Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

Acute myeloid leukemia in adults: is postconsolidation maintenance therapy necessary?

Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in patients assigned to maintenance treatment as far as adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS rate from 3 years of maintenance after standard-dose consolidation compared with that from consolidation alone (P = .00004), the German AMLCG requestioned the effect of maintenance randomly compared with sequential high-dose cytosine arabinoside (Ara-C) and mitoxantrone in patients who received intensified induction treatment. The results show an advantage for maintenance treatment (RFS rate of 32%) versus the sequential Ara-C and mitoxantrone treatment (RFS rate of 25%) (P = .021). We conclude that maintenance treatment continues to substantially contribute to the management of adult patients with AML, even as part of recent strategies using intensified induction treatment, and thus appears necessary in these settings.

Epirubicin and ifosfamide in metastatic breast cancer.

In a randomized, phase II trial, we evaluated the effectiveness of continued chemotherapy with epirubicin/ ifosfamide versus unmaintained treatment interruption in advanced metastatic breast cancer. Three hundred fifty-seven patients were enrolled and 331 were evaluable for response. Complete response was achieved in 25 patients (8%) and partial response in 121 patients (37%). Pretreatment status correlated significantly with response (complete and partial response). While 54% of unpretreated patients responded, only 42% of the patients responded who had been pretreated with adjuvant chemotherapy and 33% who had been pretreated in the metastatic stage of disease; 69 patients (21%) had disease progression. Of 11 patients pretreated in both the adjuvant and metastatic setting, only two responded. Toxicity of treatment was mild, with leukopenia being the treatment-limiting factor. Thrombocyte levels were not altered significantly by treatment. Thus, there seems to be room for dose escalation using granulocyte colony-stimulating factor. There was no considerable cardiotoxicity, central nervous system toxicity, or cystitis observed. The low rate of cardiotoxicity appeared to be related to dose fractionation of epirubicin. After randomization of patients to treatment interruption versus continuation of chemotherapy, a longer relapse-free survival was observed for patients who continued chemotherapy (mean relapse-free survival, 2+ months); however, this did not translate into prolonged survival. The cumulative scores of toxicity and quality of life parameters showed increasing superiority for treatment interruption. Therefore, a strategy of treatment until maximum response and subsequent treatment interruption seems to be superior to treatment continuation.

Establishment and characterization of an Epstein-Barr virus transformed cell line with strong phagocytic activity.

An immunoglobulin M (IgM)-positive cell line, Ms 28, apparently spontaneously transformed by Epstein-Barr virus (EBV) was established from peripheral blood cells of a patient with immature myeloblastic leukemia. It has been characterized according to phenotype, cytochemistry, and membrane antigen pattern. The cell line expresses lymphoid markers like CD 19, CD 22, and CD 30 and synthesizes and secretes IgM. Monocyte markers CD 11c, CD 14, and CD 15 are absent. Neither interleukin-1 (IL-1), nor tumor necrosis factor (TNF-alpha) are produced. But Ms 28 cells show strong phagocytic activity and engulf Latex particles and sheep RBCs (SRBCs) that need not to be opsonized. The phagocytic activity can be inhibited by chloroquine. Both phagocytosis and EBV nuclear-antigen (EBNA) expression can be observed in one and the same cell. Ms 28 cells might be useful to study immunologic activities like antigen processing and presentation.

[Alternatives and further development of therapy of acute myeloid leukemia in adults. Update of West German multicenter studies]. / Alternativen und Weiterentwicklung der Therapie der akuten myeloischen Leukämie (AML) des Erwachsenen. Update der bundesdeutschen multizentrischen Studien.

The 1982 randomized, multicenter trial on adult-AML in West Germany revealed a superiority of remission duration (p = 0.004) and survival (p = 0.06) for patients receiving monthly myelosuppressive maintenance chemotherapy after TAD9-induction and consolidation as compared to patients without maintenance. In the 1985 pilot study double induction as a new approach followed by consolidation and monthly maintenance in patients up to 60 years of age was found well practicable, with 77% complete remissions and 12% early deaths in 81 patients. In addition preliminary remission duration and survival at 1 1/2 years appear favorable.

[Internal medicine diagnosis of splenic diseases]. / Internistische Diagnostik bei Milzerkrankungen.

