Masahito Tokunaga

Reduced Frequency, Diversity, and Function of Human T Cell Leukemia Virus Type 1-Specific CD8+ T Cell in Adult T Cell Leukemia Patients

Human T cell lymphotropic virus type 1 (HTLV-1)-specific CTL are thought to be immune effectors that reduce the risk of adult T cell leukemia (ATL). However, in vivo conditions of anti-HTLV-1 CTL before and after ATL development have yet to be determined. To characterize anti-HTLV-1 CTL in asymptomatic HTLV-1 carriers (AC) and ATL patients, we analyzed the frequency and diversity of HTLV-1-specific CD8+ T cells in PBMC of 35 AC and 32 ATL patients using 16 distinct epitopes of HTLV-1 Tax or Env/HLA tetramers along with intracellular cytolytic effector molecules (IFN-γ, perforin, and granzyme B). Overall frequency of subjects possessing Tax-specific CD8+ T cells was significantly lower in ATL than AC (53 vs 90%; p = 0.001), whereas the difference in Env-specific CD8+ T cells was not statistically significant. AC possessed Tax11–19/HLA-A*0201-specific tetramer+ cells by 90% and Tax301–309/HLA-A*2402-specific tetramer+ cells by 92%. Some AC recognized more than one epitope. In contrast, ATL recognized only Tax11–19 with HLA-A*0201 and Tax301–309 with HLA-A*2402 at frequencies of 30 and 55%. There were also significant differences in percentage of cells binding Tax11–19/HLA-A*0201 and Tax301–309/HLA-A*2402 tetramers between AC and ATL. Anti-HTLV-1 Tax CD8+ T cells in AC and ATL produced IFN-γ in response to Tax. In contrast, perforin and granzyme B expression in anti-HTLV-1 CD8+ T cells of ATL was significant lower than that of AC. Frequency of Tax-specific CD8+ T cells in AC was related to proviral load in HLA-A*0201. These results suggest that decreased frequency, diversity, and function of anti-HTLV-1 Tax CD8+ T cell clones may be one of the risks of ATL development.

Effect of anti-CCR4 monoclonal antibody (mogamulizumab) on adult T-cell leukemia-lymphoma: cutaneous adverse reactions may predict the prognosis.

Adult T‐cell leukemia–lymphoma (ATL) is one of the most malignant lymphomas with poor prognosis. ATL cells express CC chemokine receptor 4 (CCR4) and mogamulizumab, a monoclonal antibody against CCR4 that exhibits very strong cytotoxicity for ATL cells via antibody‐dependent cellular cytotoxicity. Although its effect is dramatic in ATL, serious adverse reactions such as Stevens–Johnson syndrome have been reported. However, these eruptions can appear as therapeutic signs of mogamulizumab. We evaluated the effectiveness of mogamulizumab in five acute‐type ATL patients. Peripheral blood (PB) and lymph nodes (LN) were affected in three and four patients, respectively. In PB, complete response (CR) was obtained in all three patients and partial response (PR) was recorded in LN of one patient. In skin lesions, four of five patients manifested CR; in two, the lesions worsened after the start of mogamulizumab treatment and subsequently improved. In these lesions, CD4+8−25+ ATL cells were replaced by CD3+8+ cytotoxic T cells. Cutaneous adverse reactions (CAR) developed in two patients with CR; they did not show a relapse of ATL over the course of 9 months. Our findings suggest that mogamulizumab should be continued and surface marker evaluation should be performed even in patients whose skin lesions show aggravation, and that CAR may be a marker for a favorable prognosis.

Adult T-Cell Leukemia in a Liver Transplant Recipient That Did Not Progress after Onset of Graft Rejection

A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T- cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.

Human T-lymphotropic virus type I proviral loads in patients with adult T-cell leukemia–lymphoma: Comparison between cutaneous type and other subtypes

Adult T‐cell leukemia–lymphoma (ATL), characterized by various clinicopathological features, is divided into four clinical subtypes, namely, acute, lymphoma, chronic and smoldering types, and the treatment strategy differs according to the clinical subtype. The designation cutaneous type ATL has been proposed to describe a peculiar subgroup of smoldering type ATL in which the skin is predominantly affected. However, diagnostic criteria and prognostic factors for cutaneous type ATL remain to be determined. Therefore, we performed a retrospective study to obtain a precise method for subtype classification and to clearly define cutaneous type ATL. A total of 87 ATL patients (acute, n = 31; lymphoma, n = 6; chronic, n = 24; smoldering, n = 26) were enrolled. The human T‐lymphotropic virus type I (HTLV‐1) proviral load in peripheral blood and the serum soluble interleukin‐2 receptor (sIL‐2R) level were evaluated with respect to the clinical features of the different types of ATL. The HTLV‐1 proviral load was significantly increased in the acute and chronic type and the serum sIL‐2R level was increased in the acute and lymphoma type. The HTLV‐1 proviral load was significantly lower in cutaneous than other smoldering types of ATL without skin lesions. The clinical findings of cutaneous type ATL were also different from other subtypes. These results indicate that, in combination, determination of the HTLV‐1 proviral load and the serum sIL‐2R level is useful for distinguishing among the different types of ATL, and strongly suggest that cutaneous type ATL is a distinct clinical entity.

