Chemotherapeutic results and prognostic factors of patients with advanced non-Hodgkin's lymphoma treated with VEPA or VEPA-M

One hundred sixty-three patients with advanced non-Hodgkin's lymphoma including adult T cell leukemia/lymphoma (ATL) were treated from 1981 to 1983 with VEPA (vincristine, cyclophosphamide, prednisolone, and doxorubicin) or VEPA-M (VEPA plus methotrexate) in randomized fashion after stratification by surface marker. The complete response (CR) rate and the 4-year survival rate of patients treated with VEPA-M was 62.2% and 36.9%, respectively, while for those treated with VEPA the rates were 51.9% and 26.6, respectively. The difference was not statistically significant, but pretreatment characteristics predictive for response and survival were interesting. Three factors, leukemic change, poor performance status (PS), and T cell marker, were negatively associated with both CR and survival rates, and high-grade pathology was adversely associated with survival rate in a multivariate analysis. These prognostic factors are somewhat different from those in Western lymphomas. This may be reflection of major differences in patients' characteristics between Japanese and Western lymphomas: in this study, there was a high incidence of T cell lymphoma/leukemia (50%) including ATL (33%), leukemic manifestation (34%), poor PS (34%), and a low incidence of follicular lymphoma (9%). The statistically significant three factors for both CR and survival rates were used to construct a model containing eight categories of patients at increasing risk for poor response and shortened survival. These categories were divided into four groups, with respective CR and 4-year survival rates of 91% and 73%, 67% and 35%, 27% and 7%, and 10% and 5%. Ninety-three patients in whom CR was induced by VEPA or VEPA-M therapy were evaluated for prognostic factors predictive for disease-free survival. A shorter period (less than 28 days) required to achieve CR, a clinical diagnosis of ATL, and a lower hemoglobin level were found to affect disease-free survival adversely. These results have important implications for both the design of prospective randomized therapeutic trials and the determination of optimal therapy for individual patients.     

Comparison of CHOP versus VEPA Therapy in Patients with Lymphoma Type of Adult T-cell Leukemia

Forty-six Japanese patients with lymphoma type of adult T-cell leukemia (ATL) were treated with one of the 4-drug combinations, CHOP or VEPA regimen. Fourteen patients were treated with CHOP, while 32 were treated with VEPA. The complete response i(CR) rate and the 5-year survival rate of patients treated with CHOP were 35.7% and 7.1%, respectively, while for those treated with VEPA the rates were 43.8% and 18.7%, respectively. Only two patients treated with CHOP survived for more than 1 year, while the others died within 1 year. On the other hand, 13 patients treated with VEPA survived for more than 1 year. The 32 VEF'A-treated patients were divided into two groups according to the duration of survival: (A) 13 surviving for more than 1 year, and (B) 19 surviving for less than 1 year. They were compared for pretreatment characteristics. The differences between the two groups related to hepatomegaly, the presence of B symptoms, lactic dehydrogenase (LDH) and calcium levels. The results indicate that these factors are important in predicting the response and survival of patients with lymphoma type of ATL.     

Combination chemotherapy with adriamycin, cyclophosphamide, vincristine, prednisolone (VEPA) in non-Hodgkin's lymphoma, with special reference to correlation of surface phenotype with response and survival

Thirty-seven previously untreated patients with advanced non-Hodgkin's lymphoma were treated with VEPA therapy. The complete remission (CR) rate was higher in the patients with diffuse B-cell lymphoma (75%) than in those with follicular B-cell lymphoma (20%) and T-cell lymphoma (42%). Two characteristics, i.e., elevated LDH and bone marrow involvement, were negatively associated with response rate in patients with diffuse lymphoma (B-, T-). The median duration of CR has not yet been reached, and the 2-year relapse-free rate was 64% for cases of diffuse B-cell lymphoma, while for T-cell lymphoma patients, the median duration of CR was 7 months. For diffuse B-cell lymphoma patients, the median survival has not yet been reached, and the 2-year survival rate was 57%. On the other hand, median survival for T-cell lymphoma patients was 12 months. VEPA therapy was less effective for the treatment of T-cell lymphoma, and a more intensive regimen should therefore be designed to overcome the potential aggressiveness of T-cell lymphoma.     

