Long-term follow-up of patients >or=60 yr old with acute myeloid leukaemia treated with intensive chemotherapy.

It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens. We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients 70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission. Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.

Clinical experience with recombinant factor VIIa in patients with thrombocytopenia.

Platelets play a central role in primary hemostasis. The role of the coagulation mechanism during early stages of hemostasis is less clear, although increasing evidence is emerging indicating the ultimate importance of the factor VII (FVII)-tissue factor-dependent coagulation system in providing the first thrombin molecules necessary for the platelet activation to occur. Supporting this, early fibrin formation has been reported to occur within the bleeding time wound and infusion of recombinant FVIIa (rFIIa) has been shown to shorten the bleeding time in rabbits. We have investigated whether infusion of rFVIIa would enhance fibrin formation in bleeding time wounds in patients with thrombocytopenia as reflected by a shortening of the bleeding time. A reduction of the bleeding time was found in 55/105 cases (52%). The decrease was significantly more pronounced when the platelet count exceeded 20 x 10(9)/l. With the exception of an anaphylactoid reaction in 1 patient, no major adverse reactions related to the study drug were observed. Nine infusions of rFVIIa were given to 8 thrombocytopenic patients with overt bleeding. One patient received two infusions. Bleeding decreased in all patients and stopped in 6 patients.

Mitoxantrone, etoposide and ara-C vs doxorubicin-DNA, ara-C, thioguanine, vincristine and prednisolone in the treatment of patients with acute myelocytic leukaemia. A randomized comparison.

Complex-binding of anthracyclines to DNA may increase their therapeutic efficacy. In a previous randomized trial patients with acute myelocytic leukaemia (AML) receiving combination chemotherapy including a DNA-bound doxorubicin preparation had a longer duration of first complete remission (CR) and survival than patients receiving free doxorubicin. In a parallel phase I/II study a combination of mitoxantrone, activity. In this randomized study of AML patients (15-60 years) induction treatment with MEA was compared to a combination of doxorubicin/DNA conjugate ara-C, thioguanine, vincristine and prednisolone (POCAL-DNA). The study was closed after an interim analysis of 86 patients. Thirty-five/42 (83%) and 20/44 (45%) patients entered CR in the MEA and POCAL-DNA groups, respectively (p < 0.001). With rescue therapy the corresponding figures were 88 and 64% (p < 0.02). Median survival was 27.8 and 13.1 months for MEA and POCAL-DNA patients, respectively (p < 0.03). In conclusion, the MEA regimen has a very high antileukaemic activity in good accordance with our previous experience. Since we could not reproduce our earlier clinical results using DNA-bound anthracyclines, the source and preparation of DNA seem to be of major importance.

Preoperative evaluation of primary hemostasis in patients with thrombocytopenia using the Thrombostat 4000.

It is difficult to estimate the risk of hemorrhage that may follow an invasive or surgical procedure in patients with thrombocytopenia or platelet dysfunction. Conventional functional tests for the evaluation of primary hemostasis have been questioned. We have evaluated the in vitro bleeding time (IVBT) using the Thrombostat 4000 in 25 patients with thrombocytopenia in order to estimate the risk of bleeding following an invasive or surgical procedure. Using the IVBT, it was possible to suggest and evaluate preoperative treatment in order to restore primary hemostasis. All patients studied had their operations without bleeding complications. From these observations we conclude that the IVBT is a convenient and useful tool in the evaluation of primary hemostasis in these patients.

Interactions between cladribine (2-chlorodeoxyadenosine) and standard antileukemic drugs in primary cultures of human tumor cells from patients with acute myelocytic leukemia.

The semiautomated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) to fluorescein in microtiter plates, was used for in vitro evaluation of Cladribine (2-chlorodeoxyadenosine, CdA) interactions with five standard antileukemic drugs: amsacrine (Am), etoposide (VP16), daunorubicin (Dnr), cytosine arabinoside (AraC), and mitoxantrone (Mit). Samples from 31 patients with acute myelocytic leukemia (AML) were tested with continuous drug exposure. A large heterogeneity with respect to cell kill was observed for all combinations tested. An additive model provided a significantly better fit of the data compared to the effect of the most active single agent of the combination (Dmax) only for CdA+AraC. When the frequency of additive and synergistic interactions were calculated according to the multiplicative concept for drug interactions, the highest frequencies were observed for CdA+AraC and CdA+Dnr. This interaction pattern was confirmed by isobologram analysis. Cross-resistance analysis revealed high correlations between CdA and AraC whereas the correlations were weaker between CdA and the other drugs. The highest frequency of synergistic interactions was obtained for AraC+CdA, despite their cross-resistance. Of the non-cross-resistant drugs tested, Dnr appears to be the most effective adjunct to CdA in terms of interactions at the cellular level.

Intensive treatment in order to minimize the Ph-positive clone in chronic myelogenic leukemia.