Masked t(15;17) APL with the insertion of PML–RARα fusion gene in 4q21

Most cases of acute promyelocytic leukemia (APL) are characterized by the reciprocal translocation t(15;17); however, several complex variant translocations have also been reported. Here we report complex cytogenetic abnormalities without t(15;17) assayed by the G-banding method in a 62-year-old woman with the typical morphology and clinical features of APL. Based on spectral karyotyping and FISH analyses, we confirm the insertion of a cryptic chromosomal segment containing the PML/RARalpha fusion gene. The patient achieved complete remission after treatment with all-trans retinoic acid (ATRA) alone. Although the mechanism of this cryptic variant insertion is not known, we conclude that the insertion of PML-RARalpha fusion into 4q21 seems not to alter the effectiveness of treatment with ATRA.

Clinical significance of cutaneous adverse reaction to mogamulizumab in relapsed or refractory adult T-cell leukaemia-lymphoma

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Serum prohepcidin levels are potential prognostic markers in patients with multiple myeloma

Prohepcidin is the prohormone of hepcidin. Anemia is one of the main clinical features in patients with multiple myeloma (MM) and hepcidin may be associated with iron homeostasis in these patients. However, the clinical significance of prohepcidin is not fully understood. In this retrospective study, we measured serum prohepcidin levels using an immunoassay technique to study its clinical significance in 39 MM patients. Serum prohepcidin levels in patients with MM were weakly correlated with alkaline phosphatase (ALP) levels (r=0.32, P=0.048), calculated by Spearman’s rank correlation, but not with other clinical data, including hemoglobin, serum iron or ferritin. In addition, patients with severe renal insufficiency [creatinine clearance (CCr) <50 ml/min] had significantly higher prohepcidin levels compared with patients with mild or no renal insufficiency (CCr ≥50 ml/min, P=0.047). In contrast, low serum prohepcidin levels less than 110 ng/ml were an independent predictor of poor overall survival [hazard ratio (HR), 5.29; 95% confidence interval (CI), 1.65–17.03] in addition to serum creatinine levels of at least 2 mg/dl (HR, 5.32; CI, 1.10–25.64), serum calcium (HR, 3.53; CI, 1.01–12.33) and ECOG performance status grade 4 (HR, 4.15; CI, 1.32–13.09) in the multivariate analysis using Cox proportional hazards model. In the subset of 31 MM patients with CCr ≥50 ml/min, low serum prohepcidin (HR, 5.65; CI, 1.60–19.95) was an indicator of poor prognosis in multivariate analysis. These results indicate that serum prohepcidin levels may be associated with ALP and renal function but not iron homeostasis, in MM patients. In addition, lower serum prohepcidin levels are potential independent indicators of poor overall survival in MM patients regardless of renal function.

Effect of a novel anti-CCR4 monoclonal antibody (Mogamulizmab) on skin lesions of adult T-cell leukemia-lymphoma (ATL) and its adverse skin reactions (ASR)

We studied the effects of Mogamulizmab on ATL and its adverse reactions in 10 patients with ATL, among them 6 patients had skin lesions. Informed consent was obtained prior to study. Four out of 6 patients with cutaneous involvement showed complete response (CR), with 4 to 8 cycles of treatments. Of interest were two cases which appeared to have worsened in the early phase of treatment because of enlargement of cutaneous nodules or tumors. It, however, was found to be actually improving determined from histopathological examinations, i.e., more inflammatory cell infiltration and edema with less number of lymphoma cells in the skin. Eventually, these two patients showed CR. Furthermore, 2 each patients with 4 CR patients showed no recurrence with ASR, i.e., erythema and plaque, and showed reccurence without ASR. ASR were observed in 4 out of 10 patients. All these ASR fortunately subsided later. Immunohistopathological examinations revealed the infiltration of cytotoxic T-lymphocytes in the dermis. These results suggest that 1) Mogamulizmab had excellent effects (4/6) to suppress the growth of cutaneous lesions in ATL, 2) ASR might be favorable signs of the effects (2/4), and 3) ASR (4/10) were not serious. Studies of plasma and tissue levels of Mogamulizmab and T-reg cells may reveal the action mechanism of this novel anti-CCR4 agent in detail.

CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment

TO THE EDITOR: Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell lymphotropic virus type 1.[1][1][⇓][2]-[3][3] Patients, especially those with an aggressive variant (acute, lymphoma, and unfavorable chronic subtypes),[4][4],[5][5] have an extremely poor prognosis.[1][1][⇓][2][⇓][

Detection of an early adult T-cell leukemia-lymphoma clone in lymph nodes with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma involvement

A 58-year-old man was admitted to our hospital with systemic lymphadenopathy and was diagnosed with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL) by lymph node biopsy. Although he was a human T-cell leukemia virus type I (HTLV-1) carrier, Southern blot analysis of the lymph node did not show monoclonal integration of HTLV-1 provirus deoxyribonucleic acid (DNA). He achieved complete remission after chemotherapy and subsequently, autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed. Fifteen months after the auto-PBSCT, abnormal lymphocytes in the peripheral blood gradually increased. Southern blot analysis revealed monoclonal integration of HTLV-1 provirus DNA and monoclonal rearrangement of TRB. He was diagnosed with chronic type adult T-cell leukemia-lymphoma (ATL), which immediately progressed to the acute type. He died of tumor progression despite intensive chemotherapy. We analyzed genomic alterations of the ALCL and ATL cells using array comparative genomic hybridization. We found that the genomic alteration pattern differed between the two diseases. T-cell receptor clonality analysis using polymerase chain reaction (PCR) showed that the T-cell clone of the ATL was present in the lymph nodes with ALCL involvement, but not in peripheral blood. This finding suggests that lymph nodes can serve as a niche for ATL development.