Mitoxantrone in refractory acute leukemia in children: A phase I study

Summary Nine children with acute non-lymphocytic leukemia (ANLL), ages 16 months to 16 years (median 7 years), and 15 children with acute lymphocytic leukemia (ALL), ages 10 months to 18 years (median 5 years), were treated with 5-day courses of mitoxantrone (Novantrone®; dihydroxyanthracenedione) as induction therapy. All the children had leukemia which was resistant to conventional therapy and all but one patient had received anthracycline therapy prior to the initiation of this trial. Three patients (two with ANLL, one with ALL) received the drug at a dose of 6 mg/m²/day i.v. for 5 days. Both patients with ANLL achieved partial remissions (PR) (105 and 87 days duration). The child with ALL failed to respond to two courses of the drug, and died of progressive disease 45 days after the institution of therapy. Twenty-one patients (14 with ALL, seven with ANLL) were treated with 8 mg/m²/day i.v. mitoxantrone for 5 days. There were three early deaths (all ALL) which were not felt to be secondary to drug toxicity. Four of the 18 children achieved complete remission (CR) (one ANLL — 35 days; three ALL — 39, 31 and 13 days). One child with ANLL achieved a PR (13 days) and one child with ALL showed improvement in his bone marrow status. Twelve children failed to respond to this therapy.Dose-limiting toxicity was not seen among the patients who received 6 mg/m²/day for 5 days. There were five patients who had mucositis and one patient who had nausea and vomiting among those patients who received 8 mg/m²/day for 5 days. Four of these children had significant decreases in the myocardial shortening fraction as measured by echocardiography. None of these patients had clinical signs of cardiotoxicity.The CR plus PR rate for both dose levels is 33%. Mitoxantrone appears to be an effective agent for remission induction in children with late stage ALL and ANLL. Toxicity was not a significant problem at the doses used in this trial.     

供体白细胞输注治疗急慢性白血病和多发性骨髓瘤

目的　观察供体白细胞输注 (DL I)治疗急慢性白血病和多发性骨髓瘤的疗效和安全性。方法　慢性髓性白血病 (CML ) 7例 ,慢性期 (CML - CP) 5例 ,加速期 (CML - AP)和急性变 (CML - BP)各 1例 ,急性髓性白血病 (AML - m2 ) ,急性淋巴细胞白血病 (A L L )和多发性骨髓瘤 (MM)各 2例。预处理方案用去髓性和非去髓性两种。供体白细胞采用 COBE,Spectra血细胞分离机 ,回输的细胞数 (CD3 +)细胞为 (0 .6～ 3.4)× 10 7/ kg,平均细胞数 1.7× 10 7/ kg,DL I前停用免疫抑制剂。非去髓性异基因干细胞移植 (NST)患者通常在移植后每月输注 1次 ,连续 1～ 4次。对移植后或化疗、放疗后复发的患者 ,在复发的早期每月输注 1次 ,也连续 1～ 4次。结果　 4例 NST后的 CML- CP患者 DL I2次后嵌合体逐渐形成 ,其中 1例发生全血细胞减少 ,骨髓增生不良 ,经对症治疗后获得CR。 1例异基因骨髓移植后 (allo- BMT)复发的 CML- CP患者在 DL I1次后发生严重再障 ,经抢救后恢复并获CR2 ,长期生存。 1例 CML- AP及 1例 CML- BP患者 NST后虽然联合 DL I2次 ,嵌合体也未出现。 2例 NST后的A ML 患者在 DL I1次后混合嵌合体出现 ,现仍在随访中。 2例 DL I各 1次的 AL L 复发患者 (allo- BMT1例 ) (化疗及交替半身照射后复发 1例 )分别?     