Several studies indicate that interferon (IFN) treatment, intensive chemotherapy and autologous bone marrow transplantation (ABMT) effectively reduce the Ph-positive clone in Chronic Myelogenic Leukemia (CML). In the present study on patients < or = 55 years, we have combined these three treatment modalities. The aim of the study was to eliminate or minimize the Ph-positive clone to see whether a status of minimal residual or Ph-negative disease could be maintained for a longer period of time. After diagnosis, patients received interferon (IFN-a-2b) and hydroxyurea (HU) to keep the white blood cell (WBC) and platelet count below 2-4 and 100-150 x 10(9)/l, respectively. After six months of treatment, Ph-analysis was performed. Patients with Ph-positive cells in bone marrow then received 1-3 courses of intensive chemotherapy. In patients Ph-negative after two courses, bone marrow was harvested and used for ABMT. After a third course, patients with up to 50% Ph-positive metaphases were accepted for ABMT. As of January 1, 1993, 97 patients were registered in the study. Six months of IFN+HU reduced the percentage of Ph-positive metaphases in 57% of the patients (7% became Ph-negative). The corresponding figures after two intensive cytotherapies were 70% (40% Ph-negative). Eighteen patients were autotransplanted. Seven have relapsed with Ph-positivity 3-22 months after ABMT, while nine are Ph-negative at 1-32+ months after ABMT (two not yet analyzed). Seventeen patients are alive and well, while one died one month after ABMT due to interstitial pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional capacity of transfused platelets estimated by the Thrombostat 4000/2.

Post-transfusion platelet increment is a useful test for the evaluation of transfusion efficacy. It does not, however, give information about the in vivo platelet function. We have evaluated the in vitro bleeding time (IVBT) using the Thrombostat 4000/2 with ADP as activating agent in 60 platelet transfusions given to 17 chemotherapy-induced severely thrombocytopenic patients. Determinations were performed before and after transfusion of platelet concentrates (PC) prepared from buffy coat. Both fresh and stored platelets resulted in significant reductions of the IVBT already 10 minutes after completed platelet transfusion. In the majority of patients there was a correspondence between IVBT and platelet increment. However, in 30% of the cases there was no improvement of the IVBT despite an increase of the platelet count. Fresh PCs were more effective than stored. The IVBT seems to represent a clear-cut improvement in the possibilities for evaluating and monitoring the effect of platelet transfusion.

A Randomized Comparison of Doxorubicin and Doxorubicin-DNA in the Treatment of Acute NonLymphoblastic Leukemia.

In the light of previous findings that treatment of leukemia patients with DNA-linked doxorubicin gave higher doxorubicin concentrations in leukemic cells than treatment with doxorubicin alone, the Leukemia Group of Middle Sweden performed a randomized clinical trial to compare the effects of doxorubicin and doxorubicin-DNA in patients with acute non-lymphoblastic leukemia. One hundred and twenty consecutive patients within the age range 15 to 60 years were randomized to one of three treatment groups. In two of these, remission induction treatment was performed with prednisolone, vincristine, ara-C and thioguanine combined with either doxorubicin or doxorubicin-DNA. Patients entering a complete remission received intensive consolidation during 16 months with 4 courses each of doxorubicin (+/ - DNA)/ara-C, doxorubicin (+/ - DNA)/azacytidine, ara-C and amsacrine. The third treatment group followed a protocol from a previous study with daunorubicin and ara-C for induction therapy and a less intensive maintenance therapy. No further patients were assigned to this "control" group after 3 years or to the two other groups after 6 years. This report is based on a follow-up 31 months thereafter. The overall rate of complete remission was 67% and the mean time to complete remission was 71 days, with no differences between the treatment groups. Patients treated with the doxorubicin-DNA conjugate had a significantly longer survival [median for all patients 27.2 months (p < 0.01) and for patients in CR 47.0 months (p < 0.025)] and longer duration of first remission (median 23.6 months, p < 0.025) than the other groups. There were significantly fewer reports of cardiotoxicity (p < 0.05) and severe intestinal toxicity (p < 0.02) in patients treated with the doxorubicin-DNA conjugate and there was a tendency towards less hepatic (p < 0.08) and renal toxicity (p < 0.08). The frequency of myelosuppression, fever and infectious complications was similar in all three groups. Complex binding to DNA appears to increase the therapeutic effects and reduce some toxic effects of doxorubicin in patients with ANLL.

Treatment of pure red-cell aplasia and aplastic anaemia with ciclosporin: long-term clinical effects.

