Adriamycin in the Treatment of Acute Leukaemia

In a preliminary study a new antitumour antibiotic, adriamycin, was found to be capable of inducing complete remission in 6 out of 17 patients with acute lymphoblastic leukaemia and in one out of four with lymphoblastic lymphosarcoma despite the fact that these patients had either failed to respond or had relapsed after chemotherapy with agents recognized to be potentially successful in each condition. In five cases of acute lymphoblastic leukaemia adriamycin was used in combination with cytosine arabinoside—three achieved complete remission and two good partial remissions. This combination seems to merit further study in patients who have relapsed on the more conventional chemotherapeutic regimens in acute lymphoblastic leukaemia.In 13 patients with acute myelogenous leukaemia previously treated with daunorubicin and cytosine arabinoside no remissions were obtained with the dose range used.     

Remission induction with cytosine arabinoside and L-Asparaginase in acute lymphoblastic leukaemia

Nine patients with acute lymphoblastic leukaemia in relapse were treated with a course of cytosine arabinoside followed immediately by a course of L-asparaginase. Eight patients achieved complete remission of their disease. This combination of drugs is sufficiently effective to suggest that further trial is needed. It is possible that the combination has a synergistic effect.     

Adjuvant immunotherapy in acute nonlymphocytic leukemia

Summary Of 112 patients (maximum age 70 years) with acute nonlymphocytic leukemia, 62 (55%) went into remission on an induction therapy of cytosine arabinoside and daunorubicin. 20 patients were randomized for maintenance treatment consisting of chemotherapy only and 22 patients for combined chemo-immunotherapy. The chemotherapy consisted in 5-day courses of daunorubicin and cytosine arabinoside and of thioguanine and cytosine arabinoside, alternating every month. The chemo-immunotherapy group also received weekly intracutaneous injections of 10⁹ allogeneic nonirradiated leukemic myeloblasts and 10⁶ BCG organisms (Glaxo) by Heaf gun.The median duration of the first remission was 164 days for the chemotherapy group and 464 days for the chemo-immunotherapy group. The corresponding median times of survival were 344 days for the first group and 734 days for the second group. The difference concerning median duration of survival is statistically significant. Thus immunotherapy seems to prolong survival.     

Remission induction and remission maintenance in adult acute nonlymphocytic leukemia employing a modified cytostatic (COAP) regimen.

Thirty adult patients suffering from acute nonlymphocytic leukemia (ANLL) were treated according to a modified COAP regimen. Vincristine, cyclophosphamide, and prednisone were given by push injection, while cytosine arabinoside was infused over periods of 8 h. Nineteen patients (63%) achieved complete remission. Remission maintenance therapy consisted of 6-mercaptopurine daily and methotrexate twice weekly. Later in the study, COAP consolidation and reinduction was added, which improved the median duration of complete remission from 7 to 24 months. Comparison of the results with the literature shows that the modified COAP regimen is one of the most effective treatment schedules for adult ANLL.     

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.     

The efficiency of strict reverse isolation and antimicrobial decontamination in remission induction therapy of acute leukemia

The efficiency of strict reverse isolation and antimicrobial decontamination in remission induction therapy of acute leukemia was studied retrospectively in 47 patients who were treated with a standardized aggressive chemotherapy of daunorubicin and cytosine arabinoside. Twenty-two patients were treated in strict reverse isolation with antimicrobial decontamination and 25 patients in the open ward without any measures against infections. In the patients in isolation the incidence of new infections per patient was 0.77 compared to 1.42 in the control group. The rate of complete remissions was 77% in the patients in isolation vs. 56% in the control patients.     

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.     

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.     

Management of Adult Acute Myelogenous Leukaemia

Consecutive adult patients admitted to St. Bartholomew''s Hospital with acute myelogenous leukaemia have been treated with a remission induction drug schedule consisting of daunorubicin and cytosine arabinoside. Intermittent five-day courses were used in 72 patients, and a complete remission was obtained in 39 patients (54%). An alternative drug schedule in 22 patients resulted in fewer remissions but this may have been due to age differences in the two groups. Age and initial platelet count were found to be important factors in determining the success of remission induction therapy; the older patients and those with low platelet counts responded less well.A series of 23 patients who achieved remissions was divided into two groups; one received intermittent combination chemotherapy as the only form of maintenance, and the other was given weekly immunotherapy in addition to the chemotherapy. The immunotherapy consisted of irradiated allogeneic leukaemic cells and B.C.G. Eight of the 10 patients on chemotherapy alone have already relapsed compared with five out of 13 patients in the immunotherapy group. It is hoped that these promising initial results with this form of maintenance will be confirmed as more patients enter the maintenance trials.     

Prolonged remission maintenance in acute myeloid leukaemia.

Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia.     

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.     

Low dose cytosine arabinoside in the treatment of the primary myelodysplastic syndrome.

23 patients with primary myelodysplastic syndrome was observed in 1982-1988. 8 patients with RAEB and RAEB-t according to FAB criterias were treated with low dose cytosine arabinoside. No complete response and only one partial response +10 months duration was achieved. Treatment had a minor influence on the natural course of disease, and doesn't protect patients from the transformation into acute leukaemias.     

