Kentaro Yonekura

Clinical significance of serum Th1‐, Th2‐ and regulatory T cells‐associated cytokines in adult T‐cell leukemia/lymphoma: High interleukin‐5 and ‐10 levels are significant unfavorable prognostic factors

Patients with adult T‐cell leukemia/lymphoma (ATLL) are in a severely immunocompromised state. Therefore, it is assumed that ATLL cells either express particular cytokines or induce their expression in host immune cells, disrupting the balanced production of cytokines and causing the hosts immune system to break down. We examined the levels of serum cytokines including T helper type 1‐ (Th1‐) associated cytokines [IFN‐γ, TNF‐α, and interleukin (IL)‐2], Th2‐associated cytokines (IL‐4, ‐5 and ‐6) and regulatory T cell‐associated cytokines (IL‐10 and TGF‐β1) in 94 ATLL patients, 39 asymptomatic human T‐cell lymphotropic virus type‐1 (HTLV‐1) carriers and 50 healthy adult volunteers, to clarify whether elevated levels of particular cytokines are associated with the prognosis of ATLL patients. On multivariate analysis, high IL‐5 and IL‐10 levels were independent and significant unfavorable prognostic factors among the ATLL patients. The IL‐10 level significantly increased with disease progression at each step from asymptomatic HTLV‐1 carrier to ATLL of the indolent variant (chronic and smoldering subtypes) to ATLL of the aggressive variant (acute and lymphoma subtypes). Furthermore, high IL‐10 was significantly associated with high lactate dehydrogenase (LDH), indicating that the IL‐10 level reflects the tumor burden. The IL‐5 level was not associated with disease progression nor LDH. Among ATLL patients with the aggressive variant, high IL‐5, but not high IL‐10, was an independent and significant unfavorable prognostic factor on multivariate analysis. Measurement of serum IL‐5 and IL‐10 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.

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.

Guidelines for the management of cutaneous lymphomas (2011): A consensus statement by the Japanese Skin Cancer Society - Lymphoma Study Group

In 2010, the first Japanese edition of guidelines for the management of cutaneous lymphoma was published jointly by the Japanese Dermatological Association (JDA) and the Japanese Skin Cancer Society (JSCS) – Lymphoma Study Group. Because the guidelines were revised in 2011 based on the most recent data, we summarized the revised guidelines in English for two reasons: (i) to inform overseas clinicians about our way of managing common types of cutaneous lymphomas such as mycosis fungoides/Sézary syndrome; and (ii) to introduce Japanese guidelines for lymphomas peculiar to Asia, such as adult T‐cell leukemia/lymphoma and extranodal natural killer/T‐cell lymphoma, nasal type. References that provide scientific evidence for these guidelines have been selected by the JSCS – Lymphoma Study Group. These guidelines, together with the degrees of recommendation, have been made in the context of limited medical treatment resources, and standard medical practice within the framework of the Japanese National Health Insurance system.

Indication for random skin biopsy for the diagnosis of intravascular large B cell lymphoma.

Background: The use of random skin biopsy (RSB) to diagnose intravascular large B cell lymphoma (IVLBCL) has increased. Objective: To explore the indication for RSB to diagnose IVLBCL. Methods: We retrospectively evaluated the medical records of 18 Japanese adults who underwent RSB between January 2008 and December 2009. Results: A final diagnosis of IVLBCL was returned in 2 patients based on RSB findings and in 1 based on brain biopsy findings. All 3 patients manifested neurological symptoms, hematocytopenia, elevated levels of LDH and soluble interleukin-2 receptor (sIL-2R), and the absence of lymphadenopathy. Malignant lymphoma other than IVLBCL was diagnosed in 6 patients, and in 5 of 6 patients who underwent nodal or parenchymal biopsy diagnostic findings were made. Conclusion: Although RSB is useful for the early diagnosis of IVLBCL, careful selection of patients is necessary. In patients with neurological symptoms, hematocytopenia, elevated LDH and sIL-2R and no nodal involvement, RSB may be useful.

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.