6 patients with pure red-cell aplasia were treated with Ciclosporin (Cyclosporine A; CS) alone or combined with prednisolone for a period of 9-46 (median 27) months. Prior to study, 5 cases had refractory disease, steroids were contraindicated in 1, and 4/6 patients, including 2 cases with congenital disease, had a disease duration exceeding 11 years. A complete haematological response was obtained in 5/6 subjects, and a partial response in 1. When the pre-treatment Hb levels (mean +/- S.D. = 64 +/- 13 g/l, range 41-80) for all 6 PRCA patients were compared with the Hb levels after 6 months of CS therapy (104 +/- 17 g/l, 80-125), a significant improvement was registered (p less than 0.005). In half of the patients, remission is maintained with CS as single drug in a dose-dependent manner. We also treated 5 patients with refractory severe aplastic anaemia with CS (1 case) or CS plus prednisolone (4 cases) for 3-27 (median 10) months. Only 1 patient responded. In this case, a complete haematological remission was induced with CS alone, and remission has been maintained for 27 months. Side effects of CS therapy were common but were dose-dependent and reversible, with the exception of persistent nephrotoxicity in 1 patient with pure red-cell aplasia. Based on our present results and a survey of the literature, we conclude that CS therapy is effective and indicated in refractory pure red-cell aplasia. In severe aplastic anaemia resistant to conventional immunosuppression, the response rate is lower, but a small proportion (around 15%) of patients may benefit from CS therapy. Longer treatment periods may, however, be needed to evaluate the role of CS in aplastic anaemia.

Aggressive treatment improves survival in adult acute lymphoblastic leukemia.

20 consecutive adult patients with acute lymphoblastic leukemia were treated with an intense induction regimen including vincristine, doxorubicin, prednisolone, L-asparaginase and cyclophosphamide. 16 patients (80%) achieved complete remission and were then given CNS prophylaxis and 3 years of maintenance therapy. With minimum follow-up of 24 months, the median duration of first remission is 37+ months. Out of 10 patients who have completed maintenance therapy, 2 have relapsed after 14 and 22 months, respectively, and 7 are in continuous complete remission 1+-55+ months off therapy.

Biochemical markers in multiple myeloma: a multivariate analysis.

The analysis of individual biochemical and clinical variables in 121 patients with multiple myeloma showed that serum beta 2-microglobulin (S-beta 2m) had the most significant relation to survival. Other variables such as serum thymidine kinase (S-TK), serum lactate dehydrogenase (S-LDH), S-creatinine, haemoglobin (Hb), ESR, S-albumin, age and clinical stage were also significant. No such relationship was found with M-component, presence of light chains in urine, type of secreted immunoglobulin or S-calcium. The exclusion of clinical stage in the first multivariate analysis resulted in a model consisting of S-beta 2m, age and S-TK, none of the other variables gave additional information. When in the second multivariate analysis the basic variables involved in staging procedure were excluded and clinical stage included, stage III, but not stage II, was found to give additional information to the model described above. Individual analysis of the variables showed that Hb had the most significant relation to effect of initial therapy. Other significant variables were S-TK, S-beta 2m and age. When using the multivariate approach, Hb alone was found to contain all the relevant information.

Evaluation of serum deoxythymidine kinase as a marker in multiple myeloma.

A recently developed deoxythymidine kinase assay utilizing 125I-iododeoxyuridine as substrate was used in an investigation of sera from 122 untreated patients with multiple myeloma. Most patients had slightly elevated or normal serum deoxythymidine kinase activity (S-TK), although in some patients values increased by more than forty-fold were found. S-TK correlated with the haemoglobin level but did not correlate with sex, age, erythrocyte sedimentation rate, nor with the serum concentrations of creatinine, beta 2-micro-globulin, Ca or M-component. The distribution of S-TK values in IgG, IgA and pure Bence-Jones myeloma did not differ significantly. Patients with IgG and IgA myeloma excreting light-chain immunoglobulin in the urine had significantly higher S-TK than non-excreters. There was a significant correlation between S-TK values and tumour cell mass as determined by clinical staging. A high pretreatment S-TK (greater than 5.1 units) also distinguished a group of patients with a significantly shorter survival time. Patients with no response to initial therapy had significantly higher S-TK values than those who did respond. In longitudinal studies of 11 patients, S-TK was found to increase when the disease became more aggressive. The possibility of diagnosing disease progression at an early stage by an elevation of S-TK is discussed.

Alpha interferon treatment of patients with hairy-cell leukaemia.

We have treated 10 patients with hairy-cell, or hairy-cell-like leukaemia, for more than 6 months, with alpha interferon 3 X 10(6) IV/day I.M. or subcutaneously. All patients were severely pancytopenic before treatment. 7 patients had a typical hairy-cell leukaemia, whereas 3 lacked hairy cells but had the characteristic bone-marrow infiltration. The peripheral blood counts improved in all patients during treatment and the lymphoid infiltration of the bone-marrow was shown to decrease. 1 patient obtained complete remission, 6 partial remission and 3 had a minor response. It is concluded that alpha interferon is effective in the treatment of patients suffering from hairy-cell leukaemia.