Hiroo Katsuya

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.

Addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy has a high risk of developing interstitial pneumonia in patients with non-Hodgkin lymphoma

There are a few reports suggesting that rituximab (RTX) might be a risk for interstitial pneumonitis (IP). We also experienced such patients in the era of RTX. Here, we reviewed all the patients with non-Hodgkin lymphoma who were treated with RTX-CHOP-like regimen (R-CHOP) to determine the risk of developing IP. One of 59 (1.7%) patients who received CHOP alone and 8 of 129 (6.2%) patients who were treated with R-CHOP experienced IP (p = 0.28). Furthermore, three of eight patients who have had IP during R-CHOP were confirmed having Pneumocystis jirovecii pneumonia (PCP). PCP occurred during the fourth, sixth, and seventh cycle of chemotherapy, respectively. Among the patients treated by R-CHOP, 3 of 32 (9%) patients whose lymphocyte counts were <1000/μL before chemotherapy developed PCP, while 70 patients whose lymphocyte counts were >1000/μL did not (p = 0.03). In four of eight patients, IP occurred during the administration of granulocyte-colony stimulating factor. RTX seems to have a certain risk to induce IP including PCP. Patients with lymphoma who were treated by R-CHOP regimen, might be considered as PCP prophylactic, especially if the number of lymphocytes is low at the beginning of chemotherapy.

Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: in vitro and in vivo effects of the novel Bcl-2 family inhibitor ABT-737.

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). ABT-737, a small molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, significantly induced apoptosis in HTLV-1 infected T-cell lines as well as in fresh ATLL cells, and synergistically enhanced the cytotoxicity and apoptosis induced by conventional cytotoxic drugs. Moreover, ABT-737 significantly inhibited the in vivo tumor growth of an ATLL mouse model. These results suggest that the use of an agent targeting anti-apoptotic bcl-2 family proteins, either alone or in combination with other conventional drugs, represents a novel promising approach for ATLL.

A patient with acute myeloid leukemia who developed fatal pneumonia caused by carbapenem-resistant Bacillus cereus

Bacillus cereus is known as a serious bacterial pathogen in neutropenic patients. B. cereus is often resistant to β-lactams, including penicillins and cephalosporins. We report a case of fatal pneumonia caused by B. cereus in a patient with newly diagnosed acute myeloid leukemia (AML) during remission induction therapy. Cefepime was started for febrile neutropenia (FN) initially and was switched to panipem/betamipron, when fulminant pneumonia supervened. The isolated strain was resistant not only to cefepime but also to panipenem/betamipron. This is the first report of fulminant infection caused by carbapenem-resistant B. cereus in a neutropenic patient. B. cereus should be kept in mind as a target of empirical treatment when neutropenic patients develop pneumonia

A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma.

Adult T‐cell leukemia/lymphoma (ATL) is a malignancy of peripheral T‐lymphocytes with a poor prognosis. This multicenter, two‐stage, single‐arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression‐free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17‐31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression‐free survival (PFS) was 38 (95% CI; 18–106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (II): apoptosis of antiproliferactive principle (24,25-dihydrowithanolide D) against ATL cell lines and structure–activity relationships with withanolides isolated from solanaceous plants

Adult T-cell leukemia/lymphoma (ATL) is an incurable peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I. In our preceding paper, 214 extracts from 162 plants were screened to elucidate the antiproliferative principles against ATL cell lines. Several withanolides were isolated and the structure–activity relationships (SAR) examined. To extend the search for SAR, 31 further withanolides, previously isolated from solanaceous plants, were tested against ATL cell lines. The presence of a 4β-hydroxy group as well as a 5β,6β-epoxy group appeared to be essential for the activity. In contrast, the presence of a sugar moiety at either the 3- or the 27-position led to a reduction in the activity. Furthermore, 24,25-dihydrowithanolide D (13) was identified as the most potent inhibitor, showing selective toxicity against ATL cell lines by inducing apoptotic cell death.

Interferon-α and zidovudine for relapsed/refractory adult T cell leukemia/lymphoma: case reports of Japanese patients

Combination therapy with interferon-α and zidovudine (IFN/AZT) has been regarded as standard care for acute and indolent (i.e., chronic and smouldering) ATL based on reports involving a limited number of patients. This treatment approach has not been evaluated in Japan, a major endemic area of this disease in the world. This is the first Japanese report of IFN/AZT for ATL. It is impossible to draw any definitive conclusion from this small study; however, IFN/AZT showed clear anti-ATL effects for refractory/relapsed ATL patients. This report would contribute for developing future ATL treatment in Japan.

FoxP3-positive T cell lymphoma arising in non-HTLV1 carrier: clinicopathological analysis of 11 cases of PTCL-NOS and 2 cases of mycosis fungoides.

Forkhead box protein 3‐positive (FoxP3+) T cell lymphoma, in the absence of human T cell lymphotrophic virus type 1 (HTLV‐1) infection, is rare and its clinicopathological characteristics still remain unclear. The aim of this study was to elucidate its characteristics.

