Nozomi Niitsu

Sensitization by 5‐aza‐2′‐deoxycytidine of leukaemia cells with MLL abnormalities to induction of differentiation by all‐trans retinoic acid and 1α,25‐dihydroxyvitamin D3

Most chromosomal abnormalities associated with breakage at 11q23 in acute leukaemia involve the MLL gene, and the presence of this breakage strongly predicts a poor clinical outcome. We assessed the possibility of differentiation‐inducing therapy for acute leukaemias with chromosomal translocations involving 11q23. Among the cell lines with MLL translocations that we examined, KOCL48 and KOPN‐1 cells were induced to differentiate into granulocytes by all‐trans retinoic acid (ATRA) or into monocytes by 1α,25‐dihydroxyvitamin D3 (VD3). These cells expressed p16 mRNA before treatment with 5‐aza‐2′‐deoxycytidine (5‐AZA), an inhibitor of DNA methylation. On the other hand, differentiation was not induced in SN‐1, KOCL33, KOCL51 or KOCL44 cells by ATRA or VD3, and these cells did not express mRNA of this gene. However, these cells were effectively induced to differentiate by ATRA or VD3 in the presence of 5‐AZA, and concomitantly exhibited p16 gene expression, suggesting an association between DNA demethylation and restoration of sensitivity to differentiation‐inducing activity of ATRA or VD3 in leukaemia cells with MLL abnormalities. Based on these findings, combined treatment with ATRA or VD3 plus 5‐AZA may be clinically useful in therapy for acute leukaemia with MLL abnormalities.

A high serum‐soluble interleukin‐2 receptor level is associated with a poor outcome of aggressive non‐Hodgkin's lymphoma

Abstract: Soluble interleukin‐2 receptor (sIL‐2R) is produced by activated T and B cells, and the level of this receptor is elevated in patients with non‐Hodgkins lymphoma (NHL). The present study demonstrated that the sIL‐2R level was high in the following groups of patients with aggressive NHL; those aged 60 yr, those with a poor PS, those in Ann Arbor stage III or IV, and those in the high–intermediate or high risk group according to the International Prognostic Index (IPI). Overall survival was significantly poorer when the sIL‐2R level was 2000 U/ml or more. In addition, the overall survival of patients in the low (L) and low–intermediate (L–I) risk groups with an sIL‐2R level of 3000 U/ml or more was significantly poorer, suggesting that the sIL‐2R level could be particularly useful for identifying patients with a poor prognosis among the L and L–I risk groups. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors plus the five IPI prognostic factors showed that the sIL‐2R level was an independent prognostic indicator. In conclusion, the present findings established that the sIL‐2R level is a significant independent prognostic factor in patients with aggressive NHL.

Elevated serum levels of soluble CD44 variant 6 are correlated with shorter survival in aggressive non-Hodgkin's lymphoma

Abstract: A variant form of CD44 that has additional amino acids in the common protein backbone (CD44‐v6) seems to play a role in the metastasis of malignancies. We measured soluble CD44‐v6 (sCD44‐v6) by ELISA in 201 patients with malignant lymphoma. The sCD44‐v6 level was significantly elevated in patients with non‐Hodgkins lymphoma (NHL) (n=184). The sCD44‐v6 level was correlated significantly with the standard sCD44 and soluble interleukin‐2 receptor levels, but only weakly with serum lactate dehydrogenase (LDH). In 149 patients with aggressive NHL, the sCD44‐v6 level was elevated in the subgroups with a high LDH level, stage III/IV disease, T‐cell lymphoma, and high–intermediate or high risk group as identified by the International Prognostic Index (IPI). When the sCD44‐v6 level was 800 ng/ml the overall survival rate was significantly decreased (p=0.0001). In the low+low–intermediate risk group (IPI) both overall survival rates (log‐rank p=0.0005, Wilcoxon p=0.002) were significantly decreased when the sCD44‐v6 level was 800 ng/ml. In multivariate analysis, sCD44‐v6 was shown to be independent of the five prognostic factors in the IPI (age, performance status, number of extranodal sites, Ann Arbor stage and LDH level), so it may be useful for predicting the outcome of aggressive NHL.