Differences in prognostic factors between leukemia and lymphoma type of adult T-cell leukemia

Prognostic factors affecting the survival of adult T-cell leukemia (ATL) patients were analyzed in three groups: total cases, leukemia type cases, and lymphoma type cases. Factors found to be important overall, i.e. for total cases, were leukocyte count, ATL cell ratio in the peripheral blood, serum calcium levels and lactate dehydrogenase (LDH) level. Of those, LDH level proved not significant when evaluated separately for leukemia type or lymphoma type cases. Leukocyte count and ATL cell ratio were significant in leukemia type patients, whereas it was serum calcium level that was significant in lymphoma type; there were mutually exclusive sets of factors for the two groups. Thus, prognostic factors for ATL patients should be considered separately for each type of the disease.     

Major Prognostic Factors of Adult Patients with Advanced B-Cell Lymphoma Treated with Vincristine, Cyclophosphamide, Prednisone and Doxorubicin (VEPA) or VEPA plus Methotrexate (VEPA-M)

Eighty-two adult patients with advanced B-lymphoma, treatedbetween 1981 and 1983 with VEPA (vincristine, cyclophosphamide,prednisolone and doxorubicin) or VEPA-M (VEPA plus methotrexate)in a prospective randomized fashion, were evaluated for pretreatmentcharacteristics. The overall complete response (CR) and the4-year survival rates were 74% and 45%, respectively. The relapserate was 51%. Stage of disease only was negatively associatedwith the CR rate in a multivariate analysis. The primary extranodaltumor site other than upper gastrointestinal (GI) tract andhigh grade pathology were found to affect disease-free survivaladversely in a Cox proportional hazards model. Poor performancestatus, advanced stage, primary extranodal tumor site otherthan upper GI tract, advanced age, high grade pathology andprior therapy by either surgery or radiation, were significantlyassociated with shortened survival in a Cox proportional hazardsmodel. These results indicate advanced B-lymphoma in Japan tobe generally similar to advanced non-Hodgkin's lymphoma in theWest in terms of prognostic factor characteristics, but theimportance of the primary site in predicting survival has notbeen reported in the West. Also, the lack of a survival plateauin patients with diffuse large cell lymphoma indicates moreintensive chemotherapy regimens than VEPA or VEPA-M to be needed.It was also found that the significant prognostic factors inpatients with advanced B-lymphoma were very different from thosewith T-lymphoma. The five factors: pathology, stage, primarysite, age, prior therapy by surgery or radiation, for whichthe risk ratio was more than 2.3, were used to construct a modelcontaining 23 categories of patients running an increasing riskof shortened survival; this divided patients into three groups.The CR and 4-year survival rates of low-, moderate- and high-riskgroups were 90% and 74%, 74% and 58%, and 50% and 5%, respectively.The risk-grouping provides indications for determining optimaltherapy for individual patients and the need for new therapeutictrials in patients at high risk.     

Comparison of peripheral T-cell lymphomas and diffuse large B-cell lymphoma

BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are a biologically heterogeneous subgroup of lymphomas with poor prognosis. In this study, the authors analyzed the clinical behaviors of PTCLs and diffuse large B-cell lymphoma (DLBCL). METHODS: The authors compared the characteristics and outcomes of 59 patients with PTCLs, including 33 angioimmunoblastic T-cell lymphomas and 26 unspecified peripheral T-cell lymphomas, with the characteristics and outcomes of 193 patients with DLBCLs who were treated in the era before rituximab. RESULTS: Based on the clinical characteristics, elevated lactate dehydrogenase (LDH), poor PS, advanced stage, higher International Prognostic Index score, and B symptoms were more common in patients with PTCLs, and bulky mass was more common in patients with DLBCL. The rates of complete response (CR) or an unconfirmed CR (CRu) were higher in patients with DLBCL (72%) than in patients with PTCLs (56%; P = .03). The 5-year overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) rates were 31%, 26%, and 47%, respectively, in patients with PTCLs and 59%, 55%, and 73%, respectively, in patients with DLBCL (P = .001, P < .001, and P = .003, respectively). Although multivariate analysis identified several risk factors that were significant in PTCLs, but not in DLBCLs, for the CR/CRu, OS, PFS, and DFS rates, the immunophenotype was not identified as a risk factor. CONCLUSIONS: The poor response and survival of patients who had PTCLs, compared with patients who had DLBCL, was caused by numerous initial risk factors. T-cell phenotype itself did not appear to have a significant impact on either response or survival.     

