Bone marrow hyaluronan and reticulin in patients with malignant disorders.

Myelofibrosis is commonly seen in patients with chronic myeloproliferative diseases and sometimes in myelodysplastic syndrome, acute leukaemia and lymphoproliferative diseases. The fibrotic process is evaluated by grading the amount of collagen deposited in the bone marrow interstitium. The established method to evaluate bone marrow fibrosis is staining for reticulin to visualise the collagen fibres. However, the extra cellular matrix does not only contain collagens but also other components, e.g. glycosaminoglycans of which hyaluronan is the most abundant. Hyaluronan is important for structural and cellular functions. Earlier studies have shown that there is a positive correlation between hyaluronan and reticulin staining in healthy volunteers and in patients with de novo acute myeloid leukaemia. In this study bone marrow biopsies from 43 patients with a malignant disease involving the bone marrow were compared with 18 patients with a malignant disease not involving the bone marrow. The intensity of hyaluronan grading was significantly higher in the patients with disease involving the bone marrow compared to the healthy controls but not compared to the patients without disease involving the bone marrow. The staining intensity of reticulin in the bone marrow was significantly higher in the patients with disease involving the bone marrow, compared to those without disease involving the bone marrow and to the controls. In all patients and the controls there was a correlation between hyaluronan and reticulin.

No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease.

In this prospective randomized multicenter trial 93 patients, median age 72 years, with RAEB-t (n=25) and myelodysplastic syndrome (MDS)-AML (n=68) were allocated to a standard induction chemotherapy regimen (TAD 2+7) with or without addition of granulocyte-macrophage-CSF (GM-CSF). The overall complete remission (CR) rate was 43% with no difference between the arms. Median survival times for all patients, CR patients, and non-CR patients were 280, 550, and 100 days, respectively, with no difference between the arms. Response rates were significantly better in patients with serum lactate dehydrogenase (S-LDH) levels

Haematological malignancies in a general population, based on information collected from a population study, hospital records, and the Cancer Registry of Norway: the Tromsø Study.

OBJECTIVES: To investigate the prevalence and incidence of haematological malignancies, and to compare the rates found with those reported from the Cancer Registry of Norway. METHODS: Three sources of information were used: (1) automated blood cell counts from 27 145 persons older than 24 yr (72% of those invited), participating in a population study (the Tromsø Study 1994-95); (2) patient medical records at the University Hospital of Tromsø during 1991-96; (3) the Cancer Registry of Norway. RESULTS: (1) In the population study, 13 new cases of haematological malignancies were diagnosed. For five of these the early detection was probably beneficial. (2) From the hospital records another 59 participants and 36 non-participants to the population study were found to have haematological malignancies. (3) Additionally, six cases were identified from the Cancer Registry. Totally, we thus identified 114 period prevalent cases, of which 86% had been reported to the Cancer Registry. Age-adjusted period prevalence of haematological malignancies was 4.7 per thousand in men and 2.9 per thousand in women. The prevalence increased with age. There were 84 cases with leukaemia, lymphoma, or multiple myeloma diagnosed at any time and still alive at 31 December 1996 (point prevalence 2.2 per thousand). Our estimated incidence of haematological malignancies did not differ significantly from that reported from the Cancer Registry. CONCLUSION: We found approximately the same rates of haematological malignancies as the Cancer Registry, although an underreporting of 14% to the Cancer Registry was detected. The point prevalence of leukaemia, lymphoma, and multiple myeloma was 2.2%.

[High dose therapy with autologous stem cell support--finally a progress in myelomatosis]. / Høydosebehandling med autolog stamcellestøtte--endelig et fremskritt ved myelomatose.

BACKGROUND: Since the introduction of the simple cyclic oral treatment with melphalan and prednisone in the late 1960s, there has been no substantial improvement in the therapy of multiple myeloma. In 1994, the Nordic Myeloma Study Group initiated a population-based, prospective study to evaluate the impact on survival of high dose chemotherapy in newly diagnosed, symptomatic patients under 60 years of age, compared to a conventionally treated control group. MATERIAL AND METHODS: 274 patients were treated according to a specified high dose protocol and compared to 274 patients from previous population-based trials fulfilling the same eligibility criteria. RESULTS: Median survival was 44 months in the control group and 62 months in the intensive treatment group (risk ratio 1.65; 95% CI = 1.28-2.14, P = 0.0001). A study of health-related quality of life (HRQoL) which was integrated in the trial showed a moderately reduced HRQoL associated with the intensive treatment phase, but no statistically significant difference beyond the first year of follow-up. In a cost-utility analysis of the trial, the cost per (quality-adjusted life years) was estimated at USD 26,000. INTERPRETATION: The incremental cost of the treatment is within what is usually thought to be acceptable limits. Further improvement of the results and reduction of stay in hospital would give an even more favourable cost-utility ratio.

Health-related quality of life in multiple myeloma patients receiving high-dose chemotherapy with autologous blood stem-cell support.

