Shuichi Hanada

A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma : Japan Clinical Oncology Group Study 9303

This phase II trial was performed to evaluate the efficacy of a new granulocyte colony‐stimulating factor (G‐CSF)‐supported multi‐agent chemotherapy protocol, LSG15, for aggressive adult T‐cell leukaemia‐lymphoma (ATL). Ninety‐six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP (vincristine, cyclophosphamide, doxorubicin and prednisone), AMP (doxorubicin, ranimustine and prednisone) and VECP (vindesine, etoposide, carboplatin and prednisone). G‐CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty‐one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71·1–88·1%], with 33 patients obtaining complete response (35·5%) and 42 obtaining partial response (45·2%). The median survival time (MST) after registration was 13 months and the median follow‐up duration of the 20 surviving patients was 4·2 years (range 2·8–5·6). Overall survival at 2 years was estimated to be 31·3% (95% CI, 22·0–40·5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65·3% and 52·6% of the patients respectively, but grade 4 non‐haematological toxicity was observed in only one patient. LSG15 is feasible with mild non‐haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.

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.

Expression of the multidrug transporter, P-glycoprotein, in acute leukemia cells and correlation to clinical drug resistance

The overexpression of a cell‐surface glycoprotein termed P‐glycoprotein (P‐gp) is frequently associated with multi‐drug resistance (MDR) in cell lines in vitro. To evaluate the implications of P‐gp expression in clinical drug resistance, the authors examined the expression of P‐gp in leukemia cells from patients with acute myelogenous leukemia (AML) and those with acute lymphoblastic leukemia (ALL) at initial presentation and relapse, using immunoblotting with a monoclonal antibody against P‐gp, C219. Nine of 17 patients with AML and four of 11 patients with ALL had P‐gp‐positive results at the initial presentation, and most P‐gp‐positive patients did not respond to chemotherapy. Four of seven patients at the relapsed stage and all three patients with preceding myelodysplastic syndrome had P‐gp‐positive results. The expression of P‐gp and clinical refractoriness to chemotherapy were highly correlated. These data indicate that the expression of P‐gp is closely related to clinical drug resistance in acute leukemia.

Prognostic Index for Acute- and Lymphoma-Type Adult T-Cell Leukemia/Lymphoma

PURPOSE 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). PATIENTS AND METHODS 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. RESULTS 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). CONCLUSION The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.

Expression of the multidrug transporter, P‐glycoprotein, in chronic myelogenous leukaemia cells in blast crisis

The overexpression of a cell‐surface glycoprotein termed P‐glycoprotein (P‐gp) is frequently associated with multidrug resistance (MDR) in cell lines in vitro. To evaluate the implications of P‐gp expression in clinical drug‐resistance, we examined the expression of P‐gp in fresh leukaemia cells from chronic myelogenous leukaemia (CML) patients in blast crisis. By using immunoblotting with a monoclonal antibody against P‐gp, C219, we showed that leukaemia cells from three CML patients in blast crisis were P‐gp negative at the stage when these patients were in complete remission, and that the cells showed high levels of P‐gp expression at times when the same patients had relapsed and had not responded to chemotherapy. Six out of 11 patients (nine in the refractory state) were P‐gp positive and they rarely responded to chemotherapy. These data suggest that the expression of P‐gp is closely associated with drug‐resistance in CML.

HLA-A*26, HLA-B*4002, HLA-B*4006, and HLA-B*4801 Alleles Predispose to Adult T Cell Leukemia: The Limited Recognition of HTLV Type 1 Tax Peptide Anchor Motifs and Epitopes to Generate Anti-HTLV Type 1 Tax CD8+ Cytotoxic T Lymphocytes

Genetic risk for adult T cell leukemia (ATL) has been implicated by ethnic and familial segregation of ATL patients from HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To clarify the genetic risk for ATL, we characterized HLA class I alleles of ATL patients and analyzed the anchor motifs of HTLV-1 peptides binding to HLA class I molecules, using 291 lines of anti-HTLV-1 CD8(+) cytotoxic T lymphocytes (CTLs) generated in vitro with a total of 165 synthetic peptides for HTLV-1 Tax and Env proteins. Allele frequencies of HLA-A*26, B*4002, B*4006, and B*4801 were significantly higher in ATL patients than in HAM/TSP patients and asymptomatic HTLV-1 carriers in southern Japan. CD8(+) CTL analysis revealed the HTLV-1 Tax peptide sequence to completely lack anchor motifs of peptides binding to HLA-A*26,B*4002, and B*4006 molecules but to possess one anchor for HLA-B*4801, while the HTLV-1 Env peptide sequence had many anchor motifs for HLA-A*26, B*4002, B*4006, and B*4801 molecules. Most ATL patients featured heterozygous HLA class I alleles composed of HLA-A*26, B*4002, B*4006, and B*4801, with a lower number of HTLV-1 Tax peptide anchor motifs and epitopes generating anti-HTLV-1 Tax CD8(+) CTLs than individuals possessing other HLA alleles. The relationship between Tax epitope and ATL incidence was verified by the significantly decreased number of HTLV-1 Tax epitopes in ATL patients compared with asymptomatic HTLV-1 carriers (p < 0.01) as well as late onset ATL patients (p < 0.001). These results indicate that HLA-A*26, B*4002, B*4006, and B*4801 alleles predispose to ATL because of the limited recognition of HTLV-1 Tax peptide anchor motifs and epitopes capable of generating anti-HTLV-1 Tax CD8(+) CTLs.

