Vincristine and Prednisone for the Induction of Remissions in Acute Childhood Leukaemia

A total of 65 children with acute lymphoblastic leukaemia and seven with other types of acute leukaemia received treatment with a combination of vincristine and prednisone. In all 122 courses of treatment were given. Of 22 patients with acute lymphoblastic leukaemia who received this as their first treatment, all achieved complete remission. The complete remission rates were 82% for patients with acute lymphoblastic leukaemia in their first relapse, 63% in the second relapse, and much lower in subsequent relapses and in the patients with other types of acute leukaemia. Alopecia and gastrointestinal and neuromuscular toxicity occurred respectively in 51%, 29%, and 21% of instances, only the last of these side-effects of vincristine being dose-related. Most of the complete remissions were obtained with a total dose of vincristine which carried only a low risk of neurotoxicity.     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt''s lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.     

Treatment of Acute Myeloid Leukaemia according to the Hammersmith Protocol: Preliminary Report

A preliminary report is given of a trial of the T.R.A.P. regimen (thioguanine, rubidomycin, cytosine arabinoside, and prednisolone) for the treatment of acute myeloid leukaemia. Out of 27 patients treated 13 (48·1%) obtained complete remission. The treatment was well tolerated and produced especially good results in elderly patients.     

Short-term treatment for acute myelogenous leukaemia.

Short-term treatment with doxorubicin, cytarabine, and 6-thioguanine was given to 91 consecutive adults with acute myelogenous leukaemia. Fifty patients received high doses (regimen I) and 41 very high doses (regimen II). Where possible, six treatment cycles were given (total dose of doxorubicin 450 mg/m2) regardless of the number of cycles required to achieve complete remission. No additional treatment was given. The remission rate was significantly higher with regimen I than with regimen II (34/50 compared with 15/41, p less than 0.01), the latter, more intensive regimen being associated with a greater incidence of fatal infection (13/41 compared with 5/50, p less than 0.01). Duration of remission was, however, significantly longer with regimen II (p less than 0.05); the median has not yet been reached after a minimum follow-up of two years. Intensive short-term treatment is a feasible strategy for the treatment of acute myelogenous leukaemia.     

Therapy for acute myeloid leukemia in 119 adults: a comparison of two treatment protocols

Of 119 patients with acute myeloid leukemia, 69 were treated with Adriamycin, Vincristine and Cytosine Arabinoside (Therapy 1) and 50 with Daunorubicin, Cytosine Arabinoside and 6-Thioguanine (Therapy 2) as well as a consolidation therapy. The maintenance therapy with Cytosine Arabinoside and 6-Thioguanine was the same for both groups. The complete remission rate was 44% for Therapy 1 and 68% for Therapy 2 (p less than 0.05). - The median values for remission duration were 7 and 13 months respectively (p = 0.10); for survival time the median values were 18 and 19 months. These figures show in retrospect that high remission rates can be attained through intensive induction therapy and that longer remission duration is correlated with more aggressive induction therapy. A mild form of maintenance therapy seems to have little effect on the duration of complete remission.     

L-Asparaginase in Treatment of Acute Leukaemia and Lymphosarcoma

L-Asparaginase was used to treat 40 patients with acute leukaemia or lymphosarcoma. Fifteen with acute lymphoblastic leukaemia either untreated or in relapse after previous therapy were given “Squibb,” “Bayer,” or “Porton” L-asparaginase. Five of these patients had complete remission of their disease, and four had good partial remission. Eleven patients with acute myeloid leukaemia were treated for a short period with L-asparaginase alone. None of them went into remission though a pronounced fall in the numbers of circulating white cells was seen. Six patients with lymphosarcoma received L-asparaginase, two of them having good partial remissions.The toxic side-effects of the L-asparaginase from the three sources seemed to vary, and L-asparaginase from Erwinia carotovora appeared to be antigenically different from the enzyme produced by Escherichia coli.The way in which leukaemic cells become resistant to the action of the enzyme requires further investigation. To overcome this resistance asparaginase should be used in combination with other drugs in the treatment of acute leukaemia.     

Therapeutic results in acute myelogenous leukemia in the years from 1970 to 1982

In a retrospective study, three groups of patients with acute myeloid leukaemia were analyzed in respect to the outcome of remission induction therapy: group I (vincristine, daunorubicin and prednisone) was treated between 1970 and 1976, group II (daunorubicin and cytosine-arabinoside) between 1976 and 1980 and group III (daunorubicin, cytosine-arabinoside, 6-thioguanine and consolidation therapy with cyclophosphamide, vincristine, cytosine-arabinoside and prednisone) between 1980 and 1982. Complete remissions were achieved in 49% (group I), 46% (group II) and 65% (group III) of the patients (p greater than 0.05, chi-square test). The mortality rate of the remission induction therapy was significantly reduced from 27% in group I to 15% and 13% in group II and III, respectively (p less than 0.05, chi-square test). The median remission duration increased significantly from four months (group I) to nine months (group III) (p less than 0.05, log-rank test). The long term results were about the same in the three groups. After three years, the proportion of patients being still in first remission was less than 10% in group I and II 13% in group III.     

