Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109)

Aggressive adult T-cell leukemia-lymphoma (ATL) generally has a very poor prognosis. Deoxycoformycin (DCF, pentostatin), an inhibitor of adenosine deaminase, has shown promising therapeutic efficacy for ATL. To develop a new effective therapy against aggressive ATL, we carried out a multicenter phase II study of DCF-containing combination chemotherapy. Sixty-two previously untreated patients with ATL (34, 21, and 7 patients with diseases of the acute, lymphoma, and unfavorable chronic types, respectively) were enrolled, but 2 were ineligible because they were judged to be favorable chronic types. A regimen of 1 mg/m2 vincristine intravenously on days 1 and 8, 40 mg/m2 doxorubicin intravenously on day 1, 100 mg/m2 etoposide intravenously on days 1 through 3, 40 mg/m2 prednisolone orally on days 1 and 2, and 5 mg/m2 DCF intravenously on days 8, 15, and 22 was administered every 28 days for 10 cycles unless disease progression or toxic complications occurred. Fifty-two percent of 60 eligible patients responded (95% confidence interval [CI], 38%-65%), with 17 patients (28%) achieving a complete response (CR) (95% CI, 17%-41%) and 14 achieving a partial response. The CR rate was inferior to those of both the previous Japan Clinical Oncology Group (JCOG) study (JCOG8701, 43%), a 9-drug combination chemotherapy of the second generation, and the subsequent JCOG9303 study (35%), a granulocyte colony-stimulating factor-supported, dose-intensified, 9-drug regimen. The median survival time of the 60 eligible patients in JCOG9109 was 7.4 months, and the estimated 2-year survival rate was 15.5%; these results were identical with those of JCOG8701 but inferior to those of JCOG9303. Grade 4 neutropenia and infection of grade 3 or greater were frequent (67% and 22%, respectively), and treatment-related death was observed in 4 patients (7%), septicemia in 2, and cytomegalovirus pneumonia in 2. We conclude that DCF-containing combination chemotherapy is not a promising regimen against aggressive ATL.     

Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course

Sixty-four patients with adult T-cell leukemia/lymphoma (ATL; 18 patients with indolent subtype and 46 with aggressive subtype) associated with human T-lymphotropic virus type 1 (HTLV-1) were analyzed using comparative genomic hybridization (CGH). The most frequent observations were gains at chromosomes 14q, 7q, and 3p and losses at chromosomes 6q and 13q. Chromosome imbalances, losses, and gains were more frequently observed in aggressive ATL than in indolent ATL, with significant differences between the 2 ATL subtypes at gains of 1q and 4q. An increased number of chromosomal imbalances was associated with a significantly shorter survival in all patients. A high number of chromosomal losses was associated with a poor prognosis in indolent ATL, whereas the presence of 7q+ was marginally associated with a good prognosis in aggressive ATL. Paired samples (ie, samples obtained at different sites from 4 patients) and sequential samples from 13 patients (from 6 during both chronic disease and acute crisis and from 7 during both acute onset and relapse) were examined by CGH and Southern blotting for HTLV-1. All but 2 paired samples showed differences on CGH assessment. Two chronic/crisis samples showed distinct results regarding both CGH and HTLV-1 integration sites, indicating clonal changes in ATL at crisis. In 11 patients, the finding of identical HTLV-1 sites and clonally related CGH results suggested a common origin of sequential samples. In contrast to chronic/crisis samples, CGH results with all acute/relapse sample pairs showed the presence of clonally related but not evolutional subclones at relapse, thereby suggesting marked chromosomal instability. In summary, clonal diversity is common during progression of ATL, and CGH alterations are associated with clinical course. (Blood. 2001;97:3875-3881)     

Matrix metalloproteinase-9 and vascular endothelial growth factor: a possible link in adult T-cell leukaemia cell invasion

Plasma from a total of 57 patients with adult T-cell leukaemia (ATL) (acute ATL, 39 patients; lymphoma ATL, one patient; chronic ATL, 15 patients; smouldering ATL, two patients) and 20 healthy controls was analysed for the presence of type IV gelatinase activity with clinical features. A significant elevation of plasma matrix metalloproteinase-9 (MMP-9) was observed in some ATL patients, particularly in the patients with malignant cell infiltration. MMP-9 was found to be secreted into the conditioned medium from all ATL cell lines examined. Moreover, the corresponding mRNA was detectable both in all ATL cell lines examined and in the majority of primary acute ATL cells, indicating that ATL cells are capable of synthesizing and secreting MMP-9. We previously demonstrated that a high incidence of ATL cell infiltration was closely related to a high plasma level of vascular endothelial growth factor (VEGF) produced by ATL cells themselves. This present study showed that the presence of increased plasma MMP-9 was closely associated with elevated plasma VEGF in ATL patients. Furthermore, we showed that both increased plasma MMP-9 and VEGF were significantly related to high ATL cell infiltration. All these findings strongly suggest that MMP-9 and VEGF act co-operatively in the process of ATL cell invasion.     