Long-term maintenance combination chemotherapy with OPEC/MPEC (vincristine or methotrexate, prednisolone, etoposide and cyclophosphamide) or with daily oral etoposide and prednisolone can improve survival and quality of life in adult T-cell leukemia/lymphoma

Acute leukemia and lymphoma varieties of adult T-cell leukemia/lymphoma (ATL) usually carry a poor prognosis. While etoposide is generally useful for treating ATL, especially as a daily oral maintenance regimen, etoposide has not proven effective in severe types of ATL efficient in some patients. Of 87 ATL patients whom we have treated, 51 had acute leukemia, 22 lymphoma and 14 progressive chronic leukemia. Seventy-nine patients were treated with a long term maintenance combination protocol, OPEC/MPEC (weekly doses of vincristine, 0.7 mg/m2 or methotrexate, 14 mg/m2; prednisolone, 20 mg/m2; etoposide, 70 mg/m2 and cyclophosphamide, 200 mg/m2). The other 8 patients, 3 with acute leukemia, 2 with lymphoma and 3 with progressive chronic leukemia, were treated with daily oral administration of 25 mg of etoposide and 10 mg of prednisolone (DOEP). The dose administered was modified in individual cases to maintain the granulocyte count and reduce the number of ATL cells. Considering both protocols, a complete response and a partial response were achieved in 31.0% and 58.6% patients, respectively. Median survival times (MST) of all patients and, acute leukemia, lymphoma and progressive chronic leukemia types were 7.5, 6.7, 9.6 and 12.4 months, respectively. Respective MST of patients treated with OPEC/MPEC or DOEP protocols were 7.1 and 18.0 months. Relatively normal WBC counts, lower lactate dehydrogenase concentration and normal calcium concentration, limited numbers of anatomic sites involved, good performance status and good response to chemotherapy were significantly associated with long survival time. Drug toxicity was not apparent, and about half of patients were treated in an outpatient setting.     

Long-term Maintenance Combination Chemotherapy with OPECMPEC (Vincristine or Methotrexate, Prednisolone, Etoposide and Cyclophosphamide) or with Daily Oral Etoposide and Prednisolone Can Improve Survival and Quality of Life in Adult T-cell LeukemiaLymphoma

Acute leukemia and lymphoma varieties of adult T-cell leukemiallymphoma (ATL) usually cany a poor prognosis. While etoposide is generally useful for treating ATL, especially as a daily oral maintenance regimen, etoposide has not proven effective in severe types of ATL efficient in some patients. Of 87 ATL patients whom we have treated, 51 had acute leukemia, 22 lymphoma and 14 progressive chronic leukemia. Seventy-nine patients were treated with a long term maintenance combination rotocol, OPEClMPEC (weekly doses of vincnstine, 0.7 mg/m² or methotrexate, 14 mg/m; prednisolone, 20 mg/m²; etoposide, 70 mg/m² and cyclophosphamide, 200 mg/m²). The other 8 patients, 3 with acute leukemia, 2 with lymphoma and 3 with progressive chronic leukemia, were treated with daily oral administration of 25 mg of etoposide and 10 mg of prednisolone (DOEP). The dose administered was modified in individual cases to maintain the granulocyte count and reduce the number of ATL cells. Considering both protocols, a complete response and a partial response were achieved in 31.0% and 58.6% patients, respectively. Median survival times (MST) of all patients and, acute leukemia, lymphoma and progressive chronic leukemia types were 7.5, 6.7, 9.6 and 12.4 months, respectively. Respective MST of patients treated with OPECNPEC or DOEP protocols were 7.1 and 18.0 months. Relatively normal WBC counts, lower lactate dehydrogenase concentration and normal calcium concentration, limited numbers of anatomic sites involved, good performance status and good response to chemotherapy were significantly associated with long survival time. Drug toxicity was not apparent, and about half of patients were treated in an outpatient setting.     