贞芪扶正颗粒对去甲氧柔红霉素联合阿糖胞苷方案治疗成人急性髓系白血病疗效及毒副反应的影响

目的:研究贞芪扶正颗粒对去甲氧柔红霉素联合阿糖胞苷方案治疗成人急性髓系白血病疗效及毒副反应的影响。方法:选取我院2006年2月~2012年8月期间收治的成人急性髓系白血病患者134例,并将其随机分为对照组与观察组。对照组采用去甲氧柔红霉素+阿糖胞苷方案规范诱导缓解治疗,观察组在对照组治疗方案上加用贞芪扶正颗粒,观察和比较两组的临床疗效及不良反应的发生情况。结果:对照组与观察组的完全缓解率(CR)分别为73.2%(41/56)和79.5%(62/78),中位OS分别为13.9个月和14.6个月,两组比较差异均无统计学意义(P0.05)。观察组III级以上的骨髓抑制现象的发生率显著低于对照组(P0.05),粒细胞最低值显著高于对照组(P0.05),粒细胞缺乏和血小板降低持续的总体时间均明显短于对照组(P0.05);观察组各主要感染部位的发生率及感染总体发生率均显著低于对照组(P0.05);观察组各种主要非血液学毒副反应包括呕吐、腹泻、肝毒性、肾毒性、神经毒性、心率失调、口腔炎症、皮疹及发热等的发生率显著低于对照组(73.1%vs.100%,P0.05)。结论:贞芪扶正颗粒能够有效改善去甲柔红霉素联合阿糖胞苷方案治疗成人急性髓系白血病的毒副反应,且不影响其临床疗效。     

Treatment of acute myeloblastic leukemia in adults: remission induction with a combination of cyclophosphamide,cytarabine and vincristine

A regimen of intravenous cyclophosphamide, cytarabine and vincristine, given over a four-day period and repeated every two to three weeks, was used to treat 33 patients with acute myeloblastic leukemia. Of the 30 evaluable patients 9/18 previously untreated patients achieved complete remission and two others marked improvement, and 4/12 previously treated patients achieved complete remission. Twelve of 16 patients under the median age of 38 responded while only 3/14 patients over this age responded. There was no difference in response between those with elevated muramidase levels and those with normal levels. Three patients developed a previously unrecognized syndorme of fever, malaise, rash and orbital suffusion. Cytarabine was probably responsible.At least four courses of treatment are required before abandoning this regimen of therapy. Patients who achieve a complete remission and live for more than 150 days spend about 25% of their total survival time from diagnosis in hospital.     

Chronic Granulocytic Leukaemia: Multiple-drug Chemotherapy for Acute Transformation

The response to 60 trials of therapy in 50 patients with chronic granulocytic leukaemia (C.G.L.) in acute transformation is reported. None of the 13 patients who received single-agent chemotherapy had a satisfactory response. The use of two drugs in combination produced only one satisfactory response in 30 patients. Various types of multiple-drug treatments in eight patients achieved one good response which lasted four months. In contrast when nine patients with rapidly progressive acute transformation of C.G.L. received a regimen—TRAMPCO(L)—incorporating seven or eight drugs (thioguanine, daunorubicin, cytarabine, methotrexate, prednisolone, cyclophosphamide, and vincristine, with or without L-asparaginase colaspase) five improved significantly. Four patients had a good clinical and haematological response with survival for over three, eight, over 12, and 14 and a half months; and one patient had a partial response. Toxicity was not extreme and maintenance therapy with the same regimen was given on an outpatient basis. TRAMPCO(L) seems superior to previously reported regimens and should be considered for rapidly progressive transformation of C.G.L. especially when simpler treatments have failed.     

Treatment of Acute Lymphoblastic Leukaemia: PRELIMINARY REPORT BY THE LEUKAEMIA COMMITTEE AND THE WORKING PARTY ON LEUKAEMIA IN CHILDHOOD

One hundred and ninety-one cases of acute lymphoblastic leukaemia were entered in a trial in which, for five months, all received cytotoxic therapy with prednisolone, vincristine, mercaptopurine, L-asparaginase, and methotrexate (the latter in high dosage followed by folinic acid). Patients were then randomized to receive immunotherapy (B.C.G.), twice-weekly methotrexate, or no further treatment.One hundred and seventy-seven patients (93%) achieved full remission and at the time of analysis, 26 months from the beginning of the trial, 143 were still alive, including 70 in their first remission. Median “post-intensive” remission lengths were 17 weeks (no treatment), 27 weeks (B.C.G.), and 52 weeks (methotrexate). The prolongation of remission by methotrexate was most evident in those patients with low initial white cell counts. B.C.G. seemed to cause lymphocytosis but was without other conspicuous effect. The incidence of toxic reactions is reported, including an unusually low rate of anaphylaxis with L-asparaginase.These preliminary results are discussed and compared with those of similar trials.     

