Risk-oriented postremission strategies in adult acute lymphoblastic leukemia: prospective confirmation of anthracycline activity in standard-risk class and role of hematopoietic stem cell transplants in high-risk groups.

INTRODUCTION: Although definite risk classes are well known, risk-adapted modulation of first-line therapy is seldom attempted in adult ALL. So, a prospective validation of the therapeutic efficacy of a protocol (or a component thereof) in specific risk groups is uncommon. MATERIALS AND METHODS: From 1996-1999 a risk-oriented program (08/96) was evaluated in 102/121 unselected patients (median age 35 years, blast count 0-450 x 10(9)/l, 100 B(lin) (lineage), 21 T(lin)) responsive to induction therapy. The standard risk (SR) class was B(lin) CD10+ Ph- with blasts < 10 x 10(9)/l (prior studies: disease-free survival (DFS) rate 52% at five years with dose-intensive anthracycline-containing programs). The SR protocol was therefore anthracycline-rich (early consolidation cycles with total idarubicin 96 mg/m2), and comprised long-term maintenance. High-risk (HR) patients were eligible to the following three options: allogeneic hematopoietic stem cell transplantation (HSCT) from related family donor; short sequence with high-dose cyclophosphamide-cytarabine-methotrexate followed by melphalan/total body irradiation with autologous HSCT; or T(lin) ALL chemotherapy regimen inclusive of high-dose cytarabine and methotrexate. RESULTS: Treatment realization and three-year DFS rates according to risk class, HR subset and postremission treatment intensity were the following. SR group (n = 28): realization rate 93%, DFS 68.5%. HR group (n = 74): realization rate 80%, DFS 39% (P = 0.052 vs SR category). In HR group, three-year DFS rates by disease subtype were the following. B(lin) Ph- (n = 35) 43%; Ph+ (n = 19) 13% at 2.7 years (P = 0.006 vs other HR subtypes); T(lin) (n = 18) 59.5%. And DFS rates by treatment intensity were: allograft (n = 21) 40%; autograft (n = 28) 27%; shift to SR protocol (n = 13) 52% (P = ns vs allograft/autograft); T(lin) program (n = 10) 57%. Matched analyses of treatment protocols and disease subtypes suggested a possible therapeutic role of the autograft regimen in B(lin) Ph- ALL with a blast count < 25 x 10(9)/l, and of T(lin) protocol for T(lin) ALL. Comparisons with retrospective control cohorts were confirmatory of anthracycline activity in SR subclass. CONCLUSION: The intended strategy was applicable to the majority of study patients, confirming the value of anthracyclines in SR class and, preliminarily, the usefulness a T(lin)-specific treatment. Apart from the case of Ph+ ALL, the indications for high-dose procedures with HSCT remains largely undetermined in this study.

Incidence of non-Hodgkin's lymphoma and Hodgkin's disease in Sardinia, Italy: 1974-1993.

BACKGROUND AND OBJECTIVES: The reasons for the worldwide increase in non-Hodgkin's lymphoma (NHL) are not clearly understood. We investigated whether an increasing trend over time has also occurred in the Italian region of Sardinia, the population of which exhibits peculiar genetic features, due to millenary isolation and pressure from 2,500 years of malarial endemism. We also investigated the geographic variation in NHL risk within the region. DESIGN AND METHODS: We designed a descriptive epidemiology study of NHL among the Sardinian population by following up the incidence of this disease in the period 1974-1993. We calculated the standardized incidence rate (SIR) of NHL by year for the total population and by gender. The time trend of Hodgkin's disease (HD) was also evaluated as a comparison term and for validation purposes. We also mapped NHL risk in the 361 administrative units (communes) of the region. RESULTS: NHL incidence in the Sardinian population over the whole study period was 7.5 x 10(-5) year(-1) (men: 8.2; women: 6.7), and increased from 4.1 in 1974 to 9.1 in 1993. The increasing trend was consistent by gender, and mostly affected subjects aged 55 years or older. Nodal and extra-nodal forms of NHL shared the same pattern of increasing incidence. Excluding the few NHL cases related to AIDS did not change the results. No such pattern was observed for HD incidence. The NHL incidence rate (age > or = 25 years) ranged from 0.0-60.0 x 10(-5) year-1 across communes. Areas at risk were located mainly in the northern part of the region, but risk among men was also elevated in the major urban area in southern Sardinia. INTERPRETATION AND CONCLUSIONS: Our study shows that NHL incidence increased 2.2-fold in Sardinia from 1974 to 1993, a finding which is consistent with other world-wide report. The risk has risen in a few areas, mainly in central and northern Sardinia and in the major urban areas. Analytic studies are under way to investigate a broad range of risk factors, including viral, occupational, and environmental factors, that might account for our results.