Effect of human lymphoblast interferon in adult T-cell leukemia and non-Hodgkin's lymphoma

Four patients with adult T-cell leukemia (ATL) and 4 patients with non-Hodgkin's lymphoma were treated with alpha-type interferon (Human Lymphoblastoid Interferon: HLBI). Treatment regimen consisted of 3 to 12 million units (MU) of HLBI given intramuscularly once daily. The total dose varied from 36 to 520 MU. Complete remissions were obtained in one of 4 patients with ATL and one of 3 patients with B-cell lymphoma. A partial remission was yielded in one patient with B-cell lymphoma. An overall response rate (CR + PR) was 37.5%. Toxicity included flu-like symptoms, myelosuppression, G-I tract symptoms, fatigue, high fever and hepatic disturbance. On the basis of this study, we have concluded that HLBI is effective for the treatment of ATL and B-cell lymphoma.     

自体干细胞移植治疗T细胞淋巴瘤31例临床分析

目的 探讨自体干细胞移植治疗T细胞淋巴瘤的疗效和其预后因素.方法 回顾性分析31例给予自体干细胞移植治疗的T细胞淋巴瘤的临床资料,观察3年总生存率和无进展生存率,分析一般状况(PS)、乳酸脱氢酶(LDH)、移植前状况、分期、外周T细胞淋巴瘤预后指数(PIT)评分对生存的影响.结果 全组中位随访时间为28(5～68)个月...     

Differences Between Long- and Short-Term Survivors with Lymphoma Type of Adult T-Cell Leukemia

The clinical features at time of diagnosis of long-term survivors with lymphoma type of adult T-cell leukemia (ATL) were compared with those of short-term survivors. We had 51 Japanese patients with lymphoma type of ATL from 1981 to 1989 who had human T-cell leukemia virus type I (HTLV-I) antibody and monoclonal integration of HTLV-,I proviral DNA in the malignant cells. Of the 51 patients, 7 survived for more than 3 years, and they were classified as long-term survivors. Twenty-four patients died within 1 year and they were classified as short-term survivors. Differences between these two groups were investigated with the clinical findings recorded at the time of diagnosis. Findings that proved significant were serum lactate dehydrogenase (LDH) levels, calcium, total protein levels and the presence of B symptoms. Patients with lymphoma type of ATL are expected to be long-term survivors if they have no hypercalcemia or B symptoms with only mildly elevated serum LDH and total protein levels.     

The Differences between Lymphoma and Leukemia Type of Adult T-cell Leukemia

The difference between lymphoma type and leukemia type of adult T-cell leukemia (ATL) were analysed with 102 Japanese patients all positive for human T-cell leukemia virus type I (HTLV-I) antibody. They were classified into three groups on findings at first medical examination: lymphoma type cases, leukemia type cases, and mixed type (leukemia type plus lymphadeno-pathy) cases. Lymphoma type patients had several or more enlarged lymph nodes the largest of which was greater than 1 cm in diameter and with practically no abnormal lymphocytes (ATL. cells), which are characteristic of ATL, in the peripheral blood. Leukemia type patients had 10% or more ATL cells in the peripheral blood and had no detectablle lymphadenopathy Lymphoma type patients often complained of detectable lymphadenopathy, while leukemia type patients complained frequently of general fatigue and skin eruption. Mixed type patients more frequently had signs and symptoms which were characteristic of both types: lymphadenopathy and 10% or more ATL cells in the peripheral blood. Mixed type: ATL had a poorer prognosis than either lymphoma type or leukemia type. The median survival time was 3 months for mixed type patients, 10.5 months for lymphoma type patients, and 13.5 months for leukemia type patients. Complications and causes of death have also been touched upon. Clinicians are thus advised to consider ATL patients separately according to their clinical manifestations.     