Remission-induction of acute lymphoblastic transformation of chronic myeloid leukaemia, followed by long-term maintenance therapy

Acute lymphoblastic transformation of chronic myeloid leukaemia (LT-CML) of 7 consecutive patients was treated according to a remission-induction and maintenance therapy used for de novo acute lymphoblastic leukaemia (ALL). All 7 patients achieved a second chronic phase with a median remission duration of 15 months. Two patients showed an isolated central nervous system (CNS) relapse. This did not occur in the 4 patients, who received prophylactic therapy with intrathecal methotrexate. The second transformation was nonlymphoblastic in nature in 4 out of the 5 patients. A treatment protocol similar to that of a bad risk ALL, including long-term maintenance therapy and CNS-prophylaxis is indicated in lymphoblastic transformation of CML.     

Allogeneic bone marrow transplantation for leukaemia and aplastic anaemia. Results of the Leipzig BMT Group

In acute leukaemias there was a stable plateau in the survival curve at 45% after two years if grafted in first complete remission (n = 20) but only 13% of the patients are disease-free alive if grafted in a more advanced stage of the disease (n = 8). In 16 patients transplanted for chronic myeloid leukaemia the overall survival is 40%, in cases with graft-versus-host disease (GVHD) prevention by cyclosporine survival rate could be improved. Only 8 patients with severe aplastic anaemia, partially in low performance status were able to be transplanted; three died of infections, another by acute GVHD. The fatal complications in our study characterize the international well-known major problems in BMT: GVHD, interstitial pneumonitis, infections, graft failure in aplastic anaemia and recurrence of leukaemia, especially in more advanced leukaemia stage.     

Remission Maintenance Therapy in Acute Myelogenous Leukemia

Because no conclusive evidence as to the efficacy of maintenance chemotherapy in acute myelogenous leukemia (AML) existed, a study to obtain such information was done. Twenty-six adult patients with AML in whom complete remission had been achieved following induction chemotherapy were randomly assigned to receive either maintenance chemotherapy consisting of cytarabine and 6-thioguanine for two days each month or to receive no maintenance therapy. The data showed a significant difference in remission duration between the two groups, with median remission lengths for the maintained and unmaintained groups being 10.3 and 6.7 months, respectively (p<.05). In 46 percent of the maintained patients there were remissions lasting longer than 11 months, whereas in none of the unmaintained patients was there such a prolonged remission. No significant drug-induced toxicity was observed. That the prolonged exposure to these chemotherapeutic agents, which were also used in our induction program, did not adversely affect the rate of successful reinduction therapy was shown by identical 50 percent complete remission rates for second inductions in both groups. In patients with palpable splenomegaly at the time of diagnosis, there was no prolongation of remission with maintenance therapy. These data indicate the potential utility of maintenance chemotherapy for prolonging remission duration in acute myelogenous leukemia.     

Clinical and cell kinetic data on the combination of cytosine arabinoside with daunorubicin, isosfamide, thioguanine, and vincristine for remission induction and maintenance in patients with acute myelocytic leukaemia (author's transl)]

31 adult patients (study A) with acute myelocytic leukaemia were treated for remission induction with cytosine arabinoside (ARA-C, 100 mg/m2/day) by a 7 (5) day continuous infusion. 3 (2) doses of daunorubicin (DNR, 45 mg/m2 i.v.) were added at daily intervals. For maintenance 5 day ARA-C was given monthly in sequential combination with DNR, thioguanine (TG), or ifosfamide (IFOS). 16 (52%) patients achieved complete remission (C.R.) after 1.8 (1-3) courses and 6.7 (3-10) weeks from treatment start. The median survival for responders and non-responders was 11.5 months, early death rate within 6 weeks was 3 (10%). Median remission duration was 13.5 months. Among 11 patients surving for 7-22 months 7 patients are in first remission for 5.5-20.5 months. DNR, IFOS and TG were given before the 3rd day of ARA-C infusion. In a previous group of 34 leukaemic patients and in 44 therapy courses DNA histograms of bone marrow cells using pulse cytophotometry showed marked accumulation in S-phase for 75% of courses. Also (G2 + M)-cells in the DNA distribution and thymidine pulse labelling indices were markedly increased in most cases, whereas thymidine uptake by scintillation counter was diminished and mitotic indices had not changed significantly. In now 15 patients (study B) the induction regimen was intensified by adding vincristine (VCR, 2 mg i.v.) and 3 doses of IFOS (600 mg/m2 i.v.). Preliminary results are 50% C.R. after 1,7 (1-2) courses and 6.8 (5-10) weeks from initiation of therapy. 2 patients died in the first 6 weeks.     