Reply to J.J. Castillo et al

We thank Castillo and Beltran for their comments regarding our work and are pleased to have this opportunity to address their interest in the evaluation of the adult-T cell leukemia/lymphoma (ATL) prognostic index (PI) separately for patients with acute-type versus lymphoma-type ATL. Intheircorrespondence,Castilloetal describedtheclinical, genetic, and pathophysiologic differences between acuteand lymphoma-type ATL. We completely agree with their descriptions. Combination therapy with interferon alfa and zidovudine, which is one of the standard treatments outside of Japan, has been reported to be more effective against acute-type ATL than conventional chemotherapy, but ineffective against lymphoma-type ATL. Moreover, a recent study reported that the genetic differences between acuteand lymphoma-type ATL are acquired by clonal evolution in the lymph nodes. It remains to be determined whether the genetic alterations that have been observed in ATL cells have significant influence on the clinical outcomes of patients with ATL, or whether these alterations should be taken into consideration when tailoring therapy to individual patients. In our study, we attempted to establish an ATL-PI that is applicable to both acuteand lymphoma-type ATL, given that the subtypes have not been considered separately when determining therapeutic options in Japan, and also to make a simple PI that can be applied easily in clinics. Consistent with previous reports, in our study, patients with acute-type ATL (n 564) showed worse median overall survival time than patients with lymphoma-type ATL (n 243): 6.9 months (95% CI, 6.2 to 7.8 months) and 9.9 months (95% CI, 8.1 to 11.3 months), respectively (P .001). Application of the ATL-PI to each subtype revealed median overall survival times for acute-type ATL of 4.3 (95% CI, 3.3 to 5.1), 7.3 (95% CI, 6.5 to 8.4), and 15.7 (95% CI, 13.9 to 23.2) months for patients at high, intermediate, and low risk, respectively, whereas those for lymphoma-type ATL were 3.6 (95% CI, 1.5 to 4.7), 9.0 (95% CI, 7.4 to 11.1), and 14.0 (95% CI, 12.4 to 17.2) months, respectively. The three risk groups according to the ATL-PI were thus effectively prognostic both in acute-type (P .001 by log-rank test with 2 df) and lymphoma-type (P .001 by log-rank test with 2 df) ATL. In conclusion, ATL-PI is a PI for patients with aggressive ATL, and it is applicable for both acute and lymphoma types separately. We believe ATL-PI is a promising tool for risk stratification. We hope that it will be validated internationally in studies that include patients treated with a combination of interferon alfa and zidovudine.

Abstract 4524: Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: in vitro and in vivo effects of a novel Bcl-2 family inhibitor, ABT-737

Adult T-cell lymphoma/leukemia (ATLL) is a T-cell malignancy caused by the human T-lymphotrophic virus type I (HTLV-I), and its therapeutic outcome still remains extremely poor. Therefore, novel therapeutic strategies are needed to improve treatment outcomes. In this study, we elucidated the therapeutic potential of targeting the anti-apoptotic Bcl-2 family proteins for the treatment of ATLL using ABT-737 (Abbott Laboratories, Abbott Park, IL, USA), a small molecule inhibitor of Bcl-2, Bcl-X L and Bcl-w. We first validated the rationale of this study by immunohistochemically assessing the expression of Bcl-2 family proteins in 25 lymph-node specimens derived from ATLL patients. The Bcl-2 and/or Bcl-X L proteins were expressed in 80% of specimens. We next examined the cytotoxicity of ABT-737 against three ATLL cell lines by the Colorimetric method. ABT-737 significantly inhibited growth of MT-1, MT-2 and HuT 102 cells with concentrations of 50 percent inhibition of 2.4, 0.23 and 0.008μM at 72 h, respectively. We then tried to clarify the mechanism of growth inhibition induced with ABT-737 using MT-1 and MT-2 cells. ABT-737 induced apoptosis in both cells with cleavage of caspases 9 and 3, and PARP. ABT-737 also induced apoptosis in fresh tumor cells derived from patients with ATLL. We also tested if ABT-737 enhances the cytotoxicity induced by conventional chemotherapeutic agents or novel agents. The interactions between them were evaluated using the Chou-Talalay method. ABT-737 synergistically enhanced the cytotoxicity and apoptosis induced by doxorubicin, vincristine or etoposide and bortezomib or suberolyanilide hydroxamic acid, which are current key drugs and promising candidates for the treatment of ATLL, respectively. Finally, we investigated the growth inhibition of ABT-737 in ATLL-xenografted mice. The mean tumor volume and weight, and mean serum level of soluble interleukin-2 receptor α at day 21 of the treated mice with ABT-737 (100mg/kg/day) were significantly lower than those of vehicle-treated mice. Moreover, massive induction of apoptosis was observed in tumors treated with ABT-737 by the TUNEL assay. These results suggest that the use of ABT-737, either alone, or in combination with other conventional cytotoxic and novel drugs, represents a promising novel targeted approach to overcome drug resistance and to improve patient outcome in ATLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4524.