Reduced-Dose CHOP Therapy for Elderly Patients with Non-Hodgkin's Lymphoma

While CHOP therapy is effective for malignant lymphoma, the optimum schedule for elderly patients remains controversial. The present study investigated the usefulness of reduced-dose CHOP therapy for elderly patients. Previously untreated patients aged 65 years or older with intermediate to high-grade non-Hodgkins lymphoma were given up to 6 courses of reduced-dose CHOP therapy at 3-week intervals. Group A patients were given 5/6 of the standard dose and Group B received 7/12 of the standard dose. Filgrastim was administered when the white blood cell count fell below 2,000/μL. Fifty-seven patients were evaluable and the scheduled therapy was completed in 37. For patients aged from 65 to 79 years and for patients older than 80 years, the complete response rate was 79.5% and 46.2%, overall 3-year survival was 58.2% and 30.4%, and event-free 3-year survival was 49.3% and 44.4%, respectively. Major toxicities (× grade 3) included leukopenia in 42 patients and documented infection in 7 patients. Grade 3 cardiac plus renal failure, grade 3 peritonitis due to small bowel perforation, and grade 3 liver dysfunction occurred in 1 patient each. One patient died of toxicity (grade 4 hematological toxicity and pneumonia). In conclusion, it seems that in the elderly patients with non-Hodgkins lymphoma, response to reduced-dose (5/6 dose) CHOP therapy is comparable to that for standard CHOP in younger adults, mainly because of improved dose-intensity.

Biweekly COP‐BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin and procarbazine) regimen combined with granulocyte colony‐stimulating factor (G‐CSF) for intermediate‐grade non‐Hodgkin's lymphoma

Abstract:  We evaluated the efficacy and adverse effects of biweekly COP‐BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin and procarbazine) therapy combined with granulocyte colony‐stimulating factor (G‐CSF) for treating non‐Hodgkins lymphoma (NHL). A complete remission was achieved in 65 (90.3%) of the 72 patients. The median follow‐up period was 28 months, and 64 patients were alive at the time of writing. Treatment was delivered as scheduled to 61 patients. G‐CSF made it possible to shorten the interval between courses of chemotherapy. One of the 72 patients died of granulocytopenia and pneumonia; no other severe infections were noted. Further studies regarding adverse effects on organs other than the bone marrow are required to improve the long‐term results of combination therapy on NHL.

Salvage chemotherapy for relapsed or refractory non‐Hodgkin's lymphoma with a combination of ACES (high‐dose Ara C, carboplatin, etoposide and steroids) therapy

Abstract:  ACES (Ara‐C, carboplatin, etoposide, steroids) therapy using granulocyte‐colony stimulating factor (G–CSF) was designed for relapsed or refractory non‐Hodgkins lymphoma (NHL), and the therapeutic effects and adverse reactions were studied. The subjects were 40 patients, including 19 relapsed cases and 21 refractory cases, subjected to chemotherapy using anthracycline type agents. The ACES therapy consisted of carboplatin at 100 mg/m2 and etoposide at 80 mg/m2 for 4 d from the first day, Ara‐C at 2 g/m2 on the fifth day, solumedrol at 500 mg for 5 d from the first day and G–CSF at 2 μg/kg from the seventh day. This therapy was performed every 3 weeks, in principle. The doses were reduced to 70% of the above values for patients aged 70 yr or older. Among the 40 patients, complete remission (CR) was achieved in 14 (35%) and partial remission (PR) in 14 (35%) for a response of 70%. The 50% survival period was 526 d, and the 2‐yr disease‐free survival rate was 58.3%. Adverse reactions of grade 3 or higher included granulocytopenia in 62.5%, anemia in 17.5% and thrombocytopenia in 50%, but there was no death related to treatment. Four patients underwent transplantation of hematopoietic stem cells and have survived for long periods. This treatment was effective against relapsed NHL and could be performed safely with few adverse reactions.

Response and adverse drug reactions to combination chemotherapy in elderly patients with aggressive non-Hodgkin's lymphoma: comparison of CHOP, COP-BLAM, COP-BLAM III, and THP-COPBLM.

