Kazunari Yamaguchi

VCAP-AMP-VECP Compared With Biweekly CHOP for Adult T-Cell Leukemia-Lymphoma: Japan Clinical Oncology Group Study JCOG9801

PURPOSE Our previous phase II trial for treating human T-lymphotropic virus type I-associated adult T-cell leukemia-lymphoma (ATLL) with vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), doxorubicin, ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin, and prednisone (VECP) showed promising results. To test the superiority of VCAP-AMP-VECP over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), we conducted a randomized controlled trial exclusively for ATLL. PATIENTS AND METHODS Previously untreated patients with aggressive ATLL were assigned to receive either six courses of VCAP-AMP-VECP every 4 weeks or eight courses of biweekly CHOP. Both treatments were supported with granulocyte colony-stimulating factor and intrathecal prophylaxis. RESULTS A total of 118 patients were enrolled. The complete response (CR) rate was higher in the VCAP-AMP-VECP arm than in biweekly CHOP arm (40% v 25%, respectively; P = .020). Progression-free survival rate at 1 year was 28% in the VCAP-AMP-VECP arm compared with 16% in the CHOP arm (P = .100, two-sided P = .200). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085, two-sided P = .169). For VCAP-AMP-VECP versus biweekly CHOP, grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 infection rates were 98% v 83%, 74% v 17%, and 32% v 15%, respectively. There were three toxic deaths in the VCAP-AMP-VECP arm. CONCLUSION The longer OS at 3 years and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggest that VCAP-AMP-VECP might be a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATLL.

Phase I Study of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients With Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma

PURPOSE KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design. RESULTS Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses. CONCLUSION KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.

Polycomb-Mediated Loss of miR-31 Activates NIK-Dependent NF-κB Pathway in Adult T Cell Leukemia and Other Cancers

Constitutive NF-κB activation has causative roles in adult T cell leukemia (ATL) caused by HTLV-1 and other cancers. Here, we report a pathway involving Polycomb-mediated miRNA silencing and NF-κB activation. We determine the miRNA signatures and reveal miR-31 loss in primary ATL cells. MiR-31 negatively regulates the noncanonical NF-κB pathway by targeting NF-κB inducing kinase (NIK). Loss of miR-31 therefore triggers oncogenic signaling. In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of Polycomb proteins contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-κB and apoptosis resistance. Furthermore, this emerging circuit operates in other cancers and receptor-initiated NF-κB cascade. Our findings provide a perspective involving the epigenetic program, inflammatory responses, and oncogenic signaling.

Variation in the clinical courses of adult T-cell leukemia

Twenty‐nine cases of adult T‐cell leukemia were classified into four types according to the clinical features and course: smoldering, chronic, crisis, and acute. Only 2 of 14 patients with the acute type responded to therapy. The four types showed apparent differences in clinical features, complications, and prognosis, suggesting the need for different therapeutic regimens. For smoldering and chronic cases, no chemotherapy is recommended. However, in crisis and acute cases, aggressive chemotherapy is necessary, although the acute type cases showed extremely poor prognosis despite the most aggressive chemotherapy.

Human T-lymphotropic virus type I in Japan

Adult T-cell leukaemia (ATL) was first reported in Japan, where it has a high incidence in the southwest region. The retrovirus human T-lymphotropic virus type I (HTLV-I) is the cause of ATL; and in ATL-endemic areas, the rate of carriage of antibodies to HTLV-I is high. A definite diagnosis of ATL is based on the presence of HTLV-I proviral DNA in the tumour-cell DNA. ATL cells originate from the CD4 subset of peripheral T cells. ATL shows diverse clinical features but can be divided into four subtypes--acute, chronic, smouldering, and lymphoma type. It is resistant to chemotherapy, and the acute and lymphoma types have a poor prognosis. Familial occurrence of ATL is common. HTLV-I infection is caused by transmission of live infected lymphocytes from mother to child, from man to woman, or by transfusion. Infection with HTLV-I can lead to other diseases, including HTLV-I-associated myelopathy/tropical spastic paraparesis and HTLV-I uveitis, possibly via induction of immunodeficiency or hyperreactivity against HTLV-I-infected cells.

5'-long terminal repeat-selective CpG methylation of latent human T-cell leukemia virus type 1 provirus in vitro and in vivo.

ABSTRACT CpG methylation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat (LTR) has been implicated in proviral latency, but there is presently little information available regarding the pattern of LTR methylation and its effect on viral gene expression. To gain insight into the mechanisms of HTLV-1 latency, we have studied methylation of individual CpG sites in the U3-R region of the integrated proviral LTR by using bisulfite genomic sequencing methods. Surprisingly, our results reveal selective hypermethylation of the 5′ LTR and accompanying hypomethylation of the 3′ LTR in both latently infected cell lines and adult T-cell leukemia (ATL) cells having a complete provirus. Moreover, we observed a lack of CpG methylation in the LTRs of 5′-defective proviruses recovered from ATL samples, which is consistent with the selective hypomethylation of the 3′ LTR. Thus, the integrated HTLV-1 provirus in these carriers appears to be hypermethylated in the 5′ LTR and hypomethylated in the 3′ LTR. These results, together with the observation that proviral gene expression is reactivated by 5-azacytidine in latently infected cell lines, indicate that selective hypermethylation of the HTLV-1 5′ LTR is common both in vivo and in vitro. Thus, hypermethylation of the 5′ LTR appears to be an important mechanism by which HTLV-1 gene expression is repressed during viral latency.

Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan

Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL.

Uveitis Associated With Human T-cell Lymphotropic Virus Type I

Seroepidemiologic, clinical, and virologic studies were performed to determine whether human T-cell lymphotropic virus type I was closely associated with uveitis in two hospitals. One hospital was in an endemic area of the virus (Miyakonojo, Miyazaki) and the other hospital was in a less endemic area (Kurume). In the endemic area, the seroprevalence of the virus in patients with uveitis without defined causes (35.4%, 62 of 175 patients) was significantly higher than that in patients with nonuveitic ocular diseases (16.1%, 42 of 261 patients), or in patients with uveitis with defined causes (10.3%, eight of 78 patients). The seroprevalence in younger patients (20 to 49 years of age) with uveitis without defined causes in the area was 44.8% (30 of 67 patients), whereas it was only 9.3% (ten of 107 patients) in the other two groups. A similar observation was recorded even in the less endemic area (Kurume). Because the seroprevalence of the virus in the general population is known to be low in younger patients and to increase with age, these findings were interpreted to indicate that the association of human T-cell lymphotropic virus type I with uveitis was significant. Most patients, particularly those aged 20 through 49 years, had an intermediate uveitis characterized by a moderate inflammation in the vitreous body accompanied by an iritis and retinal vasculitis. The ocular symptoms in the patients differed from those of other types of uveitis common in Japan (Behçets disease, Vogt-Koyanagi-Haradas disease, and toxoplasmosis, for example).(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary complications in patients with adult T-cell leukemia

A survey of 360 patients with various hematologic diseases revealed a high frequency of respiratory complications in patients with adult T‐cell leukemia (ATL) compared to others. Among 29 patients with ATL, pulmonary complications were seen in 26 patients; leukemic pulmonary infiltration in 13, bleeding in 1, interstitial pneumonitis in 1, and pulmonary infection in 13. The incidence of Pneumocystis carinii and bacterial pneumonias were high despite adequate neutrophil count. Even in chronic and smoldering ATL, respiratory diseases were found in high frequency. Many of those were leukemic cell infiltration. In ten of 13 patients with pulmonary infiltration it occurred in the early stage and 6 of them were diagnosed as having “chronic lung disease” before the diagnosis of ATL. Its histology was accompanied by fibrosis in greater or lesser degree in almost all cases. Transbroncheal lung biopsy (TBLB) is of value in diagnosis (8 of 13 cases).

Human T lymphotropic virus type-I and adult T-cell leukemia in Japan.

HTLV-I is the first retrovirus to be associated directly with human malignancy. In ATL-endemic areas, the rate of HTLV-I carriers is high. Both HTLV-I and ATL have been shown to be endemic in some regions of the world, especially in southwest Japan, the Caribbean islands, South Americas, and parts of Central Africa. Antibodies against HTLV-I have been found in over one million individuals, and more than 700 cases of ATL have been diagnosed each year in Japan alone. The cumulative incidence of ATL among HTLV-I carriers in Japan is estimated at 2.5% (3–5% in males, 1–2% in females). In endemic areas, HTLV-I Ab were found in the sera of 6 to 37 percent of healthy adults over 40 years of age. This clustering is thought to be due to the limited transmission of virus between socially isolated populations. The diagnostic criteria for HTLV-I associated ATL have been defined as follows. 1) Histologically and/or cytologically proven lymphoid malignancy with T cell antigens. 2) Abnormal T-lymphocytes present in the peripheral blood, except in the lymphoma type. 3) Serum specimens for all patients with ATL have HTLV-I Ab. 4) Demonstration of clonality of HTLV-I proviral DNA is a definite diagnosis of ATL. ATL shows diverse clinical features but can be divided into four subtypes: acute, chronic, smoldering, and lymphoma type. The pattern of HTLV-I transmission is through one of three different modes. Infected mothers can transmit the virus to newborns mainly via breast milk. The virus also can be transmitted from male to female by sexual intercourse, and through blood transfusion. Chemotherapy is not effective; the acute and lymphoma types have a poor prognosis. ATL is generally treated with curative intent using combination chemotherapy, although long-term success has been very limited. Unfortunately that advance did not translate into an improvement in the overall survival; the median remain 10 months. In contrast, smoldering ATL, or some cases of chronic ATL, may have a more protracted natural course, which may be compromised by aggressive chemotherapy. Alternative strategies for both acute and chronic forms are clearly needed. After infection of HTLV-I, there is a long latent period before onset of ATL. Analyses by PCR showed that clearly proliferation occurred in intermediate state or even carriers with high virus load. Such clonal proliferation might be preleukemic stage, which suggested that carriers with high virus load should be risk group to have ATL.