Posttreatment M-protein nadir level is a significant prognostic factor associated with survival in multiple myeloma. Nagoya Myeloma Cooperative Study Group.

In the present study 142 patients with myeloma (102 with IgG M-protein and 40 with IgA) treated with either VMCP (65 patients) or MMCP (77 patients) as remission induction therapy were retrospectively analyzed. Response to treatment was evaluated in terms of a more-than-50% fall of pretreatment M-protein and the posttreatment M-protein nadir. Though significantly more patients treated with MMCP achieved partial response (PR) as compared with those treated with VMCP (P=0.019) and though patients achieving PR showed a significantly longer survival than those with less responsiveness (P=0.0091), the difference in survival curves between the two treatment groups was not significant (P=0.1871). The difference in response between the treatment groups evaluated in terms of posttreatment nadir was not significant (P=0.507). Multivariate analysis identified posttreatment M-protein nadir as a significant prognostic factor associated with survival, along with 3 other factors: sex, performance status, and hemoglobin. The lack of difference between the survival curves for patients treated with the 2 regimens despite the significantly different response rates evaluated in terms of percent fall of pretreatment M-protein levels was considered to be due to the lack of a difference in the ability to induce a deep posttreatment nadir between the regimens. Posttreatment M-protein nadir is an important prognostic factor associated with survival and should be included in the evaluation of the efficacy of chemotherapy.

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

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.

[Short-term intensive consolidation chemotherapy in the treatment of acute nonlymphocytic leukemia].

Thirty-four adults with AML were treated with conventional remission induction chemotherapy consisting of Ara-C and daunorubicin. The median age was 55 years. Thirty (88%) patients showing complete remission (CR) were treated with four courses of intensive consolidation chemotherapy: course 1 with 7 days Ara-C and 4 days of mitoxantrone; course 2 and 7 days Ara-C, 5 days of etoposide, vincristine day 10 and vinblastine day 12 (A-Triple-V); course 3 with 7 days Ara-C and 3 days of aclacinomycin; course 4 with 7 days Ara-C and 3 days of daunorubicin. Then patients were observed without further therapy until relapse. The median duration of relapse-free survival for patients < 60 years of age was 13 months, with 49% patients projected to continue first CR at 52 months. In contrast, only 19% of patients 60 years or older were projected to be in CR at 22 months. Most patients experienced significant side effects including fever, liver dysfunction, pneumonia and septicemia during consolidation therapies. Short-term intensive consolidation therapy appeared to be efficacious for patients < 60 years of age. The results in older individuals were worse than expected, and the use of G-CSF was suggested to improve this problem.

[Late phase II study of MST-16 (sobuzoxane) on malignant lymphoma].

Late phase II trial of MST-16 for malignant lymphoma was conducted by the multi-institutions collaboration. Out of 34 patients entered, 29 were evaluated for efficacy as well as side effects. One complete response and 8 partial responses were achieved by the treatment of MST-16. The factors which affect the response rate were prior chemotherapies, stage of disease and performance status. The main toxicities were bone marrow suppression and G-I disorders. Leukopenia was observed in 72.4% of patients, thrombocytopenia in 44.8% and nausea/vomiting in 31.0%. Patients recovered from these side effects by discontinuation of the MST-16 therapy.

[Biphenotypic acute leukemia with Ph1 chromosome, M-BCR-, myeloperoxidase+, and CALLA+].

A 63 year-old woman was referred to our hospital because of fever and increased number of blasts in the bone marrow. On physical examination she had slight hepatomegaly but no splenomegaly. Laboratory tests disclosed a hemoglobin level of 8.5 g/dl; a WBC count of 13,200/microliter with 26% blasts; a platelet count of 51,000/microliter. A bone marrow aspirate was normocellular with 74% blasts and 37% blasts were stained positive for myeloperoxidase. Cell surface markers for HLA-DR, CD10, CD19, CD13, CD33 were positive. Karyotype analysis revealed 46, XX, t (9q+; 22q-) and 45XX, -7, t (9q+; 22q-). Southern analysis showed rearrangement of immunoglobulin heavy chain but not T cell receptor beta gene. Rearrangements in M-BCR were not detected with 5' or 3' bcr probes. After 2 courses of chemotherapy, blasts decreased to 7% with recovery of normal elements and 11 out of 20 metaphases of the bone marrow cells were normal karyotype. These findings suggest that this case was de novo Ph1 positive acute leukemia which demonstrated both lymphoid and myeloid features.

