A randomized study of intermediate as compared with high doses of interferon-alpha for chronic myeloid leukemia: no differences in cytogenetic responses.

Interferon-alpha (IFN-alpha) is a therapy of unquestionable efficacy in chronic myeloid leukemia (CML) patients. The best dose of IFN-alpha in the treatment of CML still remains controversial. Our primary objective was to compare cytogenetic responses in patients treated with intermediate versus high doses of IFN-alpha. A multicenter randomized controlled trial was conducted involving 109 patients with untreated CML in chronic phase from 26 Spanish hospitals. Patients were assigned to receive either an intermediate (2.5 MU/m(2) per day) or high (5 MU/m(2) per day) target dose of IFN-alpha. Hydroxyurea was allowed in both groups. In total, 108 patients were analyzed, 53 in the intermediate- and 55 in the high-dose group. Median follow-up was 47.5 months. The dose of IFN-alpha actually given was lower in the intermediate-dose group (3.83 MU/day) than in the high-dose group (6.6 MU/day) ( p<0.001). The rate of complete cytogenetic response was 24.5% in the intermediate- and 12.7% in the high-dose group (NS). A partial cytogenetic response was obtained in 7.5% and 10.9%, respectively. Cox analysis did not reveal any influence of the randomization arm on cytogenetic response rate. Ten patients in each group discontinued IFN-alpha because of toxicity. Albeit not our primary objective, no differences were found in terms of survival or transformation rate between both groups. Median survival was 73 months; 64% of patients remained free of transformation at 5 years. In terms of cytogenetic response, intermediate doses of IFN-alpha are as effective as high doses in the treatment of CML.

Gm and Km alleles in two Spanish Pyrenean populations (Andorra and Pallars Sobirà): a review of Gm variation in the Western Mediterranean basin.

Two Spanish eastern Pyrenean populations, Andorra and Pallars Sobirà, have been tested for G1m(1,2,3,17), G2m(23), G3m(5,6,10,11,13,14,15,16,21,24,28) and Km(1) immunoglobulin allotypes. Km allele and Gm haplotype frequencies in both samples fit well into the Western Mediterranean and, more strictly, Pyrenean ranges with some peculiarities: Andorra showed an elevated frequency (14.7%) of the typical Asian and European Gm21,28;1,2,17;. haplotype, while Pallars Sobirà was characterized by high values (3.7%) of Gm5*;1,17;., a typical sub-Saharan Gm haplotype. Gm diversity assessed through genetic distance and variance analyses revealed a significant geographic partition (4.3%) of Mediterraneans among south, north-east, and north-west groups. It is interesting to note the relatively low genetic variance (2.1%) found between south and north-western Mediterraneans that could reflect ancient population relationships. More locally, genetic boundaries and diversity analyses failed to indicate any geographic pattern and/or genetic differentiation related with the political border in the Pyrenees. The present pattern of variation in this area is probably the result of genetic isolation processes, in addition to some specific demographic phenomena, in the Pyrenean valleys.

GM and KM immunoglobulin allotypes in a Spanish Pyrenean population: Val d'Aran.

Four hundred and thirteen unrelated individuals (202 autochthonous and 211 non-autochthonous) of Val d'Aran (Catalan Pyrenees) have been analysed for the GM and KM immunoglobulin genetic system using the inhibition haemagglutination method. This population was defined by eight GM haplotypes (GM*3 23 5*, GM*3 5*, GM*1,17 21,28, GM*1,2,17 21,28, GM*1,17 5*, GM*1,17 5,6,11,24, GM*1,17 10,11,13,15 and GM*1,17 10,11,13,15,16) inferred from the 17 observed phenotypes. The Val d'Aran population frequencies conform to Hardy-Weinberg expectations. The frequencies of phenotypes and haplotypes show a definite homogeneity between the autochthonous and non-autochthonous people of Val d'Aran and 11 other Pyrenean populations (Mauléon, Macaye, St. Jean Pied de Port, Vallée de L'Ouzom, Gavarnie, Barèges, Luz St. Sauveur, Esparros, Camurac, Capcir and Pays de Sault) that have already been studied for the same allotypes. A factorial correspondence analysis was performed for the 12 autochthonous Pyrenean populations, showing a high frequency of the GM*3 23 5* haplotype in the three Pyrenean regions (Western, Central and Eastern), while the GM*1,17 21,28 haplotype is mainly found in the Central region, GM*3 5* in the Eastern and Western zones, and the GM*1,2,17 21,28 is mainly present in the Central and Eastern populations. The results show a relative regional homogeneity, so there is no evidence of a frequency gradient in the Pyrenean populations for the GM and KM genetic systems. It may, however, be noticed that the Central Pyrenean populations form a group, with one population (Vallée de l'Ouzom) isolated from the rest, probably because of its particular model of inheritance by which the heritage is passed to the first born without sex consideration. It has been possible to point out some differences in the genetic structure of the autochthonous and non-autochthonous Val d'Aran population and to place the autochthonous Aranese group among its Pyrenean neighbours.