Phase I Study of Irofulven (MGI 114), an Acylfulvene Illudin Analog, in Patients with Acute Leukemia

Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF)is a semisynthetic illudin analog with broad in vitroanti-neoplastic activity. In this leukemia phase I study, weinvestigated the toxicity profile and activity of Irofulven inpatients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ormyelodysplastic syndromes (MDS). Irofulven was given as anintravenous infusion over five minutes daily for five days.The starting dose was 10 mg/m²/day (50mg/m²/course). Courses were scheduled to be givenevery 3-4 weeks according to toxicity and antileukemicefficacy. Twenty patients {AML: 17 patients; MDS: onepatient; ALL: one patient; mixed lineage acute leukemia: onepatient} were treated. Nausea, vomiting, hepatic dysfunction,weakness, renal dysfunction, and pulmonary edema were doselimiting toxicities, occurring in two of five patientstreated at 20 mg/m²/day and two of three patientstreated at 12.5 mg/m²/day. The MTD was defined as10 mg/m²/day for five days. One patient withprimary resistant AML achieved complete remission. Proposedphase II studies will further define the activity of Irofulvenin patients with better prognosis AML and in otherhematological malignancies, both as a single agent and incombination regimens, particularly with topoisomerase 1inhibitors.     

Prognostic factors in adult patients with acute leukemia

An analysis of prognostic factors was performed on a series of 50 adult patients with acute leukemia, treated in our department in the Tokai university Hospital between July, 1975 and June, 1980. The diagnosis was made in all cases on the basis of May-Grünwald-Giemsa-stained smears of peripheral blood and bone marrow. The patients were treated with two successive protocols. One course of induction chemotherapy consisted of 40 units/kg/day of neocarzinostatin, 1.2-1.6 mg/kg/day of cytosine arabinoside, 0.6-0.8 mg/kg/day of daunorubicin and 0.8-1.6 mg/kg/day of prednisolone on days 1-4 for acute nonlymphocytic leukemia, and the other consisted of 0.04 mg/kg/day of vincristine on day 1, 0.6-0.8 mg/kg/day of daunorubicin on days 1-4, 0.8-1.6 mg/kg/day of prednisolone on days 1-4 for acute lymphocytic leukemia. Consolidation and intensification therapies were given every 1-2 months after complete remission, and the protocols were basically the same as those of the induction therapy. Maintenance therapy consisted of 1.2-1.6 mg/kg/day of cytosine arabinoside, twice a week or 2 mg/kg/day of 6 MP orally. Risk factor leading to poor prognosis of acute leukemia were considered to be (1) advanced age (older than 50 years, P less than 0.05), (2) M5 (monocytic leukemia), (3) thrombocytopenia (less than 50,000 cmm-1), and (4) chromosome abnormalities of blast cells.     

HLA半相合外周血造血干细胞移植治疗急性白血病的临床观察

目的：探讨HLA半相合外周血造血干细胞移植（peripheral blood stem cell transplantation，PBSCT）治疗急性白血病的效果及安全性。方法：4例急性白血病行HLA半相合PBSCT，其中急性淋巴细胞白血病2例，急性非淋巴细胞白血病2例，移植时均处于完全缓解状态。HLA配型1、2个位点不合各1例，3个位点不合2例。预处理方案由全身照射或白消安、阿糖胞苷、环磷酰胺、甲基洛莫司汀组成。移植物抗宿主病（graft versus hostdisease，GVHD）的预防采用环胞素、甲氨蝶呤、麦考酚吗乙酯、抗胸腺细胞球蛋白四联方案。结果：4例均获得造血功能重建。2例出现Ⅰ度急性GVHD，2例出现Ⅱ度急性GVHD。1例并发巨细胞病毒间质性肺炎，2例并发真菌肺炎。至今3例无病存活29、15和2个月，1例死亡。结论：HLA半相合PBSCT疗效较好、安全可行，为无HLA完全相合供者的白血病患者提供了新的治疗手段，但要特别注意移植后病毒和真菌感染的防治。     