Characterization of the spectrum of postthymic T-cell malignancies in Taiwan. A clinicopathologic study of HTLV-1-positive and HTLV-1-negative cases

Postthymic T-cell malignancy shows marked geographic, clinicopathologic, and prognostic diversity. The frequency and spectrum of T-cell malignancies in Taiwan were investigated. Fifty-two patients (35 male and 17 female) with a median age of 49 years, were consecutively encountered between October 1983 and April 1987; these accounted for 39% of non-Hodgkin's lymphoma cases seen in our institutions. Ten patients (19.3%) had adult T-cell leukemia/lymphoma (ATL) associated with human T-cell leukemia virus (HTLV-1). Patients with ATL had disease similar to that reported from southwestern Japan and the Caribbean. They had frequent skin lesions (60%), hypercalcemia (40%), and a rapid clinical course with a median survival of 1.3 years. The 35 HTLV-1-negative peripheral T-cell lymphomas (PTL) were similar to PTL in western countries, manifesting frequent visceral, cutaneous, and vascular tropisms. Marrow involvement was documented at presentation in 39% and Stage III/IV disease in 80% of the PTL patients. The histology of PTL usually expressed prominent reactive features which is distinct from that in ATL. Several subcategories could be defined: Hodgkin's-like PTL in nine patients, T-zone lymphoma in three, angioimmunoblastic lymphadenopathy-like lymphoma in one, Lennert's lymphoma in three, and angioinvasive lymphoma in four. Two HTLV-1-negative PTL had neoplastic cells with clover-shaped nuclei and were designated as ATL-like. Morphologic classification based on the modified Working Formulation showed prognostic correlation, with median survival of less than 6 months for large cell/immunoblastic PTL, compared with 5 years for patients with small/medium cell PTL. Both low- and high-grade PTL seem to represent an incurable disease. Classical cutaneous T-cell lymphoma (seven cases) is relatively unusual in Taiwan, compared with the frequency of PTL. Post-thymic T-cell malignancies in Taiwan include HTLV-1-positive and HTLV-1-negative diseases, both of which have a poor prognosis and resemble similar T-cell malignancies in the East and West.     

Long-term follow-up results of adult patients with acute lymphocytic leukemia or lymphoblastic lymphoma treated with short-term, alternating non-cross-resistant chemotherapy: Japan Clinical Oncology Group Study 8702. Lymphoma Study Group.

BACKGROUND: Patients with acute lymphocytic leukemia (ALL) and those with lymphoblastic lymphoma (LBL) have overlapping clinical and immunophenotypic features and they have been treated with the same or very similar chemotherapy regimens. The goal of this multi-institutional phase II trial was to evaluate the therapeutic efficacy of a short-term, six-drug chemotherapy regimen for adult patients with untreated ALL or LBL. METHODS: Forty-six eligible patients, 41 with ALL and five with LBL, were treated with a short-term (planned total therapy duration; 36-38 weeks), simplified chemotherapy program; two courses of VEPA-L (vincristine, cyclophosphamide, prednisolone, doxorubicin, I-asparaginase plus intrathecal methotrexate and prednisolone) followed by four courses of M-VEPA (methotrexate plus VEPA), without the traditional maintenance therapy using daily 6-mercaptopurine and weekly methotrexate. RESULTS: Thirty-six (78%; 95% confidence interval 64-89%) of the 46 eligible patients achieved complete remission (CR). Among the 36 patients who achieved CR, four (11%) died of treatment complications, 26 (72%) relapsed and six (17%) remain alive in continuous CR. The median survival for all 46 eligible patients is 14 months and the median disease-free survival (DFS) for the 36 patients who achieved CR is 11 months. The estimate of the proportion of survival at 7 years of all 46 eligible patients is 15% at a median follow-up time of 96 months and that of DFS of the 36 patients achieving CR is 17% at a median follow-up time of 93 months. Subgroup analysis showed that an elevated serum C-reactive protein (CRP) level, age of 30 years or older, the presence of B-symptom and T-cell phenotype were likely to be associated with shortened survival. Although the observed CR rate (78%) is within the range of satisfaction, the long-term survival rate (15%) is inferior to those of published programs incorporating maintenance therapy. CONCLUSIONS: A fraction of adult patients with ALL or LBL are curable with a short-term, six-drug chemotherapy regimen. However, this simplified therapy of shorter duration cannot be recommended.     