Multi-drug combination therapy with vincristine-melphalan-cyclophosphamide-prednisolone was more effective than cyclophosphamide-prednisolone in stage III myeloma. The Nagoya Myeloma Cooperative Study Group.

A cooperative randomized clinical trial to compare the effectiveness of multi-drug combination chemotherapy (VMCP), vincristine-melphalan-cyclophosphamide-prednisolone) with CP (cyclophosphamide-prednisolone) for the treatment of multiple myeloma was performed. When the whole group of patients was evaluated, the choice of chemotherapy (VMCP or CP) was not a significant prognostic factor associated with response or survival by uni- or multivariate analysis, and the difference between the survival curves of the treatment groups was only marginally significant. However, when the analysis was confined to stage III patients, the choice of chemotherapy became a significant prognostic factor associated with both response rate and survival, and the statistical difference between survival curves was significant. Taking the disease characteristics of multiple myeloma into consideration, the better result obtained with multi-drug combination chemotherapy in the treatment of stage III patients is consistent with other studies supporting the superiority of multi-drug combination chemotherapy for patients with overt systemic disease.

[Weekly CHOP chemotherapy in the treatment of intermediate-grade non-Hodgkin's lymphomas--cooperative group study by seven institutes].

Between 1985 and 1988, 49 previously untreated patients with intermediate-grade non-Hodgkin's lymphoma (LSG classification large cell 35 including 11 large cell immunoblastic by Working Formulation, medium-sized cell 7, mixed 7) were treated with the Weekly CHOP regimen (three successive weekly administration of cyclophosphamide, doxorubicin, vincristine and prednisolone) as a cooperative group study by seven institutes (Nagoya Lymphoma Study Group). Complete remission was achieved in 63.3% with Weekly CHOP alone and finally in 79.6% after the addition of radiotherapy and/or combination chemotherapies including etoposide, methotrexate, procarbazine, bleomycin. Patients with T cell phenotype, high grade PS and the presence of bulky mass had significantly lower rates of CR. After a median follow-up 36 months Kaplan-Meier estimates showed that overall survival was 60.4%, disease-free survival 51.4% and relapse-free survival 64.6%. The major toxicities were alopecia, leukopenia, infection, neuropathy and gastrointestinal symptoms. No treatment-related deaths were observed. Survival was adversely affected by high LDH level, poor PS, T cell phenotype, the presence of B symptoms and the bulky mass. But these characteristics gave no significant effects on relapse rate and relapse-free survival. Thus, Weekly CHOP is an effective treatment for intermediate-grade NHL.

[Effects of ceftriaxone on severe infectious complications in hematological disorders. Tohkai Research Group on Infections in Hematological Disorders].

Ceftriaxone (CTRX), a new long acting antibiotic in the 3rd generation cephem group, was administered intravenously once or twice a day in daily doses of 1-6 g for at least 3 days to 86 patients with severe infections complicating hematopoietic disorders. Underlying diseases were acute leukemia in 41 cases, chronic leukemia in 3 cases, malignant lymphoma in 19 cases, myeloma in 7 cases and others. Most patients (55 cases) suffered from sepsis or suspected sepsis. As for efficacy rates classified by underlying diseases, the treatment was effective in 61.0% of patients with acute leukemia. As for efficacy rates classified by infections, the treatment was effective in 60.0% of patients with sepsis. No side effects were noted except rash in 2 patients. Abnormal hepatic functions were recognized in 3 patients but were not attributed to the agent in any case. The results indicate that CTRX is a safe and useful antibiotic for the treatment of severe infections accompanied by hematopoietic disorders.