索拉菲尼单药治疗FLT3-ITD突变阴性和CD117高表达的复发/难治型急性髓系白血病临床观察

目的 初步分析索拉菲尼单药治疗FLT3-ITD突变阴性和CD117高表达的复发/难治型急性髓系白血病（R/R AML） 患者临床疗效。方法 回顾性分析7例高表达CD117但FLT3-ITD突变阴性的R/R AML患者应用索拉菲尼单药治疗后的临床反应和生存情况。治疗不良反应依据常见不良反应事件评价标准 （CTCAE） v4.0进行评估, 缓解标准依据NCCN指南确定。结果 7例患者中4例治疗获得缓解, 诱导完全缓解所需中位时间为36 d。索拉菲尼维持治疗过程中1例因皮疹疼痛中断治疗。3例对索拉菲尼治疗无反应者中2例接受挽救性移植治疗, 1例接受挽救性化疗, 均再度缓解。治疗期间, 1例出现1级肝脏不良反应, 1例出现3级皮损不良反应, 所有患者均有粒细胞缺乏 （> 7 d）, 但未出现早期死亡。患者中位随访时间达到22个月, 3例缓解患者在索拉菲尼维持治疗后AML复发死亡, 其无病生存时间为2~20个月。无论索拉菲尼诱导治疗是否缓解, 接受了骨髓移植治疗的4例患者至今仍存活。7例患者的中位生存时间达650 d。结论 高表达CD117的R/R AML患者使用单药索拉菲尼治疗缓解表现较好, 有利于患者的长期生存。     

Mitoxantrone in the treatment of relapsed and refractory acute leukemia

Summary Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone®; dihydroxyanthracenedione) was administered in a dose of 8–13 mg/m² on five consecutive days. Five of 20 evaluable patients were induced into complete remission, one patient achieved a partial remission. Side-effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.     

达沙替尼治疗伊马替尼耐药的 BCR／ABL阳性白血病

目的评价达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性。方法对9例伊马替尼耐药的慢性髓系白血病（CML）或Ph阳性急性淋巴细胞白血病（Ph＋ALL）患者,给予达沙替尼100～140 mg·d-1口服治疗,评估疗效和耐受情况。结果 9例伊马替尼耐药的BCR/ABL阳性白血病,2例CML-CP患者均获得CHR,1例达CCyR;5例CML-BC患者中4例获得CHR和PCyR,1例NR;2例Ph＋ALL患者中1例检测到E255V突变,采用达沙替尼治疗达CHR和PCyR,1例诱导缓解时,同时行VDP方案化疗,继发严重感染死亡。结论达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病患者可获得血液学甚至细胞遗传学缓解,且耐受性好。     

Marrow transplantation: the Seattle experience

Marrow transplantation is effective treatment for a number of hematological diseases in patients under the age of 50 who have an HLA-identical sibling donor. It is successful in the treatment of aplastic anemia with 70-85% long-term survival. It offers 10-30% apparent cures for patients with acute leukemia who have relapsed at least once, and for those with chronic myelocytic leukemia in blast crisis. Although still somewhat controversial, it appears to be the treatment of choice for patients with acute nonlymphoblastic leukemia in first chemotherapy induced remission, and for those with chronic myelogenous leukemia in the chronic phase since approximately 50-60% of these patients experience long-term, disease-free survival. Patients with acute lymphoblastic leukemia grafted in second or subsequent remission may expect a 30% "cure" of their disease. Marrow grafting is the only effective treatment for many patients with inherited immunologic deficiencies and certain genetic storage diseases. Cures of congenital Fanconi's anemia, Blackfan-Diamond anemia, osteopetrosis, paroxysmal nocturnal hemoglobinuria and thalassemia major have been achieved. Marrow transplantation is being explored for the therapy of patients with lymphoma, Hodgkin's disease, preleukemia, multiple myeloma, hairy cell leukemia, small cell lung cancer, testicular cancer, ovarian cancer and neuroblastoma. Marrow transplantation has been limited by the fact that many patients do not have HLA-identical siblings and very few have monozygotic twins. More recently, marrow transplants from HLA-nonidentical family members and even from unrelated donors have been successfully explored.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase I clinical and pharmacokinetic study of menogaril (7-con-O-methylnogarol) in previously treated patients with acute leukemia