Phase I/II study of the oral retinoid X receptor agonist bexarotene in Japanese patients with cutaneous T-cell lymphomas

Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)‐selective retinoid, were evaluated in Japanese patients with stage IIB–IVB and relapsed/refractory stage IB–IIA cutaneous T‐cell lymphomas (CTCL). This study was conducted as a multicenter, open‐label, historically controlled, single‐arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m2 for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m2 in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m2 met the response criteria using the modified severity‐weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose‐limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m2: two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m2 bexarotene. In the 13 patients at 300 mg/m2, common drug‐related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment‐related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m2 once daily and effective in Japanese patients with CTCL.

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

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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.

Sézary syndrome in an anti-human T-cell lymphotropic virus type 1 seropositive carrier

Dear Editor, An 84-year-old man, seropositive for human T-cell lymphotropic virus type 1 (HTLV-1), was referred to our clinic because of erythroderma (Fig. 1a,b). Multiple enlarged lymph nodes (≤2 cm) were palpable in the axilla and inguinal area. A skin biopsy specimen from his back showed perivascular infiltration of atypical lymphoid cells in the upper dermis (Fig. 1c, d). Immunohistochemical examination revealed that most cells were strongly CD3and CD4-positive with partial CD25 positivity, and a few were CD8(Fig. 1e–h) and CD20-positive. Inguinal lymph node biopsy showed dermatopathic lymphadenopathy. Serological tests using enzyme-linked immunoassay and western blotting yielded positive results for anti-HTLV-1 antibody. The leukocyte count was 10 023/lL, with 53% abnormal lymphoid cells with cerebriform nuclei, containing 84% CD4-positive cells, and the CD4/CD8 ratio was elevated (31). CD4CD7 and CD4CD26 cells constituted 90% and 93% of lymphoid cells, respectively. Southern blot analysis revealed a monoclonal T-cell receptor-Cb1 rearrangement in peripheral blood mononuclear cells (PBMC) but not in enlarged lymph nodes. Albumin-adjusted calcium (9.3 mg/dL) and blood urea nitrogen (21.9 mg/dL) were within normal limits. Serum lactate dehydrogenase and albumin levels were elevated (403 IU/L; normal, 124–222) and slightly below normal (3.9 g/dL; normal, 4.1–5.1), respectively. Serum soluble interleukin-2 receptor was elevated (2318 U/mL; normal, 127–582). On flow cytometry, CD4/CD25 double-positive cells comprised 44% of lymphoid cells, whereas the CD25 fluorescence intensity was medium (Fig. 1i), and cells positive for cell adhesion molecule 1, a cell surface marker for adult T-cell leukemia/lymphoma (ATLL), accounted for only 1% of lymphocytes. These findings excluded a diagnosis of ATLL. Furthermore, monoclonal HTLV-1 integration was not detected on Southern blot, and HTLV-1 proviral DNA copy number was 0.1/1000 PBMC. Therefore, we arrived at a diagnosis of S ezary syndrome (SS, T4N1M0B2, stage IVA1) in a HTLV-1 carrier without ATLL, and started treatment with 200 mg/day vorinostat, which was reduced to 100 mg after a month because of adverse effects such as fatigue, diarrhea and thrombocytopenia. Because the reduced-dose vorinostat showed limited effectiveness, the patient was started on bexarotene and his symptoms were well controlled at 24 months from his first visit. Distinguishing SS in HTLV-1 seropositive patients from ATLL with erythroderma is critical because, despite having similar clinical symptoms, they have markedly different prognosis and treatment strategies. With an ATLL diagnosis, the present case would have been classified as chronic type ATLL with poor prognosis; moreover, erythrodermic ATLL has poor outcomes. Hence, the patient would have been treated with combination chemotherapy with cytotoxic agents. In SS cases, chemotherapy decreases the median time to next treatment, and multi-agent chemotherapy often induces immunosuppression, increasing the risk of serious infection and poor tolerance. Therefore, chemotherapy should only be used when other treatment options have been tried and become ineffective. We were able to treat SS in this HTLV-1 seropositive patient successfully without combination chemotherapy. This case highlights the importance of the precise diagnosis of lymphoma in HTLV-1 seropositive patients by performing molecular biological examination to evaluate HTLV-1 monoclonal integration into the genomic DNA of host T cells.

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][⇓][