Interferon alpha 2A in the treatment of chronic myelogenous leukemia in chronic phase. Results of the Spanish Group.

Fifty-one patients with CML in chronic phase, less than two years after diagnosis, were included in one multicentric study aiming to assess the therapeutic value of interferon alpha 2a (IFN alpha 2a) in this setting. The therapeutic scheme was biphasic: The patients were first treated with hydroxyurea, and afterwards only received IFN alpha 2a, at a planned dose of 5MU/m2/day, s.c. Thirty-eight patients (81%) achieved an hematologic response, which was complete in 57% of the total group. The median time to response was of 42 days. In the last evaluation, a complete hematologic response was sustained in 21 patients (47%). Philadelphia suppression was obtained in 44% of the patients who achieved hematologic responses; major cytogenetic responses were obtained in 16% of the patients. The patients who obtained genetic responses were significantly younger and had a shorter interval from diagnosis to IFN than the patients who did not respond. At the moment of evaluation, 90% of the patients are alive, but the median follow-up of the series (217 days, range 21-1150) is too short to analyze any impact of IFN over survival. Six patients (12%) discontinued IFN because of toxicity, three of them because of severe flu-like syndrome. Leukopenia and thrombocytopenia were frequent, but rarely severe. Hypertriglyceridemia has been a very frequent finding.

[Non-Hodgkin's lymphomas. I. Clinico-biological features of 307 cases]. / Linfomas no hodgkinianos. I. Características clínico biológicas de 307 casos.

PURPOSE: To assess the clinico-biological features appearing in 307 patients with non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: The clinical records of 338 patients diagnosed of NHL between January 1975 and December 1988 were revised in retrospect. All cases with histologic diagnosis of NHL aged over 14 years were included, and classified in accordance with the Working Formulation criteria. The following data were analysed: age, sex, first complaints, time elapsed since onset, histologic type, number of sites involved, bulky disease, anaemia, thrombocytopenia, LDH, stage, type of treatment and initial response, survival, and cause of death. The statistical evaluation was performed by actuarial analysis (Kaplan and Meier) and comparison (log-rank test) of survival. RESULTS: According to the three categories of the malignancies, the NHL were distributed into low-grade (37.8%), intermediate (36.1%) and high-grade (26.9%). The mean age of the series was 56.6 years and the M/F ratio was 1.3. Lymph node enlargement was the commonest finding; 36.4% of the patients had symptoms related with the disease, and 26.7% had bulky disease. Anaemia was present in 37.7% of the cases and thrombocytopenia in 14.3%, with similar distribution among the three grades. High LDH levels were found in 44% of the patients. At diagnosis, 85% of the patients were in advanced stages (III+IV) already. Complete response was attained in 51.1% of the cases, with median survival of 48 months. CONCLUSIONS: The clinico-evolutive data found here are similar to other reports in the literature. In one-half of the patients the cause of the first visit is lymph node enlargement. Complete remission is achieved by one out of two patients, this figure being similar for each of the histologic groups. The Working Formulation is useful in determining the different prognostic groups with respect to survival.

[Non-Hodgkin's lymphomas. II. Analysis of the prognostic factors in a series of 307 patients]. / Linfomas no hodgkinianos. II. Análisis de los factores pronósticos en una serie de 307 enfermos.