Summary Fifteen patients with relapsed or refractory acute leukemia were treated in this phase I study of menogaril (7-con-O-methylnogarol), a nogalamycin anthracycline derivative. Doses ranged from 50 mg/m²/day to 130 mg/m²/day, administered daily for 5 days. Pharmacokinetic studies were performed at each dose level and confirmed the findings of pharmacokinetic data derived from previous studies in patients with solid tumors. All patients experienced grade 4 hematologic toxicity and the dose limiting toxicity was mucositis. Two patients, one with acute myeloid leukemia and one with acute lymphoid leukemia, achieved complete responses. The AML complete response lasted 10 months and the ALL patient died in CR at 2 + months. Both patients were treated at a dose of 100 mg/m²/day for five days. At this dose, a second induction or consolidation course could be given without severe mucositis, and this is the dose recommended for further phase II studies in leukemia using this schedule.     

Mitoxantrone (dihydroxyanthracenedione) in acute leukemia

Fifty-eight evaluable patients with acute leukemia were treated with Mitoxantrone (DHAD) according to two schedules: 14 mg/M2 as a single I.V. pulse dose administered three-week intervals, and 4 mg/M2/day for five days every three weeks. Six of 58 patients achieved a complete remission. One complete remission and 1 partial remission were observed among 26 patients treated with the single pulse schedule. Five (16%) complete remissions were attained among 32 patients treated on the daily × 5 schedule. Responses were observed only in patients with non-lymphoblastic leukemia. DHAD was very well tolerated with myelosuppression as the major toxicity. Nausea and vomiting were minimal. Subclinical cardiac toxicity occurred in two patients. This was identified by serial reductions in cardiac ejection fractions. DHAD appears to have significant activity in acute non-lymphoblastic leukemia with minimal toxicity.     

Treatment of acute myeloid leukemia during the second and third trimesters of pregnancy

Fortunately, the occurrence of acute myeloid leukemia (AML) during pregnancy is rare. We report a case of successful fetal outcome with standard induction and consolidation treatment in the second and third trimesters, respectively. A 37-year-old woman in her second trimester (21 wks) of pregnancy was found to have acute myeloid leukemia. She elected to maintain the pregnancy and underwent induction with cytarabine and idarubicin. Her hospital course was complicated by Pseudomonas vesicularis and gram-positive bacilli (not Bacillus anthracis) septicemia, but she obtained complete remission. After discharge, a fetal echocardiogram at 26 weeks revealed a mildly dilated right ventricle with mild systolic dysfunction, and the left ventricle appeared smaller than normal with mild systolic dysfunction. The patient then received consolidation therapy with high-dose cytarabine. On day 14 of consolidation, filgrastim 16 mug/kg was added to improve stem cell mobilization. A total of 19.8x10(6) CD34+ cells/kg were collected with a single apheresis session. At 37 weeks, she delivered a viable female infant weighing 3 lbs 12 oz. Fetal abnormalities included acrocyanosis, shallow sacral dimple, short digits and limbs, and prominent frontal skull with mild macrognathia. A postnatal echocardiogram revealed a moderate-sized membranous ventricular septal defect. The ventricular septal defect proved significant and required surgical repair at 5 months. Approximately 4 weeks after delivery, the mother underwent autologous peripheral stem cell transplantation. Unfortunately, 100 days after transplantation, she had a relapse of AML. After a brief remission from a second induction, the patient died.     

