Ayumu Kubota

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.

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.

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.

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.

Cutaneous adverse reactions and anti-tumor effects of anti-CCR4 monoclonal antibody (mogamulizumab) on adult T-cell leukemia-lymphoma

The novel defucosylated humanized monoclonal antibody against CC chemokine receptor 4 (CCR4), mogamulizumab, exhibited strong effects on adult T-cell leukemia-lymphoma (ATL) in a phase II clinical study. It has been also reported that mogamulizumab frequently developed cutaneous adverse reactions (CAR) and a close association between CAR and the prognosis. [1] We studied the effects of mogamulizmab on ATL and CAR in 32 patients with ATL. Informed consent was obtained prior to study. Nineteen patients received more than 4 cycles of mogamulizumab therapy. Twenty patients developed an infusion reaction, and eight patients suffered from CAR. These eight patients were administered mogamulizumab more than 4 cycles (median: 7 cycles). The severity of CAR according to CTCAE v3.0 was grade 1 in one patient, 2 in two, 3 in three and 4 in two patients respectively. In six of 8 patients, CARs appeared or most worsened in more than 4 weeks after the last administration. All CARs fortunately subsided later. One patient, however, suffered from toxic epidermal necrolysis and other CARs (erythroderma and generalized exudative erythema in two each patients) prolonged for several months. As for anti-tumor effects with more than 4 cycles of treatments, overall response rate (complete remission (CR) and partial remission (PR)) was 58% (CR: 6, progressive disease (PD): 2) with CAR, and 36% (CR:3, PR:1, stable disease (SD):4, PD:3) without CAR. These results suggest that 1) the incidence of CAR were associated with the frequency of mogamulizumab administration, 2) CARs might be favorable signs of the effect, and 3) follow-up with careful attention to CAR was recommended for at least several months after the finish of treatments.

Chronic type adult T-cell leukemia-lymphoma after autolougous stem cell transplantation for ALK-negative anaplastic large cell lymphoma

An adult male patient was admitted to our hospital with systemic lymphadenopathy. He was diagnosed as having ALK-negative anaplastic large cell lymphoma (ALCL) by lymph node biopsy. Immunohistochemical staining revealed positive reaction for CD4, CD30, CD25, TIA-1, and Granzyme B, but negative for ALK and EBER. Although anti-HTLV-1 antibody in his serum was positive, monoclonal integration of HTLV-1 provirus DNA was not detected in his lymph node by Southern blot analysis. He was treated by combination chemotherapy, and complete remission was obtained by 8 courses of CHOP therapy. Subsequently he received autologous stem cell transplantation (auto-SCT). Fifteen months after auto-SCT, abnormal lymphocytes in the peripheral blood gradually increased. Southern blot analysis of abnormal lymphocytes revealed monoclonal integration of HTLV-1 provirus DNA and monoclonal rearrangement of T-cell receptor b. The patient was therefore diagnosed as chronic type of adult T-cell leukemia-lymphoma (ATL), and immediately progressed to acute type with central nervous system involvement. He died of tumor progression regardless of intensive chemotherapy. We analyzed genomic alterations of the ALCL cells and the chronic type ATL cells using high-resolution array comparative hybridization. These results revealed that the genomic alteration pattern of ALCL was different from those of the chronic type. Chronic type ATL cells had the genetic alterations such as 1q gain and CD58 loss that were frequently observed in acute type ATL than the chronic type, suggesting that these genetic events might contribute to the transformation of this case. TCR rearrangement analyses using PCR were performed for the tumor cells of ALCL and ATL to evaluate the origin of these tumor cells. Results showed that tumor cell clone of the ATL might have already proliferated in ALCL lymph node. This finding suggests that lymph nodes can serve as a niche for ATL development.

Presence of cutaneous lesion is a poor prognostic factor in patients with smoldering-type adult T-cell leukemia-lymphoma

Background Prognosis of indolent types of adult T-cell leukemialymphoma (ATL) including the smoldering type was recently reported to be poorer than that shown in previous studies. Prognostic factors of smoldering-type ATL have not been defined. Cutaneous-type, which is defined as cases of smoldering type predominantly involve skin with or without peripheral blood involvement has been proposed as a distinct clinical subtype. Prognosis of cutaneous-type ATL was reported to be poorer than that of smoldering-type without cutaneous involvement. Aim To determine prognostic factors for survival and disease progression of smoldering-type ATL. Patients Thirty-one patients with smoldering-type ATL including 21 with cutaneous lesion. Methods Multivariate Cox proportional hazards model was used to identify variables associated with survival and disease progression. Peripheral blood abnormal lymphocytes (<5% vs ≥5%), serum lactate dehydrogenase (normal vs high), albumin level (<4 vs ≥4 g/dl), and cutaneous lesion (none vs present) were used as variables. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Results In the multivariate analysis, presence of cutaneous lesion was the significant prognostic factor for PFS (hazard ratio, 8.69; 95% confidence interval, 1.4-54.0; P = 0.02). Peripheral blood abnormal lymphocytes, serum lactate dehydrogenase, or albumin level was not significant. None of the variables was significantly associated with OS in the multivariate analysis. OS (P = 0.117) and PFS (P = 0.089) of the patients with cutaneous lesion were worse as compared to those of the patients without cutaneous lesion, though statistically not significant. Conclusions In this study we confirmed that presence of cutaneous lesion is an independent prognostic factor in patients with smoldering-type ATL. Cases of smoldering-type with cutaneous lesion should be classified as cutaneous-type ATL irrespective of the peripheral blood involvement.