Abstract: We retrospectively compared therapeutic results and adverse events in 198 elderly patients (≥70 yr old) with aggressive non‐Hodgkins lymphoma diagnosed between 1981 and 1995 who underwent CHOP, COP‐BLAM, COP‐BLAM III, or THP‐COPBLM chemotherapy. Complete remission (CR) was achieved in 138 patients (69.7%). The CR rate was 47.0% for CHOP, 76.3% for COP‐BLAM, 67.9% for COP‐BLAM III, and 74.4% for THP‐COPBLM therapy (p = 0.013). The 5‐yr survival rate was 37.0% for CHOP, 49.0% for COP‐BLAM, and 53.5% for COP‐BLAM III. The event‐free survival rate showed no significant differences between the four treatments. Adverse events of Grade 3 or worse were commonly anemia or granulocytopenia in patients receiving THP‐COPBLM therapy. Cardiac sympathetic dysfunction and cardiac mitochondrial damage were less common with pirarubicin than with doxorubicin.

CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) regimen with granulocyte colony-stimulating factor (G-CSF) for patients with aggressive non-Hodgkin's lymphoma : a pilot study

Abstract: We conducted a multi‐institutional collaborative study to examine the usefulness and safety of third‐generation chemotherapy CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) combined with granulocyte colony‐stimulating factor (G‐CSF) in the treatment of aggressive non‐Hodgkins lymphoma (NHL). Subjects included patients with aggressive NHL who were 60 yr of age or younger and had been diagnosed as having a low–intermediate, high–intermediate, or high risk using the International Prognostic Index (IPI). A total of 24 patients were enrolled in the study between May 1997 and March 1998, including 9 low–intermediate‐risk cases, 13 high–intermediate‐risk cases and 2 high‐risk cases. Although all 24 patients were originally enrolled in the study, one adult T‐cell leukemia/lymphoma case was subsequently excluded. Thus, in the end, 23 cases were evaluated. Evaluation of the efficacy of therapy revealed complete remission in 20 patients (87%). Of these 20 patients, 8 were low–intermediate‐risk cases (89%) and 12 were either high–intermediate‐ or high‐risk cases (86%). Partial remission was achieved in 2 patients (8.7%). The 2‐yr survival rate was 91.3%, and the 2‐yr disease‐free survival rate was 81.8%. Grade 3 or higher adverse reactions were granulocytopenia (87%), thrombocytopenia (17.4%) and liver dysfunction (4.3%).

Human herpes virus-8 associated with two cases of primary-effusion lymphoma.

Abstract Primary-effusion lymphoma (PEL) is a rare form of non-Hodgkins lymphoma which predominantly occurs in patients with acquired immunodeficiency syndrome and is characterized by the presence of a malignant effusion in one or more of the body cavities, generally in the absence of a primary tumor mass. Recently, we encountered two cases of PEL presenting as cardiac tamponade. In both cases, a diagnosis of diffuse large B-cell lymphoma was made by examination of the pericardial fluid. Because human herpes virus-8 (HHV-8) antibodies were positive and human immunodeficiency virus antibodies were negative, HHV-8 seemed likely to be an etiologic agent for the PEL. One of the two patients (case 1) was not treated for religion reasons and died. The other (case 2) achieved complete remission after treatment using the CHOP regimen and is alive at present. The prognosis of this disease is believed to be poor, therefore more cases should be collected to establish reliable therapy for PEL.

COP-BLAM regimen combined with granulocyte colony-stimulating factor and high-grade non-Hodgkin's lymphoma.

Abstract: The clinical efficacy of COP‐BLAM chemotherapy combined with human recombinant granulocyte colony‐stimulating factor (G‐CSF) was evaluated in 104 previously untreated patients with non‐Hodgkins lymphoma (NHL). According to the method of Laurence et al., a modified COP‐BLAM regimen was administered every 21 days. G‐CSF was added when the granulocyte count fell below 1000 × 109/l. Ninety‐eight of 104 (94.2%) patients achieved a complete remission; the 4‐year survival rate was 82.4% with a median duration of observation of 26 months. Survival was significantly longer in patients with low serum LDH levels, B‐cell type or low CRP or in earlier clinical stages, than in patients with high serum LDH levels, T‐cell type or higher CRP levels or in advanced clinical stages. The mean duration of administration of G‐CSF was 5.4 days. Twelve patients developed infections during treatment. The adverse effects of G‐CSF included interstitial pneumonia, bone pain and fever. Patients administered COP‐BLAM combined with G‐CSF achieved a high rate of remission and had a low incidence of infection. Nearly all the patients could be treated in 21‐day cycles. The results suggest that G‐CSF combined with COP‐BLAM was effective in treating NHL, because the patients can tolerate a higher dose of the anticancer agents.