Allogeneic bone marrow transplantation in the treatment of hematologic diseases

The current use of allogeneic bone marrow transplantation in various hematologic diseases is reviewed. Bone marrow transplantation (BMT) involves infusion of bone marrow from a suitable donor into a properly conditioned recipient. Most BMT is allogeneic, in which the donor is genetically dissimilar but shares some common tissue antigens with the recipient. Almost all patients undergoing allogeneic BMT must be "prepared" with high-dose cyclophosphamide to prevent graft rejection. Most patients with hematologic malignancy also receive total body irradiation to eradicate malignant cells located in areas inaccessible to the systemic circulation. Bone marrow transplantation is the treatment of choice for severe aplastic anemia. In acute myelogenous leukemia, the best results are observed in young patients undergoing BMT in first remission. In acute lymphoblastic leukemia, BMT is usually reserved for patients in second or subsequent remission. Early results are promising in patients with chronic myelogenous leukemia who receive BMT before the accelerated phase or blast crisis of this disease. Allogeneic BMT offers an opportunity for cure in some patients with relapses of Hodgkin's disease or those with certain subtypes of non-Hodgkin's lymphoma. Other diseases for which BMT has been used include severe combined immune deficiency disease, Fanconi's anemia, and multiple myeloma. Complications of BMT include graft failure or rejection, acute and chronic graft-versus-host disease, and infectious complications; late complications, such as restrictive and obstructive pulmonary disease, cataracts, sterility, and secondary malignancies, may also occur. Bone marrow transplantation has become an important treatment for many hematologic diseases, but it will probably remain a treatment reserved for only a few highly specialized centers. If morbidity and mortality caused by transplant-related complications can be reduced, BMT may be offered to older patients and those without HLA-identical sibling donors.     

Streptozotocin (NSC-85998) in children with acute lymphocytic leukemia. A Southwest Oncology Group study.

Streptozotocin (NSC-85998), a nitrosourea antibiotic, was given to 18 children with acute lymphocytic leukemia in relapse in a dose of 500 mg/m2/day intravenously every day for five days. There were no responses in 14 fully evaluable patients. The principal toxicity consisted of gastrointestinal disturbances. Based on our findings and those of others in adults, steptozotocin appears to play no role in the management of acute lymphocytic leukemia.     

较高剂量柔红霉素诱导老年急性髓性白血病缓解的疗效分析

目的 探讨较高剂量柔红霉素(DNR)对诱导老年急性髓性白血病（AML）缓解及疗效的作用。方法 随机将123例老年AML分为三组,分别给予标准剂量、低于标准剂量和高于标准剂量的DNR,联合阿糖胞苷（Ara-c）作为首次诱导缓解方案,对比分析化疗产生的不良反应、完全缓解率和两年生存情况。结果 DNR高于标准剂量组血液学毒性反应的发生较标准剂量组未明显增加,而缓解所用时间短（P<0.01）、完全缓解率（63.4% vs 29.3%）和两年无事件生存率（58.5% vs 26.8%）提高（P值均<0.05）。结论 较高剂量DNR可作为诱导老年AML缓解较理想的选择。     

Liver transplantation for viral hepatitis

Current one year survival rates of 73-83% for elective transplantation, and 55-70% for emergency transplantation, render liver transplantation an appropriate treatment for both end-stage chronic liver disease and acute liver failure. Candidates for transplantation for acute liver failure need to be identified as early as possible, and a model for selection using clinical criteria is described. Recurrent viral infection after transplantation is either a possible or proven problem in all patient subgroups, but the clearest manifestation is in patients with chronic hepatitis B infection. In our series of 29 patients surviving at least 60 days after transplantation, 41% died as a consequence of recurrent infection at 3-13 months. Delta virus infection appears to confer some protection in this regard, and the role of long-term immunoprophylaxis in preventing this serious complication remains to be established.     