PURPOSE: To analyse different clinico-biologic data in order to assess their prognostic value in non-Hodgkin's lymphoma (NHL) patients. MATERIAL AND METHODS: The series comprises 307 patients with NHL diagnosed and treated between 1975 and 1988. The histopathologic diagnosis was revised in accordance with the working formulation system, three prognostic groups being thus considered: low-grade (LGL), intermediate-grade (IGL) and high-grade (HGL) lymphomas. Age, sex, clinical course prior to diagnosis, presence of B symptoms, histologic type, number of lymph-node areas involved, bulky disease, anaemia, thrombocytopenia, LDH, stage and response to therapy were all evaluated for the study. Survival curves were drawn with the Kaplan-Meier method, and the log-rank test was used for comparison of median survival. Whenever the univariate analysis achieved statistical significance, a multivariate analysis was performed by means of a multiple correlation and regression study in accordance with the Cox's model, in which the variables were expressed in a binary model. RESULTS: The following 8 values were found significant in the univariate study of low-grade lymphomas: age, number of involved areas, bulky disease anaemia, thrombocytopenia, LDH, stage, and initial response to treatment. In intermediate-grade lymphomas, the significant findings were age, number of affected areas, bulky disease, thrombocytopenia, LDH, stage, and initial response. For high-grade lymphomas, number of affected areas, thrombocytopenia, LDH, stage and initial response were found statistically significant. Although no significant differences were found for survival within each of the three grades, such differences were significant between them. In the multivariate analysis, age was significant only in the LGL (p < 0.0001) in IGL, age (p < 0.07) and initial response to therapy (p < 0.0001) achieved significant value, and in HGL, stage (p < 0.02) and initial response to treatment (p < 0.0001) attained significance. CONCLUSIONS: The univariate analysis provides various prognostic factors of statistically significance, as reported in the literature, but these after the multivariate analysis was applied, were reduced to age, stage and initial response to treatment.

[Analysis of 4 prognostic scoring systems in 197 myelodysplastic syndrome patients]. / Análisis de cuatro sistemas de puntuación pronóstica en 197 síndromes mielodisplásicos.

PURPOSE: To evaluate the prognostic significance of four scoring systems applied with predictive trends to myelodysplastic syndromes (MDS). MATERIAL AND METHODS: This study is comprised of 197 patients with MDS diagnosed in accordance with the FAB criteria and followed-up in our Department between Jan '75 and Dec '89. The following MDS subtypes were found: refractory anaemia (RA), 58 cases; sideroblastic refractory anaemia (SRA), 42 cases; refractory anaemia with excess of blasts (RAEB), 46 cases; RAEB in transformation (RAEB-T), 39 cases; and chronic myelomonocytic leukaemia (CMML), 12 cases. The following scoring systems were applied: Mufti's 1985, Varela's 1985, Sanz's 1989 and our own of 1991. The statistical analysis was performed according to Kaplan-Meier actuarial system and the log-Rank test of actuarial survival. RESULTS: (1) Three groups (A, B and C) can be defined by the Bournemouth system, with median survivals of 57.6, 17 and 7.6 months, respectively. The majority of cases (118) were included in group B. Group A has not reached 25% of actuarial survival probability, whereas groups B and C did at 32 and 10 months, respectively. With regard to the morphologic subtypes, RA and SRA were included in groups A and B, and RAEB, RAEB-T and CMML pertained mostly of group C. Sixty cases (90.9%) evolving into acute leukaemia (AL) corresponded to those last groups. (2) The three groups defined by Varela's system (0-1, 2-5 and 6 or more) have median survival of 85.6, 24 and 14 months, respectively. Like in the former system, group 0-1 has not reached 25% actuarial probability, this appearing at 70 and 20 months, respectively, in groups 2-5 and greater than 6. The distribution of the cytological varieties, RA and SRA amongst the groups is heterogeneous although there are more common within the cases included in groups 0-1. All the cases evolving into AL were included in the groups 2-5 and greater than 6. (3) The 3 groups of the system proposed by Sanz (0-1, 2-3 and 4-5) had median survival of, respectively, 58, 15 and 14 months. Like in the preceding cases, group 0-1 has not reached the 25% actuarial probability, while this figure appears at 28 months for group 2-3 and at 20 months for group 4-5. RA and SRA varieties are included chiefly in group 0-1, while RAEB and RAEB-T appear mostly in groups 2-3 and 4-5. The distribution of the cases and evolving into AL in heterogeneous according to this system, although they predominate in groups 2-3 and 4-5. (4) The prognostic groups are defined by the system proposed by us (namely 0-2, 3-5, 5 greater than or equal to 6) with median survivals of 89.3, 17 and greater than 11 months, respectively. Striking difference was seen when studying the cumulated survivals observed, on each of the three percentages considered, between the groups. The different cytological varieties distributed reasonably with higher incidence of RA and SRA in group I and RAEB, RAEB-T and CMML in group III. This system offers statistical significance when comparing RA with SRA, RAEB with RAEB-T and, obviously. RA+SRA with RAEB+RAEB-T+CMML. The evolution into AL showed also statistical significance with respect to the three groups. CONCLUSIONS: 1. Three prognostic groups regarding the patient's survival could be established in our series with all the scoring systems analyzed, except that of Sanz. 2. Low risk (RA and SRA) and high risk (RAEB, RAEB-T and CMML) cytological varieties can be identified with all the scoring systems; that of Sanz is also capable of discriminating RA from SRA. 3. Some prediction on the possibility of evolution into AL can be attained of with each system. 4. The scoring system proposed by us shows higher discriminating capability on the cytologic varieties as well as higher predictive value on the possibility of evolution into AL. Nevertheless, it must be evaluated in other series in order to reach general acceptance.