Infiltration of central nervous system in adult acute myeloid leukaemia.

Out of 64 consecutive unselected patients with acute myeloid leukaemia studied during 1973-6, five developed clinical evidence of spread to the central nervous system (CNS). Neuroradiological examination showed cerebral deposits in three, in whom rapid symptomatic relief was obtained with radiotherapy. In two of these patients who developed solid intracranial deposits haematological remission could be reinduced or maintained; they were still alive 86 and 134 weeks later. When patients presented with spread to the CNS complicating generalised uncontrolled leukaemia they had short survivals. CNS infiltration may respond dramatically to appropriate treatment provided that it is not associated with generalised uncontrolled leukaemia, which has a poor prognosis. In view of this, routine "prophylaxis" of the CNS in adult acute myeloid leukaemia does not seem justified at present.     

Disturbances in iron utilization in acute leukemia and preleukemia]

With Prussian blue reaction nonhaemoglobin iron in the erythroblasts is demonstrable. Three pathological sideroblast types are recorded separately: abnormal intermediate type I and II sideroblasts and ring sideroblasts, representing increasing levels of sideroachrestic disturbance. This permits the classification of sideroachrestic disturbances into four degrees of seriousness. The frequency of a sideroachrestic disturbance in 47 untreated patients with acute myeloid leukaemia was 87%. Among 11 patients with preleukaemic condition, 8 had a disturbance of iron utilisation. In both preleukaemia and leukaemia mainly intermediate sideroblasts were present. All patients with preleukaemia developed leukaemia within 1-20 months. In the course of preleukaemic condition a slight increase of iron misutilisation was obvious when terminating in overt leukaemia. This could be of prognostic importance. After treatment, pathological sideroblasts disappeared only in 2 out of 15 patients with complete remission. There was no correlation between effect of therapy and course of iron misutilisation.     

Myelosuppressive Effect of Colaspase (L-Asparaginase) in Initial Treatment of Acute Lymphoblastic Leukaemia

Analysis of the remission induction phase in three Medical Research Council trials of treatment of acute lymphoblastic leukaemia has provided evidence of the adverse effect of the combination of colaspase (L-asparaginase) with vincristine and prednisolone. Significant myelosuppression, particularly of the granulocytic series, resulted in an increase in Gram-negative sepsis and death during the neutropenic phase induced by colaspase. The rate of blast-cell regression was increased by colaspase. It is suggested that the introduction of colaspase should be delayed until there is evidence of bone marrow regeneration in order to procure this benefit without the attendant toxicity.     

Active Immunotherapy Used Alone for Maintenance of Patients with Acute Myeloid Leukaemia

A total of 32 patients suffering from acute myeloid leukaemia were initially treated with daunorubicin and cytosine arabinoside, and eight who achieved full remission were given a brief cytoreduction course of cyclophosphamide and thioguanine. Of these eight patients seven were then actively immunized with 10 irradiated allogeneic acute myeloid leukaemia cells and B.C.G. at weekly intervals. Six of these patients have survived in apparent good health for more than one year. Bone marrow changes suggestive of relapse were used as an indication for further short courses of chemotherapy, and except on single occasions in two different patients clinical relapse has been prevented. The average duration of first (bone marrow) remission appears to be comparable with the best achieved in trials using regular chemotherapy for maintenance, though criteria for determining relapse may be different. The rate of reinduction of remissions (bone marrow) in this series was high, with a subsequent increase in overall survival time. Possible explanations for the high rate of reinduction include, firstly, the effects of active immunization with specific leukaemia antigen; secondly, non-specific adjuvant effect; thirdly, avoidance of drug resistance; and, fourthly, early diagnosis of relapse by frequent bone marrow examinations.     

Comparison of combined and single-agent chemotherapy in non-Hodgkin's lymphoma of favourable histological type.

Sixty-six untreated patients with advanced non-Hodgkin''s lymphoma of favourable histological type were allocated alternately to initial treatment with cyclophosphamide, vincristine, and prednisolone or with chlorambucil. The complete remission rate was higher in the group receiving combination chemotherapy, but the overall response rate was the same for both groups. The mean duration of complete remission was the same as that of good partial remission, and was the same for both treatments. The duration of remission was influenced by histological type and extent of disease at presentation, but not age. Those who responded to the initial treatment (whether with complete or with good partial remission) survived significantly longer than did non-responders. It is concluded that neither treatment is satisfactory and that new treatment programmes are needed for patients with a favourable prognosis, especially young patients with extensive disease.