奈拉滨治疗2例成人复发/难治性T淋巴细胞白血病的疗效并文献复习

目的观察奈拉滨治疗成人复发/难治性T淋巴细胞白血病的疗效及不良反应。方法奈拉滨1 500 mg/(m2.d)静滴2 h(第1、3、5天),21 d为1个疗程。1例复发性T-ALL给予2个疗程,1例难治性T-ALL给予1个疗程。结果 1例复发T-ALL在第1个疗程后获完全缓解伴不完全血象恢复(CRi),继续应用奈拉滨1个疗程后获CR。但4个月后疾病再次复发。8个月后死于急性心肌梗塞。另1例难治性T-ALL应用1个疗程后无治疗反应,停用奈拉滨,应用其他联合化疗后获CR,已行异基因造血干细胞移植,病情稳定。2例患者均出现Ⅲ～Ⅳ级血液学不良反应,Ⅰ～Ⅱ级神经系统毒性,Ⅰ级消化道反应,1例出现轻度肝功异常。无奈拉滨治疗相关死亡。结论奈拉滨用于治疗复发/难治性T淋巴细胞白血病,疗效尚可,不良反应可以耐受,可作为T-ALL治疗的一个新选择。     

Present status of bone marrow transplantation in Japan

One hundred and seventy three bone marrow transplantations (BMT) including 133 allogeneic, 17 syngeneic and 23 autologous BMT were recorded in Japan during the period between September, 1975 and March, 1984. The number of cases of BMT increased rapidly over the years, i.e., 16 cases in 1980, 27 in 1981, 39 in 1982 and 57 in 1983. All cases were treated in clean rooms, many of them receiving intensive gut decontamination containing vancomycin. In 110 cases with acute leukemia, the main causes of death were interstitial pneumonitis, relapse of leukemia, infection and GvHD. Favorable factors determined from 180-day survival were remission, no infection, low dose rate and fractionated total body irradiation (TBI), ABO minor mismatch and positive graft versus host reaction. Long-term survival of patients who received BMT during remission and were without infection amounted to 70% of acute lymphocytic leukemia (ALL) and 40% of acute myelogenous leukemia (AML) patients. Cyclosporin A (Cy-A) administered in 21 cases was compared with methotrexate (MTX) given in 20 cases. A statistically significant decrease of stomatitis was observed, while no difference in GvHD or survival was seen. There were seven cases giving a more than good response out of 11 cases treated with cyclosporin because methotrexate or immuran was ineffective or could not be administered due to toxicity. Such data suggest that allogeneic BMT is acceptable as a very promising form of treatment for acute leukemia in Japan.     

流式细胞术检测急性杂合性白血病的临床分析

目的分析流式细胞术检测急性杂合性白血病的临床效果。方法对本院收治的急性杂合性白血病（HAL）患者、伴有淋系抗原表达型急性髓细胞白血病（Ly＋AML）患者及伴有髓系抗原表达型急性淋巴细胞白血病（My＋ALL）患者于治疗一、二疗程后分别行流式细胞术检测,对比检测结果。结果 HAL患者在髓系CD33免疫表型的阳性率最高为95%,在B系CyCD22免疫表型的阳性率最高为75%,在T系CD7免疫表型的阳性率最高为30%,且在CD2、CyCD3、CD5中均有表达。第一、二疗程Ly＋AML与My＋ALL的诱导缓解率均明显高于HAL（P〈0.05或P〈0.01）。结论流式细胞术检测急性杂合性白血病具有较高的阳性检出率,对于临床治疗的效果评估具有重要的指导意义。     

急性白血病多药耐药性检测的临床应用

目的 探讨急性白血病（急白）患者多药耐药基因（ＭＤＲ１）表达的临床意义放应用。方法 对３５例初治急白患者采用Ｓ－Ｐ免疫组化染以法检测ＭＤＲ１表达产物,地部分患者进行动态观察并配合药敏测定,了解急白患者化疗前后耐药情况的变化。结果 本组３５例ＭＤＲ,表达阳性者１４例（４０％）,其中急性淋巴细胞白血病（急淋）９便,急性晨淋巴细胞白血病（急非淋）５例,两者无显著差异,１４例ＭＤＲ１表达阳性者,达完全缓解