[The continuous-DCMP therapy for acute nonlymphocytic leukemia in elderly patients--comparison with younger patients].

Twenty seven previously untreated patients of acute nonlymphocytic leukemia with age ranging from 30 to 77 years, received a 7-day remission induction regimen consisting of daunorubicin, cytosine arabinoside, 6-mercaptopurine and prednisolone (continuous-DCMP). Patients who achieved complete remission were given ten courses of consolidation therapy and followed without any maintenance therapy. The complete remissions were obtained in 7 of 15 patients (46.6%) 60 years and older, and in 11 of 12 patients (91.7%) 30-59, years of age. Although a high mortality during periods of marrow hypoplasia after the intensive induction therapy, and early relapses in the 60 years and older patients remain major problems, our data suggest the elderly patients deserve a trial of intensive combination chemotherapy.

[A case of RAEB in transformation successfully treated by low-dose Ara-C treatment].

A 65-year-old male admitted to the Anjo Kosei Hospital due to pancytopenia. The findings at the time of admission were; leukocyte count 2,000/microliters, erythrocyte count 1,580,000/microliters, and platelet count 88,000/microliters. Bone marrow specimen revealed mild hypocellularity with 26% of the blast cells. He was diagnosed RAEB in transformation. Chromosome analysis showed 46, XY, -7, +8, -17, + marker in three cells and 45, XY, -7, -17, + marker in two cells out of five cells. He was treated with the low-dose Ara-C (20mg/body s.c. injections every 12 hrs) for 9 days. Twenty five days later, the blast cells in the bone marrow decreased to 4%, and the complete remission was obtained. The duration of remission is 27+ weeks. At the time of complete remission, the bone marrow cells showed the normal karyotype. In this case, the effect of low-dose Ara-C to the blast cells may have not resulted from induction of differentiation but cytocydal action.

[Phase II study of carboplatin in malignant lymphoma].

A phase II study of carboplatin for malignant lymphoma was conducted. Thirty-nine patients with malignant lymphoma were entered into this study, and 6 of them were excluded from evaluation due to violation of selection criteria. The remaining 33 cases were studied to assess the effectiveness and safety of this drug. Two CR and 11 PR were obtained with this medication (effective rate 39%). The significant affecting factors were previous treatment, disease stage and P.S. score. Many cases suffered from gastrointestinal symptoms and reduced hematopoiesis. The former complication was self-limited without any fatal episodes. However, the latter included severe cases, especially thrombocytopenia, which is suggested to be a dose limiting factor (DLF) of this drug.

[Effects of combination chemotherapy M-VEMFH including mitoxantrone in advanced breast cancer].

The effects of combination chemotherapy including mitoxantrone (MXN) "M-VEMFH" for advanced breast cancer were studied. The M-VEMFH regimen consisted of MXN 7 mg/m2, VCR 0.7 mg/m2, EX 333 mg/m2, MTX 13.3 mg/m2 i.v. on day 1, 5-FU 333 mg/m2 i.v. from day 1 to day 5 and pred. (H) 60 mg/m2 p.o. with tapering off in 2 weeks. In 7 cases heavily pretreated with combination chemotherapy including ADR, CR 2, PR 2, NC 2 and PD 1 were observed (response rate 57.1%). In 5 cases without prior ADR, PR 1, NC 2 and PD 2 were obtained. One case given 586 mg/m2 of prior ADR died of congestive heart failure after administration of 47 mg/m2 of NXN. One case died of sepsis. The other side effects were stomatitis, vulvitis, abnormal gustation, nausea, vomiting and alopecia. M-VEMFH is effective combination chemotherapy for advanced breast cancer resistant to ADR, but care must be exerted due to the accompanying cardiotoxicity and leukopenia.