Role of early anthracycline dose-intensity according to expression of Philadelphia chromosome/BCR-ABL rearrangements in B-precursor adult acute lymphoblastic leukemia.

INTRODUCTION: The use of anthracycline antibiotics in adult acute lymphoblastic leukemia (ALL) has resulted in an improved outcome to remission induction therapy. However,the exact role of these drugs in consolidation therapy is less clear, especially in specific ALL subsets. MATERIALS AND METHODS: A retrospective analysis was conducted on the outcome of 308 patients (median age 35 years, range 13-75) with the most frequent subtype, early-B ALL, treated between 1974 and 1998 on eight consecutive protocols. Anthracycline-related effects were assessed by evaluating the impact of planned anthracycline dose-intensity (A-DI) on long-term outcome. A-DI (in mg/m(2)/week) during the first twelve weeks of consolidation therapy was classified as either "high" (doxorubicin>20, idarubicin>7) or "low". RESULTS: Complete remission was achieved in 78% of cases. With a median follow-up of 6.5 years, on multivariate analysis, disease-free survival (DFS) correlated only with expression of the Philadelphia (Ph) chromosome and/or associated BCR-ABL rearrangements (Ph/BCR(+)) (P=0.0001) and planned A-DI (P<0.0001). On this basis, four major prognostic groups with significantly different DFS could be identified: (1) Ph/BCR(-), "high" A-DI (n=102), median 3.5 years and 41% at five years, respectively; (2) Ph/BCR(-), "low" A-DI (n=64), 1.3 years and 16%; (3) Ph/BCR(+), "high" A-DI (n=35), 1.7 years and 20%; (4) Ph/BCR(+), "low" A-DI (n=39), 0.75 years and 0%. When analyzed separately for Ph/BCR(-) (n=166) and Ph/BCR(+) (n=74) patients, the A-DI effect on DFS was preserved in the former (P=0.018) whereas, in Ph/BCR(+) patients, only age <50 years (P=0.004) and blast count <25 x 10(9)/l (P=0.02) correlated with better DFS. However, Ph/BCR(+) patients with the best prognostic profile (age <50 years and blast count <25 x 10(9)/l; n=21) who were treated on "high" A-DI regimens experienced a median DFS of 2.2 years with DFS 21% at five years, compared to 0.67-1 years and 0-10% in other cases (n=53, P<0.01). CONCLUSION: A "high" A-DI may act as a positive treatment-related prognostic factor in early B-lineage ALL. Although mainly restricted to patients with Ph/BCR(-) ALL, A-DI could also influence the outcome in Ph/BCR(+) patients with other favorable prognostic factors.

Fractionated cyclophosphamide added to the IVAP regimen (idarubicin-vincristine-L-asparaginase-prednisone) could lower the risk of primary refractory disease in T-lineage but not B-lineage acute lymphoblastic leukemia: first results from a phase II clinical study.

