Eiichi Nagura

Nation-wide randomized comparative study of doxorubicin, vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and withoutL-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P=0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP (P=0.955 by generalized Wilcoxon test [GW],P=0.952 by log-rank test [LR]). Median diseasefree survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance (P=0.141 by GW,P=0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype (P=0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP (P=0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL.

Treatment of plasma cell neoplasm with recombinant leukocyte A interferon and human lymphoblastoid interferon

SummaryThisty cases of plasma cell neoplasms (24 multiple myeloma, one plasma cell leukemia, and three primary macroglobulinemia) were treated with two kinds of highly purified α-interferons, recombinant human leukocyte interferon (rIFN-αA) (16 cases) and human lymphoblastoid interferon (HLBI) (14 cases). Partial remission (PR) was obtained in two of 16 evaluable cases treated with rIFN-αA and in two of 12 evaluable cases treated with HLBI. If minor response (MR) was included, responses were observed in seven (31.3%) and six (50%), respectively. Response (PR+MR) was noted in 38% of 21 previously treated patients and 71% of seven previously untreated patients. Side-effects were noted in more than two-thirds of the patients. They included fever, malaise, nausea/anorexia and myelosuppression. Thus, these two kinds of highly purified α-interferon were effective in plama cell neoplasm, producing unequivocal response in 14.3% of the cases without unacceptable side-effects.

Leukemia relapse in long-term survivors of acute leukemia

Between 1964 and 1982, 862 patients with acute leukemia who were collected from medical institutions throughout the country had a survival of 5 years or longer. Their remission has been achieved mainly with a combination therapy of vincristine and prednisone in childhood acute leukemia and daunomycin, cytosine arabinoside, 6‐mercaptopurine, prednisone (DCMP) regimen in adult acute leukemia. Among 320 relapsed patients, 88 (38.8%) of 227 children had a primary relapse in the marrow, 85 in the central nervous system (CNS), 37 in the testis/ovary, and 13 in a combined site. The large majority of adult relapsed patients relapsed in the marrow. Ninty‐three patients who experienced only one relapse had a much longer prolongation of survival, not yet reaching a median over 14 years after diagnosis, compared to those experiencing two or more relapses. Survival curves in five groups of patients divided by length of maintined remission were investigated by the life table method. In children as well as adults, survival duration in patients on 5 or more years maintained remission was significantly longer than that in the other maintained groups. With respect to relation between frequency of CNS relapse and type of CNS prophylaxis, there was no statistically significant difference between patients who received CNS prophylaxis and patients who did not. However, a better survival was observed in patients who received CNS prophylaxis with cranial radiation plus intrathecal methotrexate. Thus, long‐term clinical follow‐up might provide important information for the therapeutic strategy against acute leukemia.

Primary Plasma Cell Leukemia in the Era of Novel Agents: A Multicenter Study of the Japanese Society of Myeloma

We investigated the treatment and outcome of Japanese patients with primary plasma cell leukemia (pPCL) in the era of novel agents and analyzed the risk factors affecting survival. Among 3,318 patients with symptomatic multiple myeloma (MM), 38 patients were diagnosed with pPCL. The median overall survival (OS) of the pPCL patients was 2.85 years, which was significantly extended compared with that in previous reports. The proportion of patients treated with novel agents was 61%. The OS of the patients treated with novel agents was significantly extended compared with that of patients treated without novel agents according to the generalized Wilcoxon test (2.85 vs. 1.16 years, p = 0.049). This statistical finding suggests that treatment with novel agents could have prevented early death in the patients with pPCL. Age was the only statistically significant prognostic factor associated with an inferior OS (hazard ratio 4.57). Five patients received maintenance therapy with novel agents, and their OS tended to be longer than that of the other patients without maintenance (4.45 vs. 2.85 years). Unlike MM, OS for pPCL has not been improved significantly over the last decade, especially in elderly patients. Therefore, it is important to establish the treatment strategy, particularly after induction treatment.