Day-6 bone marrow aspirate for the prediction of response to remission induction therapy for acute myelogenous leukaemia

Seventy-two adults were treated for acute myelogenous leukaemia (AML). Forty-two had previously untreated AML and 30 had AML after a preleukaemic phase, refractory AML or relapsed AML. The previously untreated patients received a 7-day course of cytosine arabinoside (100 or 200 mg/m2 daily), daunorubicin and vincristine while the remaining patients received a 7-day course of cytosine-arabinoside (1 g/m2 q 12h for 6 days) and amsacrine (on day 7). The percentage of malignant cells and the reduction in the percentage of malignant cells were determined by means of bone marrow aspirates taken on day 6 of the chemotherapy course and at the time of diagnosis. Both variables correlated significantly with the ultimate treatment outcome; the reduction in the percentage of malignant cells correlated even more significantly than the absolute percentage malignant cells in the day-6 bone marrow. By means of multiple regression analysis it became possible to calculate the probability of achieving complete remission for the individual patient; this is given by the equation: probability = 1.9-0.009X (% malignant cell reduction). In addition, the mean percentage of malignant cells in the day-6 bone marrow was significantly higher for patients who failed to achieve than those who entered complete remission. Eighty-six per cent of the patients with less than 20% malignant cells on day 6 entered remission, while 75% of the patients with more than 21% malignant cells failed to achieve complete remission (p less than 0.001). Although all of these calculations support the predictive value of the day-6 bone marrow aspirate, the 95% confidence intervals are too large to allow reliable and safe predictions; therefore more patients must be studied to demonstrate the reliability of this test.     

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.     

Secondary leukemia after severe aplastic anemia

We describe a patient with acute myeloid leukemia (AML) occurring 5 years after successful treatment of severe aplastic anemia (SAA) with antilymphocyte globulin (ALG). Four years after ALG, SAA had relapsed. A second remission of SAA was achieved, but was followed by transformation of the myelodysplastic syndrome into overt AML. After 2 courses of high-dose cytosine arabinoside and VP-16 complete remission occurred. This case shows that chemotherapy of secondary leukemia after SAA is feasible, and that ex-aplastic bone marrow is capable of complete recovery from chemotherapy-induced aplasia. Morphological anomalies of bone marrow noticed early during remission of SAA might predict a late transformation in leukemia.     

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.     

Efficacy of lomustine, teniposide, doxorubicin, bleomycin and prednisone (LTABP) or adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in the treatment of malignant lymphogranulomatosis resistant to MOPP]

LTABP regimen was applied to 18 patients in IIB and IV stage of malignant lymphogranulomatosis resistant to MOPP. The obtained results were compared with historical control group of 18 patients with similar stage of the disease treated according to ABVD regimen. In both regimens courses were repeated every 28 days or more rarely, when leucopenia and thrombocytopenia prolonged. Only patients who had received at least 3 courses were analysed. In the LTABP group the complete remission was obtained in 10 cases (55%) while partial remission in 6 (33%). In the group treated with ABVD complete remission was obtained in 4 cases (22%) and partial in 9 cases (50%). In the LTABP group 11 patients are still alive and remain in complete remission, while in ABVD group--4 patients. The most frequent side effects in both groups included leucopenia, thrombocytopenia and symptoms of gastrointestinal intolerance. The LTABP regiment allows to obtain higher percentage of the complete remission than ABVD.     

Low dose cytosine arabinoside in refractory anemia with excess of blasts in transformation

Myelodysplastic syndromes (MDS) are heterogeneous diseases. Patients with blast counts of more than 20% of nucleated bone marrow cells have a high risk of short survival. We treated six patients with refractory anemia with excess of blast in transformation (RAEBiT) with low dose cytosine arabinoside (LD Ara-C). We had one partial remission (PR), surviving 16 weeks and two complete remissions (CR), surviving 22 and 55+ months. Myelosuppression was dominant in all patients, but was not as serious as with conventional remission-induction treatments for leukemias. Bone marrow aplasia occurred in all responding patients, but a differentiation effect is possible too. Maintenance therapy with LD Ara-C may be important for the two long-lasting CR.     

Response-oriented therapy with CHOP and VIM-Bleo in high-grade malignant non-Hodgkin's lymphomas

Twenty four patients with high grade malignant NHL (stage II 8, stage III 4, stage IV 12 patients respectively) were treated with a response-oriented regimen: Treatment was initiated according to the CHOP-protocol. Patients achieving at least a partial remission after 2 and a complete remission (CR) after 4 cycles were continued on CHOP to a total of 9 cycles. Patients not meeting these criteria were switched to a combination of Etoposide, Ifosfamide, Methotrexate, and Bleomycin (VIM-Bleo). With CHOP treatment, 16 patients (67%) achieved a CR. Of the remaining 8, 7 were treated with VIM-Bleo; 5 of these entered CR for a overall CR rate of 21/24 (88%). With a median follow up of 28 months 7 patients relapsed: 6 relapses occurred in patients with a rapid initial response and treated only with CHOP. We conclude, that there is a significant risk of relapse even in patients readily responding to CHOP and that consolidation therapy with a non cross-resistant regimen may improve results in these patients.     

Intravenous and oral demethoxydaunorubicin (NSC 256-439) in the treatment of acute leukemia and lymphoma: a pilot study

Demethoxydaunorubicin (DMDR), a new anthracycline available both for intravenous and oral administration, was given in 14 cases of leukaemia, non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) replacing either daunorubicin (DNR) or doxorubicin (DOX) in conventional chemotherapy regimes. In acute leukaemia (6 myeloblastic and 1 common lymphoblastic) there were 5 complete (CR) and 2 partial (PR) remissions; one patient, previously brought into remission with a regime including i.v. DMDR was thereafter maintained in CR with oral DMDR. Among the patients treated with the oral DMDR, 2 NHL cases were treated; 1 patient had a sustained remission of 12 months so far, with DMDR alone; another patient had a CR with a combined regime. In MM, one patient with very advanced disease treated with i.v. DMDR/CHOP did not respond, but three cases treated with oral DMDR plus other drugs showed a partial remission. Toxic effects were limited to brief episodes of nausea and vomiting in a few i.v. treated patients; a prolonged bone marrow depression was observed in one case only. No cardiotoxic effect was recorded.