BACKGROUND AND OBJECTIVE: In a prior study, primary resistant acute lymphoblastic leukemia (RES-ALL) was observed in 11 of 176 (6%) adult patients treated with a four drug regimen (IVAP), its incidence being higher in T-cell or Philadelphia (Ph) chromosome/BCR-ABL rearrangement positive ALL cases with a blast cell count >25x10(9)/L (RES-ALL rate 19%, p=0.04). Aiming to minimize this percentage of resistant disease, fractionated cyclophosphamide (f-CY) was then added to the IVAP regimen. DESIGN AND METHODS: Study 08-96 was a prospective, collaborative phase II trial carried out at eight general hospital centers specialized in the care of hematologic malignancies. Historical IVAP-treated patients served as a retrospective control group. All consecutive, untreated patients (>15 years) with a diagnosis of ALL or advanced-stage lymphoblastic lymphoma (LBL) were eligible. RES-ALL was defined as the persistence of >5% ALL cells in the bone marrow 28-40 days after the start of the IVAP regimen (idarubicin 10 mg/m(2)/d on days 1 and 2; vincristine 2 mg on days 1, 8 and 15; L-asparaginase 6,000 U/m(2) on alternate days 3 6 from day 8; prednisone 60 mg/m(2)/d on days 1-21). In the new study, two f-CY schedules were sequentially adopted: CY 150 or 75 mg/m(2)/bd, given for 4 consecutive days before IVAP (f-CY 1200 or 600, expressing total CY dose in mg/m(2)). RESULTS: Eighty-eight patients were evaluable (age range 15-74 years, blast count 0-240x10(9)/L, 14 T-lineage, 74 B-lineage, 13 Ph/BCR-ABL+). The first 39 patients received the f-CY 1200 schedule, 22 patients received f-CY 600, and the last 27 patients were not given any f-CY. These changes were dictated by the results of interim analyses of the f-CY groups (RES-ALL rate not reduced, myelotoxicity increased). Altogether, compared with the historical IVAP and no f-CY groups, the incidence of RES-ALL was not decreased by the addition of f-CY 1200/600 in B-lineage ALL, regardless of Ph/BCR-ABL expression and blast count. However, none of 14 T-ALL cases in the new study had RES-ALL (8 in f-CY groups, 5 of whom with >25x10(9)/L blast cells), compared to 5/39 (13%, overall) or 4/21 (19%, with >25x10(9)/L blast cells) among the control cases. Owing to small sample size, this difference was not statistically significant. INTERPRETATION AND CONCLUSIONS: This preliminary experience suggests that T-ALL may be more sensitive than B-lineage ALL to an early therapy including f-CY. The hypothesis could be tested in a larger clinical trial.

Chronic myelocytic leukemia in pregnancy: report of a case treated with leukapheresis.

CML was diagnosed by chance in a 24-year-old woman at the 15th week of pregnancy which, on being informed of her disease she decided to continue. No treatment was given until the 24th week, when WBC reached 140,000/mm3 and it was believed necessary to begin treatment. A program of leukapheresis was started, with the sole aim of reducing the expanding leukemic pool. With 8 leukapheresis, performed at intervals of 2-8 days, WBC were reduced and kept at about 100,000/mm3; after the 8th procedure there was a progressive reduction of WBC to 40,000/mm3, which level was maintained without further treatment for about 4 weeks. Pregnancy and fetal development continued normally. Labor was induced at the 37th week of gestation, and a normal male infant was delivered whose development to date (20 months of age) is normal.

Preliminary bioavailability study on protacine: a new, non-steroidal anti-inflammatory agent.

Time versus concentration curves of unchanged protacine were measured in the blood of 5 healthy volunteers by high pressure liquid chromatography after a single oral dose of 4 capsules (600 mg). These curves showed a maximum at 8 hours after administration, with an absorption half-life of 3.4 hours, and were interpreted according to the two-compartment open model with invasion. The elimination half-life was found to be 10 hours. This may allow a maintenance treatment, where necessary, with 1 capsule (150 mg) of protacine twice daily and strongly suggests that, apart from acute cases, protacine would be particularly well suited for long-term treatment.

Pharmacological study of a new non-steroidal anti-inflammatory drug: protacine (CR 604).

