Hideo Takeyama

Human urinary macrophage colony-stimulating factor reduces the incidence and duration of febrile neutropenia and shortens the period required to finish three courses of intensive consolidation therapy in acute myeloid leukemia: a double-blind controlled study

PURPOSE To determine whether macrophage colony-stimulating factor (M-CSF) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy. PATIENTS AND METHODS In 198 adult patients with acute myeloid leukemia (AML) in complete remission (CR), M-CSF (8 x 10(6) U/d) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days. RESULTS The duration and incidence of febrile neutropenia was significantly reduced by 34% (P = .00285) and 17% (P = .02065), respectively, in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group. Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk, while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk. The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group, which was significantly shorter than 110 days in placebo group (P = .0050). In the M-CSF group, the recovery of neutrophils and platelets was significantly faster (P = .0348 and P = 0.0364, respectively), the administration of systemic antimicrobial agents tended to be less (P = .0839), and the frequency of platelet transfusion (P = .0259) and the total volume of transfused platelets (P = .0292) were significantly less. However, there was no significant difference in the disease-free survival. CONCLUSION M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy, and shortened the time to complete consolidation chemotherapy in AML.

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.

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.

Multi-drug Combination Therapy with Vincristine-Melphalan-Cyclophosphamide-Prednisolone Was More Effective than Cyclophosphamide-Prednisolone in Stage III Myeloma

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.

Posttreatment M-Protein Nadir Level Is a Significant Prognostic Factor Associated with Survival in Multiple Myeloma

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.

SEPTICEMIA IN PATIENTS WITH ACUTE LEUKEMIA AND RESULT OF ITS TREATMENT

1969年より1977年までの9年間に名古屋大学第一内科および愛知県職員病院内科に入院した成人急性白血病患者179例に合併した48症例延54例の敗血症を対象とし,起炎菌の種類ならびに抗生物質療法の効果を中心に検討した.起炎菌はE. coli15例, Pseudomonas aeruginosa 12例, Pseudomonas sp. 2例, Klebsiella pneumoniae 6例, Serratia marcescens 5例, Aeromonas hydrophila 4例, Acinetobacter anitratus 3例等グラム陰性桿菌が計51例で全体の89.5%を占めた.グラム陽性菌はStaph. aureusの1例のみであり,嫌気性菌が2例,真菌が3例みられた.発症時の末梢血成熟好中球数は0であつたもの19例を含み,中央値で40/cmmであつた.これらの高度の顆粒球減少状態にある敗血症に対しcarbenicillin, sulbenicillin, cephalothin, cefazolin, gentamicin, dibekacin, amikacinを中心とする抗生物質の大量併用療法を試みた所,白血病治療開始前に発症した4例中全例,初回寛解導入期に発症した22例中18例,再発寛解導入期の5例中4例,強化療法期の1例中1例,計32例中27例(84.4%)が治療可能であつたのに比し,終末増悪期に発生した22例中治癒したのは6例のみで, 16例は死亡した. 54例中27例はショック状態におちいつたが,内15例は治癒可能であり,このような重篤な敗血症でも,抗生物質大量併用投与,白血球輸血等の積極的な治療により充分治癒可能であると考えられる.