Nationwide randomized comparative study of daunorubicin and aclarubicin in combination with behenoyl cytosine arabinoside, 6-mercaptopurine, and prednisolone for previously untreated acute myeloid leukemia

Aclarubicin was evaluated in combination chemotherapy for adult acute myeloid leukemia in a randomized trial involving 58 institutions throughout Japan. Behenoyl cytosine arabinoside (BH-AC)•daunorubicin, 6-mercaptopurine, and prednisolone (DMP) was compared with BH-AC•aclarubicin, 6-mercaptopurine, and prednisolone (AMP). In the 360 evaluable cases among the 433 cases enrolled, complete remission (CR) rates were 63.7% (116/182) for BH-AC•DMP and 53.9% (96/178) for BH-AC•AMP (P=0.0587). Median survival periods and 7-year survival rates were 15.8 months and 19.3% for BH-AC•DMP and 9.5 months and 20.2% for BH-AC•AMP (P=0.0091 according to the generalized Wilcoxon test [GW],P=0.196 according the log-rank test [LR]). Median disease-free survival periods were 15.4 months for BH-AC⊙DMP and 14.1 months for BH-AC•AMP (P=0.851 by GW,P=0.439 by LR). Among the 346 cases of extramurally confirmed FAB subtypes, CR rates were 67.9% (19/28) with BH-AC•DMP and 31.8% (7/22) with BH-AC•AMP for subtype M3 (P=0.011) and 63.3% (93/147) with BH-AC•DMP and 56.8% (84/148) with BH-AC•AMP (P=0.254) for subtypes M1, M2, M4, and M5. Diarrhea, ileus, pneumonia, and renal failure were more frequent with BH-AC•AMP than with BH-AC•DMP. The results indicate, at least on the basis of the long-term outcome, that BH-AC•AMP has antileukemic effects on subtypes M1, M2, M4, and M5 that are comparable with those of BH-AC•DMP.

Management of patients with multiple myeloma in Japan: data of 1,383 patients from 16 hospitals and 1 treatment group.

The available information regarding relevant treatment approaches and outcome in Japanese myeloma patients has been fragmentary and clarification of the position is required. The Japan Myeloma Study Group collected data on 1,383 patients who had been diagnosed and treated during the 11 year period between 1990 and 2000 from 16 participating hospitals and 1 treatment group to investigate the status of the management of multiple myeloma across Japan. There were 724 (53%) male and 643 (47%) female patients with median age being 66-years-old. More than 60% of the patients were classified as having stage III disease. As initial therapy, 1,162 (84.4%) patients were treated with chemotherapy and the median survival was 3.1 years. High-dose therapy followed by stem cell transplantation (SCT) as part of first-line therapy was given in 113 (7.4%) patients with median survival being 4.4 years.

Production of anti-self-H-2 antibodies by C3D2F1 mice hyperimmune to L cell/L1210 hybrids and L1210 leukemia cells

Abstract During the course of immunization of (C3H × DBA/2)F 1 mice (genotype H -2 k / b ) with L cell ( H -2 k / k )/L1210 leukemia cell ( H -2 d / d ) hybrids and L1210 leukemia cells, some of them produced a good titer of anti-self-H-2 (H-2 d ) antibodies. Antigens recognized by this anti-self-H-2 antiserum were shown to be controlled by the H-2K-IA-IB-IJ-IE subregions of the H -2 d but not H -2 k nor H -2 b haplotypes of parental as well as F 1 origins and to have a tissue distribution identical to that of class 1 H-2 (H-2K/D) antigens.

A randomized study comparing VMCP and MMPP in the treatment of multiple myeloma.