The pharmacological activities of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropylglutaramate(+/-)dimaleate (protacine, CR 604), a new indolyl derivative with strong anti-inflammatory, analgesic and antipyretic activities, are described. The dose-dependent activity of protacine on inflammation has been shown both in short-term experiments, like the hind paw edema induced by carrageenin and several other irritants, and long-term tests, like the aminoacetonitrile-induced osteolathyrism, the adjuvant-induced arthritis and the cotton pellet-induced granuloma. The analgesic activity of the drug has been evidenced in the phenylquinone-induced writhing and the Randall-Selitto tests, and the antipyretic effects in the yeast-induced hyperthermia in rats. Other general pharmacological effects have been studied, too. Contrarily to several other anti-inflammatory drugs, including indometacin, showing advers effects at doses which are in the same range of those active on experimental inflammation, protacine shows these effects to a minor degree and at doses which are much larger than those pharmacologically active. The therapeutic index of protacine therefore is superior to that of other anti-inflammatory drugs.

Pharmacokinetic approach to proglumide long-term activity.

In order to explain the long-term therapeutic activity of (+/-)-4-benzamide-N,-di-n-propylglutaramic acid (proglumide, Milid) a pharmacokinetic study was carried out in rats by three administration routes. As a result, experimental data could have been fitted to a tri- or tetra-exponential equation, with terminal half-life of about 24 h. Since human pharmacokinetics was found to be rather similar to that in rats, it can be extrapolated that steady state plasma level of drug during therapeutic dosage regimen should range around 60% of peak level of single administration.

Double-blind clinical evaluation of a new anti-inflammatory drug, protacine, versus indomethacin.

A double-blind clinical trial was carried out in 69 rheumatic in-patients to compare the efficacy and tolerance of a new, non-steroidal anti-inflammatory agent, protacine, with that of indomethacin. Patients received either 150 mg protacine or 50 mg indomethacin 3-times daily for 21 days. The time course of symptoms was recorded by semiquantitative scoring, as were side-effects. Uropepsinogen excretion, occult blood in faeces and standard physiological parameters were also monitored. Protacine globally decreased symptom scores by 58.5% and indomethacin by 24.3% (p less than 0.001). The computed time to reduce symptom scores by 50% was 17.2 days with protacine as compared to 39.2 days with indomethacin (p less than 0.001). Physiological parameters did not change, except white blood cells which decreased after protacine (each subject however, remaining well within the physiological range) and erythrocyte sedimentation rate, which decreased in both groups. Uropepsinogen excretion increased by 70% after protacine, and threefold after indomethacin (p less than 0.001). Occult blood search was positive in 1 patient receiving protacine, while 2 who were already positive before receiving protacine became negative during the treatment. Four patients taking indomethacin were found to be positive, 1 showing melaena. The one who was already positive before treatment showed increasing severity of occult bleeding during indomethacin administration. Frequency and severity of side-effects were significantly less with protacine (p = 0.004). In conclusion, protacine showed analgesic and anti-inflammatory actions significantly more potent and rapid than those of indomethacin, with significantly fewer and less severe side-effects.

Double-blind clinical comparison between a gastrin-receptor antagonist, proglumide, and a histamine H2-blocker, cimetidine.

A double-blind trial was carried out in 30 patients with peptic ulcers to assess the effects of treatment with a gastrin-receptor antagonist, proglumide, compared with a histamine H2-blocker, cimetidine. Patients received either 1200 mg proglumide or 1200 mg cimetidine per day for 28 days. The results showed that both drugs significantly reduced clinical symptoms and gastric secretion. In patients treated with cimetidine there was a significant increase in blood gastrin levels and marked hypertrophy and hyperplasia of the antral mucosa was observed in almost all patients. No such changes were found in the patients treated with proglumide.

A study of the development of fracture callus in the presence of an experimentally induced osteosarcoma.

The results of two experiments are reported in which the formation of an osteosarcoma was induced in mice by the intraosseous injection of Moloney's virus. In the first group of fifty mice, a complete diaphyseal fracture was carried out nine days later at the site of the tumour. In the second group of 200 mice, a partial fracture was produced at the time of injection so that immobilisation was assured. The effects of cyclophosphamide and calcitonin administration were also studied in this group. The course of the repair processes of the bone was studied in both groups, and showed that, even in the presence of an osteosarcoma, these begin and can reach completion, though obstructed and delayed by the tumour.