Myelodysplastic Syndrome

International Journal of Hematology -     

Nerve growth factor accelerates regeneration of cultured adult sympathetic ganglion cells

To evaluate the regenerative capacity of adult nerve cells, a tissue culture study was made on the superior cervical ganglion (SCG) from adult mice. Explants of SCG from mice of various ages were cultured in medium after the method of Wood for 12 days in the presence of 10 ng/ml or 100 ng/ml nerve growth factor (NGF). The number of explants with regeneration, and the maximum length of processes from the explants, were reduced in the explants of 24 month old mice. The number of processes decreased with age. Application of 100 ng/ml NGF increased the regenerative capacity of 24 month old mice explants.     

Arm span–height difference is correlated with gastroesophageal reflux symptoms in aged Japanese subjects

Previous studies have indicated an association between the symptoms of gastroesophageal reflux disease (GERD) and aging plus height. In this study we investigated whether the arm span–height difference was related to GERD symptoms with a focus on aged subjects in the general population, since the arm span reflects the height in young adulthood before decreasing due to vertebral deformities from aging. A total of 285 elderly individuals (105 females) who visited nursing homes for the elderly in Japan were enrolled in this study. The GERD symptoms were evaluated by the Frequency Scale for the Symptoms of GERD (FSSG). The body weight, height and arm span were measured, and information regarding medications and complications were reviewed in each nursing record. 50.5% of women had more than 3 cm of arm span–height difference. In contrast, only 37.3% of men had more than 3 cm of arm span–height difference. The FSSG scores indicated more than 70% of subjects complained of any GERD symptoms. There was a significant correlation between the FSSG score and the arm span–height difference in the subjects with more than 3 cm of arm span-height difference (r = 0.236; p = 0.012). The correlation between the arm span–height difference and the FSSG score was significant only in women in females in the present study. In conclusion, our findings indicate that vertebral deformity evaluated by the arm span–height difference might have some positive relationship to the pathogenesis of GERD symptoms in elderly Japanese individuals.     

Study on pathophysiology of the myelodysplastic syndromes (MDS)--pattern of dysmegakaryopoiesis related to leukemic transformation

A series of 116 patients with MDS consisted of 74 cases of RA, 10 cases of RARS, 14 cases of RAEB, 9 cases of RAEB-T and 9 cases of CMML, were studied on the quantity and morphological abnormalities of megakaryocytes in relation to over all survival and leukemic change. The amount of megakaryocytes was graded into four groups; marked hypoplasia (O), moderate hypoplasia (L), normoplasia (N) and hyperplasia (H), RA cases showed heterogeneous pattern; containing 14 cases (18.9%) of group (O), 18 cases (24.3%) of group (L), 31 cases (41.9%) of group (N) and 11 cases (14.9%) of group (H). RARS, RAEB, RAEB-T and CMML cases were classified into group (N) or group (H). The heterogeneous pattern of RA did not relate to leukemic change, but over all survival tended to be shorter in group (N) cases. A significant number of young female cases of RA were involved in group (O). Morphological abnormalities of MDS megakaryocytes were classified into five types; I, mononuclear micromegakaryocytes, II, binuclear micromegakaryocytes, III, mononuclear small megakaryocytes, IV, multiseparated-nuclear megakaryocytes and V, megakaryocytes with bizzare nuclei. RAEB and RAEB-T cases uniformly showed marked dysmegakaryopoiesis ranging from type I to V. whereas RA, RARS and CMML cases showed mild dysmegakaryopoiesis. Only five cases (6.4%) of RA cases had type I micromegakaryocytes. Eight RA cases with type I on diagnosis or obtaining it during the clinical course tended to develop acute myeloid leukemia (5 cases) or to transform to RAEB sooner or later. In two cases of RAEB in which hematological improvement was obtained with low dose cytosine arabinoside regimen, disappearance of type I micromegakaryocytes was noted. A female case with 5q-anomaly surviving more than 10 years showed marked megakaryocyte hyperplasia and almost exclusively type III and IV megakaryocytes. These findings indicated that pattern of dysmegakaryopoiesis, especially appearance of type I, was closely related to leukemic change in MDS. Thus quantitative and qualitative evaluations of MDS megakaryocytopoiesis seemed important to understand the further heterogeneity of pathophysiology in MDS subtypes.