Arsenic trioxide inhibits growth of human T-cell leukaemia virus type I infected T-cell lines more effectively than retinoic acids.

Adult T‐cell leukaemia (ATL) is difficult to cure using conventional therapies. Recently the therapeutic possibility of retinoic acids (RA) has been reported. In this study, suppression of in vitro growth of human T‐cell leukaemia virus type I (HTLV‐I) infected T‐cell lines and fresh ATL cells by arsenic trioxide (As2O3) were evaluated by comparison with a series of RA derivatives. Proliferation of four HTLV‐I‐infected T‐cell lines was significantly reduced within 72 h by 1.0 μmol/l As2O3. Growth of two out of four HTLV‐I‐infected T‐cell lines was also inhibited by 1.0 μmol/l RA, but to a lesser extent than by As2O3. The mechanism of this growth inhibition was due to the induction of apoptosis. Apoptosis was also induced in fresh ATL cells from patients by As2O3, but far less by RA. As described in patients with acute promyelocytic leukaemia, 1.0 μmol/l of As2O3 can be safely achieved in the serum of patients; however, it is difficult to maintain this concentration of RA. In conclusion, As2O3 has therapeutic potential for the treatment of ATL and may be far more clinically beneficial than RA.

The prevalence of human T-cell leukemia virus type I infection in patients with hematologic and nonhematologic diseases in an adult T-cell leukemia-endemic area of Japan

In order to clarify the prevalence of human T‐cell leukemia virus type I (HTLV‐I) infection in the Kagoshima district, Japan, a highly endemic area for HTLV‐I, antibodies for HTLV‐I (anti‐HTLV‐I) were examined in the sera of 6167 from healthy residents and patients with various hematologic and nonhematologic diseases. In healthy residents, including blood donors, the prevalence of anti‐HTLV‐I was 11.9% (562/4741 persons). The prevalence increased with age, and was significantly higher in females than in males (P < 0.01). The prevalence of anti‐HTLV‐I in blood donors was 8.5%. In hematologic diseases, the prevalence of anti‐HTLV‐I was 98.3% in ATL, 28.9% in lymphoproliferative disorders except ATL, and 10.6% in myeloproliferative disorders. In nonhematologic diseases, the prevalence of anti‐HTLV‐I was shown to be 29.5% in pulmonary tuberculosis, 25.8% in leprosy, 33.8% in chronic renal failure (CRF), 21.9% in autoimmune diseases, and 47.8% in strongyloidiasis. The various diseases except myeloproliferative disorders had significantly higher prevalence of anti‐HTLV‐I than healthy residents (P < 0.01 or 0.05). For autoimmune diseases, the prevalence of anti‐HTLV‐I in patients with blood transfusion (55.6%) was higher than in those without blood transfusion (8.7%), and healthy residents. In hemodialysis patients with CRF who had received blood transfusions the prevalence of anti‐HTLV‐I increased with the number of blood transfusions. Therefore, HTLV‐I transmission via blood transfusion would partially explain these high prevalence of anti‐HTLV‐I. However, the prevalence of anti‐HTLV‐I in hemodialysis patients with CRF was statistically higher than that in healthy residents, regardless of blood transfusion (P < 0.01). Furthermore, hemodialysis patients showed significantly higher prevalence of anti‐HTLV‐I than healthy residents, even at a younger age. Patients with pulmonary tuberculosis and leprosy showed the same results as hemodialysis patients. These results suggest the possibility that HTLV‐I infection has some relation not only to ATL but also to other diseases. Therefore, it seems very important to halt the spread of HTLV‐I transmission as soon as possible.

Adult T-cell leukemia with leukemia cell infiltration into the gastrointestinal tract

Five cases of untreated adult T‐cell leukemia (ATL) with leukemia cell infiltration into the gastrointestinal (GI) tract were reported. X‐ray findings of the GI tract showed diffuse abnormal mucosal patterns throughout the GI tract in all five patients. Endoscopic findings corresponded well with the x‐ray findings. Pathologic examination of biopsied specimens from all five patients revealed diffuse and extensive leukemic infiltration into the stomach and/or the large intestine.