Saburo Momita

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.

Significance of soluble interleukin‐2 receptor levels for evaluation of the progression of adult T‐cell leukemia

Background. The authors conducted a survey of a large cohort of patients with adult T‐cell leukemia (ATL) and a group of human T‐cell leukemia virus type 1 (HTLV‐1) carriers to elucidate whether measurements of soluble interleukin‐2 receptor (sIL‐2R) levels are indicative of ATL tumor burden and correlate with clinical progression.

An intensive chemotherapy of adult T-cell leukemia/lymphoma: CHOP followed by etoposide, vindesine, ranimustine, and mitoxantrone with granulocyte colony-stimulating factor support.

SUMMARY An intensive combination chemotherapy regimen supported by granulocyte colony-stimulating factor (G-CSF) was evaluated in adult T-cell leukemia/lymphoma (ATLL) patients in a multiinstitutional, cooperative study. Vincristine 1 mg/m2 i.v. day 1, Adriamycin 40 mg/m2 i.v. day 1, cyclophosphamide 400 mg/m2 i.v. day 1, prednisolone 40 mg/m2 i.v. days 1 to 3 and 8 to 10, etoposide 35 mg/m2 i.v. days 1 to 8, vindesine 2 mg/m2 i.v. day 8, ranimustine 50 mg/m2 i.v. day 8, mitoxantrone 7 mg/m2 i.v. day 8, and G-CSF 50 mg/m2 s.c. days 9 to 21 were given for 2 to 4 courses every 3 weeks to 83 patients with ATLL. Complete remission (CR) and partial remission (PR) were achieved in 35.8 and 38.3 percent, respectively, of 81 evaluable patients. The median survival of all patients was 8.5 months, with a predicted 3-year survival of 13.5 percent by the Kaplan-Meier method. The median duration of response was 7.6 months (range 0.2-42.7), and 13 patients were alive. Their median survival time was 29.1 months (range 19.2-44.7). In 67.6 percent of courses, white blood cell (WBC) nadirs were < 1.0 x 10(9)/L. Days required for the recovery of WBC from the nadir to > 1.0 x 10(9)/L were <5 days in 71.4 percent of the treatment courses. The G-CSF supported an intensified chemotherapy regimen for ATLL and yielded better response rate and longer survival compared to previous reports in Japan. Because duration of remission is still short, further studies of postremission therapy or other strategies are warranted.

Phenotypic diversity and prognosis of adult T-cell leukemia

We examined phenotypically 107 patients with adult T-cell leukemia (ATL), using a panel of monoclonal antibodies, in order to clarify the occurrence of aberrant phenotypes, and to determine the correlation between phenotypic diversity and prognosis. The incidence of the typical (CD4+.CD8-) phenotype, the double-negative (CD4-.CD8-), the double-positive (CD4+.CD8+), and the CD8-positive (CD4-.CD8+) phenotypes was 81%, 7%, 7%, and 4%, respectively. The median survival time (MST) for all patients was 10.0 months with 17% survival at 2 years. The patients with typical phenotypes had a 10.2 month MST with 20% survival at 2 years, significantly better than the patients with the unusual phenotypes whose MST were 4.9, 7.8, and 2.6 months, respectively, for the double-negative, double-positive, and CD8-positive phenotypes. Lack of antigens reactive with CD2, CD3, CD5, and WT31 monoclonal antibody panels was one factor in bad prognosis, but the presence of CD4 and CD8 antigen abnormalities was much more significant.

Characteristics of chemotherapy-induced clinical remission in long survivors with aggressive adult T-cell leukemia/lymphoma

The acute and lymphoma types of adult T-cell leukemia/lymphoma (ATL) usually have a very poor prognosis, although some patients achieve long survival after chemotherapy. A total of 114 patients with these aggressive types of ATL were newly diagnosed at our institution from 1975 to 1989. By multivariate analysis, poor performance status and high serum creatine levels were associated with shortened survival. With combination chemotherapy, 20 patients achieved complete remission (CR), 53 achieved partial remission (PR) and 35 showed no response. Fifteen of the CR or PR patients survived for more than two years and all other patients survived for less than two years. As compared with short survivors (< 2 years) after remission, long survivors (> or = 2 years) after remission had a higher CR/PR ratio, a longer time until remission and a higher doxorubicin dose to achieve remission. Death due to causes other than the primary disease occurred in 18% of short survivors after remission and in 11.2% of nonresponders, but in none of the long survivors. Long survivors with acute ATL included 6 patients with CR and 5 patients with PR. All four lymphoma type ATL long survivors achieved CR. Monoclonal integration of HTLV-I provirus was detected in the peripheral blood mononuclear cells of all 3 PR long survivors with acute ATL studied, but was not detected in all 4 CR cases studied at remission. The minimum CD4/CD8 ratio of peripheral mononuclear cells at remission was < 1.0 in all acute ATL long survivors with CR, and was > 1.0 in all acute ATL long survivors with PR. Three out of six acute ATL long survivors with CR developed suspected viral infection just before achieving CR. Our findings show that in aggressive ATL the characteristics of remission are heterogeneous even among long survivors.