[Monoclonal gammopathies of undetermined significance. Clinical course and biological aspects of 397 cases]. / Gammapatías monoclonales de significado indeterminado. Aspectos clínicos, biológicos y evolutivos de 397 casos.

The diagnostic criteria, incidence, clinical characteristics and outcome of 397 patients with monoclonal gammopathies of undetermined significance, all of them diagnosed and followed-up at the Haematology Service of the Miguel Servet Hospital, in Zaragoza, between January 1970 and December 1988, were revised. The patients' mean age was 64.7 years (range: 2-89). The M/F ratio was 236/161. The mean concentration of the M component (MC) was 1.17 g/dL (range: 0.20-3.50), this being under 0.50 in 65 cases. IgG was the most frequent MC (71.26%), followed by IgA (14.34%) and IgM (10.82%). Multiple MC was present in 14 cases (3.58). Light chains were passed in urine by 33 patients (8.31%). No associated pathology was found in 213 patients (53.65%) upon MC discovery, while 65 other (16.31%) were carriers of different blood disorders, chronic lymphoproliferative diseases being the commonest (11.57%). In 30 patients (7.30%) the MC was associated to nonhaematological malignancies, and 29 others had an underlying chronic infection. Chronic liver disease was present in 25 cases, and autoimmune disease in 14. Transient monoclonal gammopathy was seen in a small group of patients (6.54%), most of them suffering from acute infectious illness. With regard to the group of patients without any associated pathology, their median follow-up was 37.8 months (range: 18-228). Of them, the MC kept unchanged in 134 cases (62.91%); 47(22.06%) died from any unrelated cause, and 10 others evolved into malignant monoclonal gammopathy. The median clinical course of these last expanded to 60 months (range: 11-124), with an accumulated actuarial risk of 4.5% at 5 years, 15% at 10 years and 26% at 15 years.

[Incidence of monoclonal components in lymphoproliferative syndromes. Apropos of 234 cases ]. / Incidencia de componentes monoclonales en síndromes linfoproliferativos. A propósito de 234 casos.

A series of 234 sera from 104 patients with non-Hodgkin's lymphoma (NHL), 77 with Hodgkin's disease (HD) and 53 with chronic lymphocytic leukaemia (CLL) was studied by cellulose acetate gel electrophoresis, agarose gel electrophoresis, immunoelectrophoresis and electroimmunodiffusion, in order to assess the incidence and type of monoclonal components (MC) in these diseases. Monoclonal component was found by cellulose acetate gel electrophoresis in 22 of the 234 cases studied (9.8%); agarose gel electrophoresis disclosed MC in 22 other cases (18.8%), all of them showing rates lower than 5.0 g/L. MC was present in 29 of the 104 NHL cases (27.9%), it being characterised as IgM in 16 patients and IgG in 13 others. The MC was observed in 13 of the 21 cases of lymphoplasmacytoid forms, but it was less conspicuous in the remaining histological forms. With regard to HD, MC was present in 5 cases (6.5%), of IgG, type in all instances, and in 10 of the 53 CLL patients (18.9%), IgG in 8 and IgM in two other cases. The methods used in the present study made it possible to detect and characterise MC in about 20% of the lymphoproliferative syndromes studied. It can be inferred that the use of more sensitive techniques would disclose the presence of MC in the majority of B-cell lymphoproliferative syndromes.

Nonsecretory multiple myeloma.

Among 186 patients with multiple myeloma (MM), five women were diagnosed as having MM without M-component in serum and or urine at the diagnosis and along the evolution. Bone marrow plasmacytosis at greater than 30% was found in all patients and bone x-rays showed lytic lesions in all but one case, osteoporosis in all, and pathologic fractures in two. Serum electrophoresis showed a striking hypogammaglobulinemia in all, and polyclonal immunoglobulin levels were markedly reduced. The immunofluorescence of plasma cells in bone marrow was positive for monoclonal light chain polypeptides in four patients, and the ultrastructure showed mature plasmocytes with a wide rough endoplasmic reticulum (RER) and an intact Golgi apparatus. In three patients, therapy with melphalan plus prednisone was started. The remaining two were treated with an M-2 protocol. Death was an early event in two patients; the response was good in the remaining patients, without differences regarding secretory MM. Despite some reports stressing an unfavourable prognosis in MM without M-component, in our series it is roughly the same as in MM with secretion.