Final Results of Cooperative Study of VEPA [Vincristine, Cyclophosphamide (Endoxan), Prednisolone and Adriamycin] Therapy in Advanced Adult Non-Hodgkin's Lymphoma: Relation Between T- or B-Cell Phenotype and Response

One hundred previously untreated adult patients with advancednon-Hodgkin's lymphomas were treated with VEPA (vincristine,cyclophosphamide, prednisolone and adriamycin in combination)therapy. The overall complete remission rate was 52%. The completeremission rate was markedly higher in the patients with lineage-undeterminedlymphomas (72.2%) as well as in the patients with B(non-T)-celllymphomas (58.5%) than in the patients with T-cell lymphomas(36.6%). The median duration of complete remission has not beenreached for lineage-undetermined lymphomas and most (77%) ofthe patients have been in remission for more than 2-yr, whilethe median duration of complete remission for B(non-T)-celltype was 16 mo with a 3-yr remission rate of 14%, and medianduration for the T-cell type was only 4 mo with a 2-yr remissionrate of 15% or less. Both complete remission and cell lineageof lymphomas markedly affected the survival period. Of the patientswho were not induced into complete remission, about 90% diedwithin 12 mo regardless of the cell lineage of the lymphoma,and their median survival was only 5–7 mo. On the otherhand, more than 90% of the patients with lineage-undeterminedlymphomas who were induced into complete remission are stillalive after 36 mo. Median survival was 37 mo and the 3-yr survivalrate was 56.1% in the case of B(non-T)-cell lymphoma with completeremission. Even in the T-cell lymphomas, significantly (a fewmonths) longer survival time will be expected in the patientsin complete remission. These facts indicate that complete remissioninduced by VEPA therapy contributes greatly to longer survivalof the patients, but its contribution is limited by the celllineage of the lymphoma. B(non-T)-cell lymphoma as well as lineage-undeterminedlymphoma responded well to VEPA therapy and some of the patientsmay be cured. On the other hand, T-cell lymphoma responded poorlyto VEPA therapy.     

96例外周T细胞非霍奇金淋巴瘤预后分析

目的：分析外周T细胞淋巴瘤的临床特征、近期疗效、远期生存及预后因素。方法：对96例患者的临床特征、治疗效果及预后因素进行分析。外周T细胞淋巴瘤-非特异型（PTCL-U）66例,间变大细胞性淋巴瘤（ALCL）6例,NK/T淋巴廇（NK/TCL）17例,肠道T细胞性淋巴瘤（ITCL）5例,血管免疫母T细胞性淋巴瘤（AITCL）2例。结果：96例患者中89例接受CHOP方案为主的联合化疗,有效率（RR）为88.8%,完全缓解（CR）率为57.3%。中位随访时间30（2～98）个月,死亡52例,中位生存期31.9个月,1、3、5年生存率分别为83.3%、42.7%、35.1%。多因素分析结果显示,IPI评分是PTCL的独立预后指标（P〈0.05）。结论：外周T细胞淋巴瘤常规化疗近期疗效尚可,但远期生存率低,预后不良,需进一步探索新的治疗策略。     

The International Prognostic Index predicts outcome in aggressive adult T-cell leukemia/lymphoma: analysis of 126 patients from the International Peripheral T-cell Lymphoma Project

