivors among 37 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy without mogamulizumab, a monoclonal antibody for C‐C chemokine receptor four antigen. Reversal of the CD4‐to‐CD8 ratio (CD4/CD8) in peripheral mononuclear cells was observed in all six patients. Three of these six patients showed reversed CD4/CD8 immediately after herpes virus infection. Four of these six patients who could be examined demonstrated long‐term maintenance of HTLV‐1 Tax‐specific CTLs. We subsequently identified four long‐term survivors among 38 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy plus mogamulizumab. All four patients showed reversed CD4/CD8, and three of the four patients contracted herpes virus infection during immunochemotherapy. Six of the total 10 patients were subjected to CTL analyses. Tax‐specific CTLs were observed, and the CTLs that were almost entirely composed of memory CTLs in all patients were recorded. HTLV‐1 provirus was also detected in all six patients.
Conclusions
These data suggest that Tax‐specific memory CTLs probably, together with anticancer agents, eradicate ATLL cells and exhibit long‐term preventive effects from relapse ATLL. Thus, the strong activation of cellular immunity, such as herpes virus infection, seems to be necessary to induce such a potent number of Tax‐specific CTLs.
Long‐term survivors with complete remission of newly diagnosed aggressive‐type adult T‐cell leukemia/lymphoma were investigated clinically and immunologically. HTLV‐1 Tax‐specific memory cytotoxic T lymphocytes were observed in all survivors. Strong activation of cellular immunity, such as herpes virus infection during or immediately after chemotherapy, may be necessary to induce such a potent number of Tax‐specific cytotoxic T lymphocytes.
The efficacy of azacitidine (AZA) on survival of lower risk (LR) ‐ myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long‐term survival benefit ...of AZA for patients with LR‐MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR‐MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis‐stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection‐related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR‐MDS patients.
Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR‐MDS patients.
We present the case of a patient with multiple tyrosine kinase inhibitor (TKI)-refractory chronic phase chronic myeloid leukemia (CP-CML) with a T315I mutation of abl1. Dasatinib, a second-generation ...TKI, was administered as the initial treatment but achieved neither a cytogenetic nor molecular response. A mutational analysis of abl1 revealed that the patient had a T315I mutation. The patient was then administered ponatinib, a third-generation TKI, which is thought to be effective against T315I; however, the complete blood counts became within normal limits, and neither a cytogenetic nor molecular response was achieved. However, the patient has maintained a healthy chronic phase (with no blast crises) for more than 5½ years since the diagnosis of CP-CML. T-cell receptor (TCR) repertoire analyses using peripheral blood revealed a remarkable clonal expansion of effector cytotoxic T lymphocytes (CTLs) that contained TCR V beta 13.6. We observed the clonal expansion of naïve CTLs with TCR V beta 13.6; however, no clonality was observed in the memory CTLs. The naïve and effector CTLs persisted at very high percentages since the seventh month after starting dasatinib. The CTLs could not have led to the molecular response; therefore, there might be plenty of CML stem cells remaining in the bone marrow. Therefore, although the CTLs might have prevented the disease from developing blast crises over more than 5 years, the CTLs might not have been able to become memory CTLs.
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