Frequency of eosinophilia in adult T‐cell leukemia/lymphoma

Cases of adult T‐cell leukemia/lymphoma (ATLL) display several peculiar clinical features, including skin rash, hypercalcemia, and an increase in the absolute neutrophil count. The patients rarely have pronounced eosinophilia. In this study, the eosinophilia observed in lymphoproliferative disorders of 62 patients with ATLL, 27 with T‐cell lymphoma (TL), and 19 with B‐cell lymphoma (BL) was investigated. The incidence of eosinophilia (⩾ 570/μl) was higher in patients with ATLL than in patients with TL or BL. Thirteen patients with ATLL (21.0%), 3 with TL (11.1%), and 2 with BL (10.5%) had eosinophilia. Of these patients, three with ATLL and one with TL who had a pathologic diagnosis of immunoblastic lymphadenopathy (IBL) showed pronounced eosinophilia up to 10,934/μl. Because the number of eosinophils in the peripheral blood of these patients correlated both with the number of ATLL cells and the degree of lymphadenopathy and because this fluctuated with chemotherapy, it seems likely that the secretion of some lymphokines by the lymphoma cells is responsible for the eosinophilia. Cancer 1992; 69:966–971.

Prognostic significance of the proportion of Ki‐67‐positive cells in adult t‐cell leukemia

The authors examined peripheral blood samples from patients with adult T‐cell leukemia (ATL) using the monoclonal antibody Ki‐67 which detects a nuclear antigen present in actively proliferating cells. In patients with chronic ATL, the percentage of Ki‐67‐positive cells was significantly lower than in acute ATL patients (median values, 3.3% versus 18.9%, P < 0.001). Furthermore, there was a significant inverse correlation between the percentage of Ki‐67‐positive cells and the length of survival (P < 0.001). Serum lactic dehydrogenase (LDH) levels also showed a significant inverse correlation with survival, but this was less strong than that for Ki‐67 (0.01 < P < 0.02). Thus, Ki‐67 positivity appears to indicate the aggressiveness of ATL, and can possibly be used for the clinical classification of ATL patients as well as for the prediction of prognosis.

Established IL‐2‐dependent double‐negative (CD4‐ CD8‐) TCRαβ/CD3+ ATL cells: induction of CD4 expression

Summary. We established IL‐2‐dependent T cells from an adult T‐cell leukaemia (ATL) patient whose leukaemic cells changed from CD4 single‐p‐positive in the initial phase to double‐negative (CD4‐ CD8‐) at the time of exacerbation. The cells termed SO‐4 were of ATL cell origin and showed the double‐negative TCRαβ/CD3+ T‐cell phenotype. SO‐4 cells acquired CD4 antigen expression following stimulation with concanavlin A (ConA) or immobilized anti‐CD3 antibody. The induction was inhibited by herbimycin A, an inhibitor of protein tyrosine kinase (PTK) activity. No CD4 mRNA was detectable in unstimulated SO‐4 cells but a 3.0 kb signal specific for CD4 mRNA was detected after stimulation. These findings indicate that SO‐4 cells return to their original phenotype (CD4 single‐positive) by stimulation involving PTK. The results indicate that there is a pathway of phenotypic cycling between CD4 single‐positive and double‐negative T cells.

DNA aneuploidy of adult T-cell leukemia cells

To clarify the biological characteristics of adult T-cell leukemia (ATL), immunophenotyping and DNA aneuploid analysis were performed in 72 ATL cases, using flow cytometric techniques. DNA aneuploidy was found in 45 cases (62.5%); the DNA index ranged from 1.03 to 2.16 (mean: 1.24). The incidence of aneuploidy in smoldering, chronic, acute, and lymphoma ATL subtypes was 20.0%, 46.6%, 76.3%, and 77.8%, respectively. The aneuploid patients had a greater tumor burden (adenopathy, hepatosplenomegaly, and leukocytosis with ATL cells), a higher level of serum LDH, and a higher incidence of hypercalcemia, compared with the diploid group. Further, unusual aberrant immunophenotypes were identified predominantly in the aneuploid group. Patients with aneuploidy had a 7.6 month median survival time (MST) with a 2 year survival rate of 24.6%, significantly worse than in the patients with diploidy, whose MST was 25.4 months with a 2 year survival of 60.1%. In some aneuploid patients, the disease often progresses from a static to an aggressive form. Thus, the determination of aneuploidy and unusual immunophenotype should be useful for detecting clinical behavior and for monitoring ATL patients, particularly in regard to such progression.

De novo acute myeloid leukemia in the elderly; a consistent fraction of long-term survivors by standard-dose chemotherapy

To clarify the characteristics of de novo acute myeloid leukemia (AML) among the elderly, we reviewed 112 patients over 60 years old (median age 72 years) who were treated at hospitals in Nagasaki Prefecture with a population of 1.5 million between 1987 and 1994. Reclassification of morphological diagnosis revealed that the proportion of M3 was lower but that of M6 and the incidence of cases with trilineage dysplasia (TLD), known as poor prognostic features, were higher in the elderly than in patients less than 60 years old. Similarly, chromosomal data showed a lower frequency of favorable karyotypes such as t(8;21) and t(15;17) in the elderly. The overall survival of all 112 patients was 10.3% at 5 years. Multivariate analysis indicated that good performance status (PS), low WBC at diagnosis, standard dose multi-drug chemotherapy and all-trans retinoic acid (ATRA) treatment for M3 patients, and morphological findings without TLD were significantly correlated with longer survival. Most of the long-term survivors were found among those who received standard dose therapy in this series, although no consensus has been established how to treat elderly AML patients. We propose that a prospective controlled trial is necessary to confirm the role of standard dose chemotherapy for elderly patients with de novo AML.