Abstract Purpose: To compare VMCP, a multidrug combination chemotherapy comprising vincristine (VCR), melphalan (MPH), cyclophosphamide (CPM) and prednisolone (PSL), with MMPP comprising MPH, ranimustine (MCNU), procarbazine, and PSL as induction, to elucidate the value of alternating combination chemotherapy, and to search for an appropriate maintenance therapy in multiple myeloma. Methods: At 16 institutions in the Nagoya City area, we carried out a randomized trial of VMCP versus MMPP as the initial treatment. Patients who were refractory or resistant to the initial therapy were crossed over into the other arm (crossover trial). For patients who achieved a partial response (PR) or a minor response (MR) and in whom the paraprotein level ceased to decrease, the maintenance therapy was randomized either to an MPH/PSL combination (MP) or to alternating combination therapy (AT) with VMCP and MMPP. Results: In the 94 evaluable patients of the 111 enrolled, the response rate (PR rate) was 27.7% (13/47) in the VMCP arm and 44.7% (21/47) in the MMPP arm (P=0.0859). The crossover trial resulted in a PR rate of 15.8% (3/19) for the VMCP→MMPP crossover and 14.3% (2/14) for the MMPP→VMCP crossover. The median survival time was 23.4 months for those initially begun in the VMCP arm and 24.9 months for those in the MMPP arm, showing a tendency for better survival during a follow-up of 2–6 years with MMPP treatment, but without statistical significance. The survival time of patients with progressive disease was significantly shorter than that of patients with PR, MR or no change (NC). However, there was no significant difference in the survival rate among those who achieved PR, MR, or NC. As to the maintenance therapy, there was no significant difference in survival between MP therapy and AT. Patients who reached a plateau phase survived significantly longer than those who did not. Except for six cases of grade 3 or 4 neurotoxicity in the VMCP arm, there was no significant difference in the hematologic or gastrointestinal toxicity between the two arms. Conclusions: We conclude that VMCP is less effective for myeloma than MMPP as the induction treatment, that alternating noncrossresistant chemotherapeutic combinations do not offer an advantage in multiple myeloma, and that patients who reach a plateau phase have a significantly longer survival time.

Mechanism of Methotrexate-sensitivity of Choriocarcinoma Cells in Culture

Four cell lines established from choriocarcinoma were compared for sensitivity to methotrexate (MTX). In this paper, we have compared the relative gene copy number of dihydrofolate reductase (DHFR), the target enzyme of methotrexate (MTX), in order to clarify whether or not amplification of the gene is involved in the relative resistance to MTX observed for one of the cell lines, designated NaUCC‐1, which is 4‐ to 5‐fold more resistant to MTX as compared with the other cell lines and exhibits a reduced uptake of [3H]MTX. Neither dot blot nor Southern blot hybridization revealed any significant difference in the gene copy number among the four cell lines. Therefore, the resistance to MTX of the NaUCC‐1 line is explained by a reduced uptake of the drug, rather than amplification of the target gene.

Simultaneous development of humoral and cellular tumor-specific immunity against L1210 mouse leukemia

We have recently described that a variant of L1210 leukemia cell (L1210/LN-1) originally fused with Lesch-Nyhan fibroblast is highly immunogenic for inducing tumor-specific transplantation immunity in (BALB/cxDBA/2)F1 mice. This finding has clearly been confirmed in the present study by in-vitro cell-mediated cytotoxicity assay. Direct cytotoxic tests and competitive inhibition tests using tumor cells such as P388, LS-1 and L5178Y as target or inhibitor cells showed that the cell-mediated immunity is specific to L1210 leukemia. In the process of this study, we found that the CD2F1 mice hyperimmune to L1210 leukemia cells developed co-existing humoral anti-L1210 leukemia immunity. In an in vitro complement-dependent cytotoxicity test and absorption test, antisera from hyperimmune mice reacted specifically to L1210 leukemia cells, but not other tumor cells such as P388, L5178Y, LS-1, DB27C and BW5147 or normal cells from various tissues of DBA/2, BALB/c and AKR mice. In an in vitro cytotoxicity blocking test, the cytotoxic antisera specifically reactive to L1210 cells totally failed to inhibit lysis of L1210 cells by cytotoxic cells, suggesting that antigens recognized by cell-mediated cytotoxicity assays are not identical to serologically defined tumor-cell surface antigens.