In an adult man the spleen serves two physiologic functions. It is an organ of the immune system, the second function is the sequestration and removal of normal and abnormal blood cells. Most diseases of spleen are associated with enlargement of the organ. Causes of splenomegaly are liver diseases with portal hypertension, infections, malignant leukemias or lymphomas often combined with lymph node enlargement, collagen vascular diseases or Felty's syndrome, chronic hemolytic syndromes and infiltrative diseases such as Gaucher's disease. Some diseases associated with splenic enlargement respond to splenectomy.

Neuraminidase-treated allogeneic blasts for maintenance in acute myelogenous leukemia: results of a prospective randomized trial.

Between July 1, 1981, and July 1, 1985, 167 patients with acute myelogeneous leukemia (AML) were treated with one or, if necessary, two courses of a modified TAD regimen (TAD9) for induction. 96 patients (58%) achieved a complete remission (CR); 62 achieved CR after one and 34 patients after two courses of TAD9. 29 patients (17%) were considered early deaths, and 42 patients (25%) nonresponders. For CR maintenance 64 patients were eligible according to protocol criteria; 33 patients were randomized to chemotherapy, only, (CT) by monthly courses of cytosine arabinoside (ARA-C) alternatingly combined with daunorubicin or thioguanine or cyclophosphamide, while 31 patients were randomized to receive immunotherapy in addition to chemotherapy (CIT) by intradermal injections of 10(10) neuraminidase-treated viable allogeneic blasts per immunization interspersed between the CT courses. Maintenance therapy was given for up to 3 years. The median survival in CT patients is 23 months, while in CIT patients the median has not been reached after 54 months; corresponding median relapse-free survival is 15 months for the CT patients as opposed to 40 months for the CIT group. The differences are not significant. Comparing CT with CIT, the survival data show a persistent trend in favor of CIT; under the conditions of the study, however, a substantial benefit of immunotherapy may be restricted to a certain subset of patients with low risk for early relapse.

[Acute myeloid leukemia (AML) in adults. Further development of therapy based on clinical phase II and phase III studies]. / Akute myeloische Leukämie (AML) des Erwachsenen. Weiterentwicklung der Therapie auf der Basis klinischer Phase-II-und Phas-III-Studien.

By a review of relevant clinical studies on adult AML no substantial progress can be seen in the eighties so far. After the development of successful chemotherapy regimens during the seventies, further improvement can only be expected in small steps. Clinical studies, therefore, should concentrate on the analysis of the different components and new elements of treatment in order to utilize and combine them more effectively. For this purpose, a standardization of treatment and, for many aspects, a randomized comparison is inevitable. Thus, the role of monthly maintenance as well as of a special type of immunotherapy could be elucidated for the first time by our multicenter trial.

Immunotherapy with allogeneic neuraminidase-treated blasts for maintenance in acute myelogenous leukemia (AML). Significant prolongation of remission duration in patients receiving at least 3 cycles of therapy.

102 patients with AML (leukemia after preleukemia, 2nd neoplasia included) were treated for remission induction by a modified TAD regimen in Munster; 55 patients (54%) achieved a complete remission (CR). For CR maintenance 40 patients were eligible for randomization according to the study protocol: cyclic chemotherapy (CT) alone vs. chemoimmunotherapy (CIT: plus allogeneic Neuraminidase-treated blasts in high dosage). 5 CR patients, induced identically in Essen, were randomized additionally. Evaluating all patients randomized there is only a marginally beneficial effect of CIT (21 patients) compared to CT (24 patients) concerning median survival (1020+ vs. 612 days) and relapse-free survival (494 vs. 380 days) until now. For patients receiving more than 2 cycles of maintenance therapy, however, CIT prolongs relapse-free survival significantly (930+ vs. 409 days; p = 0,02); that is also true for remission duration. This suggests that only repeated application of blasts may induce an immune response leading to a biologically relevant antileukemic effect.

Immunotherapy in the treatment of acute myelogenous leukemia (AML): rationale, results and future prospects.

Patients with AML in complete remission (CR) are immunosuppressed; remission lymphocytes of at least a part of the patients are able to recognize autologous leukemic blasts; the CR represents a minimal residual disease. Thus, important conditions for a potentially successful active immunotherapy are given. Results of most earlier randomized trials on immunotherapy revealed some, but limited benefit with respect to survival. Encouraging effects, however, have been achieved by immunizing CR patients with high-dose neuraminidase-treated allogeneic blasts. Because these data have not been confirmed until now we recently initiated a randomized study utilizing identical treatment protocols. The preliminary results of the ongoing study still do not allow to draw any firm conclusions. Specific monoclonal antibodies or autologous cytotoxic T-cells may be useful tools for future immunotherapy of AML.