BackgroundThe International Peripheral T-cell Lymphoma Project was organized to better understand the T-cell and natural killer (NK) cell lymphomas, and our task is to present the clinicopathologic correlations and therapeutic results for adult T-cell leukemia/lymphoma (ATL).Patients and methodsAmong 1153 patients with T-cell or NK cell lymphomas, 126 patients (9.6%) with ATL were represented in this project. All were categorized as aggressive ATL, i.e. acute or lymphoma type, and 87% fell into the lymphoma type.ResultsThe median age was 62 years and the male to female ratio was 1.2 : 1. Significant prognostic factors for overall survival (OS) by univariate analysis were the presence of B symptoms (P = 0.018), platelet count <150 × 10⁹/l (P = 0.065), and the International Prognostic Index (IPI; P = 0.019). However, multivariate analysis indicated that only the IPI was an independent predictor of OS. Combination chemotherapy including anthracyclines was given as the initial therapy in 109 of the 116 patients (94%) who received treatment, and the overall and complete response rates were 70% and 34%, respectively. However, there was no survival benefit for those receiving an anthracycline-containing regimen.ConclusionPatients with aggressive ATL have a poor clinical outcome and the IPI is a useful model for predicting outcome in ATL of the lymphoma type.     

Serum deoxythymidine kinase in adult T-cell leukemia-lymphoma and its related disorders

Serum deoxythymidine kinase (TK) was measured in 15 patients with the acute type of adult T-cell leukemia (ATL), in 4 with chronic ATL, in 10 with lymphoma type ATL, in 9 with pre-ATL, in 11 with human T-cell leukemia virus type I (HTLV-I) associated with myelopathy (HAM) and in 19 HTLV-I carriers. All these patients were positive for anti-HTLV antibody. The level of TK in pretreatment serum was highest in acute ATL (15.6-1600 U/l, median 107 U/l). It was elevated in chronic ATL (5.4-55.0 U/l, median 37.6 U/l) and lymphoma ATL (6.8-316 U/l, median 16.8 U/l) but normal in pre-ATL (1.8-4.7 U/l, median 2.8 U/l), HAM (1.2-6.0 U/l, median 3.0 U/l) and HTLV-I carriers (1.1-4.6 U/l, median 2.3 U/l). Statistical examination revealed a significant difference between the levels of acute ATL and chronic ATL/lymphoma ATL. In the patients of this series, a close correlation between the level of TK and lactic dehydrogenase (LDH) was statistically present (p less than 0.01). These facts indicate that TK level is a useful indicator of the aggressiveness of ATL cells.     

Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma.

PURPOSE: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. EXPERIMENTAL DESIGN: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). RESULTS: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. CONCLUSIONS: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).     

Serological survey of antibodies to the adult T-cell leukemia virus-associated antigen (HTLV-A) in Taiwan

A serological survey of antibodies to the adult T-cell leukemia virus-associated antigen (HTLV-A) conducted in Taiwan revealed II seropositive individuals among 2,565 serum donors tested, which included 1,187 hospital or free clinic patients, 1,065 blood donors and 313 aborigines. The overall prevalence rate was 0.43% and was 0.90% (9/995) for adults aged 40 years or over, which was similar to the rates observed in the non-endemic areas in Japan. No highly prevalent area was demonstrated. The II seropositive individuals identified were 8 hospital or clinic patients, 1 blood donor and 2 aborigines. Among 108 various leukemia/lymphoma patients also studied, 7 were positive. These 7 anti-HTLV-A-positive patients also had clinicopathologic features of adult T-cell leukemia/lymphoma (ATL). Among 21 relatives of 3 seropositive individuals in the epidemiologic study, 2 were positive; and among 25 relatives of 5 ATL patients, 6 were positive. Our data support the contention that horizontal familial transmission of human T-cell leukemia virus (HTLV-I) is an important route and HTLV-I infection can occur on a different genetic background. Furthermore, the antibody titer did not correlate with the manifestation or the state of the disease.