In a population-based study, the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age (risk ratio: 1.62; confidence interval [CI] 1.22-2.15; p = 0.001). A study of health-related quality of life (HRQoL) was integrated in the trial, using the EORTC QLQ-C30 questionnaire. Of the 274 patients receiving intensive therapy 221 (81%) were compared to 113 (94%) of 120 patients receiving conventional melphalan-prednisone treatment. Prior to treatment, there were no statistically significant differences in any HRQoL score between the two groups. One month after the start of induction chemotherapy, the patients on intensive treatment had more sleep disturbance than the control patients. At 6 mo, corresponding to a mean of 52 d after high-dose melphalan, the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss. At 12 and 24 mo, the HRQoL was similar to that of the control patients. At 36 mo, there was a trend toward less fatigue, pain, nausea, and appetite loss in the intensive-treatment group. Thus, the 18 mo of prolonged survival seem to be associated with a good health-related quality of life. Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase, this treatment modality must be regarded as an important step forward in the care of multiple myeloma.

CD68+/CD83+/CD1a- dendritic cell subsets from patients with multiple myeloma are not infected with human herpesvirus 8.

Recently, a subset of dendritic cells with the phenotype CD68+/CD83+/CD1a-, present in patients with multiple myeloma (MM), was reported to be infected with human herpesvirus 8 (HHV-8). Therefore we wished to clarify whether HHV-8 infection might be related to the pathogenesis of MM. In an attempt to identify HHV-8 infected cells in patients with MM, long-term bone marrow cultures from 8 MM patients and dendritic cell cultures from 11 MM patients were established. In addition, fresh bone marrow aspirates from 10 MM and 10 patients with monoclonal gammopathy of undetermined significance (MGUS) were included in the study. All samples were analysed by a sensitive semi-nested PCR assay and were found to be consistently PCR negative. Phenotyping of day 7 dendritic cell cultures demonstrated the presence of a sufficient number of CD68+/CD1a- and CD83+/CD1a- cells. However, to exclude the presence of infrequent HHV-8 infected cells, the CD68+/CD1a- subset from 3 dendritic cell cultures was sorted in numbers of 105 for each PCR test, and again a negative PCR result was observed. This study documents that the CD68+/CD83+/CD1a- dendritic cells in patients with MM are not generally infected with HHV-8 and, as a consequence, it is unlikely that HHV-8 plays a role in the pathogenesis of MM.

Serum syndecan-1: a new independent prognostic marker in multiple myeloma.

Serum samples drawn at diagnosis from 174 myeloma patients were analyzed for the presence of the heparan [corrected] sulfate proteoglycan, syndecan-1. Syndecan-1 was elevated in 79% of patients (median, 643 units/mL) compared with 40 healthy controls (median, 128 units/mL), P <.0001. Serum syndecan-1 correlated with the following: serum creatinine, secretion of urine M-component over the course of 24 hours, soluble interleukin-6 (IL-6) receptor, C-terminal telopeptide of type I collagen, beta(2)-microglobulin, percentage of plasma cells in the bone marrow, disease stage, and serum M-component concentration. In order to evaluate syndecan-1 as a prognostic marker in multiple myeloma, it was entered into a multivariate Cox regression model. Data from 138 patients were available for this analysis. As a continuous variable, syndecan-1 was an independent prognostic parameter in addition to serum beta(2)-microglobulin and World Health Organization performance status. When syndecan-1 was dichotomized by the best cutoff (66th percentile, 1170 units/mL), the survival difference between the groups was highly significant: "high" syndecan-1 group had a median survival of 20 months, and the "low" syndecan-1 group had a median of 44 months (P <.0001). We conclude that syndecan-1 is a new independent prognostic parameter in multiple myeloma, and its role in prognostic classification systems should be further investigated. (Blood. 2000;95:388-392)

Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Nordic Myeloma Study Group.

High-dose therapy has become a common treatment for myeloma. The objectives of this study were to estimate in a prospective, population-based setting the impact on survival of high-dose therapy in newly diagnosed, symptomatic patients less than 60 years old and to compare the results with those of conventionally treated historic controls. The prospective population comprised 348 patients. Of these, 274 were treated according to a specified intensive-therapy protocol (Nordic Myeloma Study Group [NMSG] #5/94) and constituted the intensive-therapy group. The historic population consisted of 313 patients identified from 5 previous population-based Nordic studies. Of these, 274 fulfilled the eligibility criteria for high-dose therapy stated in NMSG #5/94 and constituted the control group. The expected numbers of patients in the prospective population and the historic population were 450 and 410, respectively, estimated from previously established data on the incidence in this population and the population base for each study. Survival was prolonged in the intensive-therapy group compared with the control group (risk ratio for the control group 1.62; 95% confidence interval 1.22-2.15; P =.001). These groups represented more than 60% of the expected number of patients. When survival for all the registered patients in the 2 populations was compared, representing more than 75% of the expected number of patients, the advantage for the prospective population persisted (risk ratio for the historic population 1.46; 95% confidence interval 1.14-1.86; P =. 002). These results indicate that the introduction of high-dose therapy for newly diagnosed myeloma has resulted in prolonged survival for the total patient population aged less than 60 years. (Blood. 2000; 95:7-11)

Serum hyaluronan in patients with multiple myeloma: correlation with survival and Ig concentration.

Serum from 386 myeloma patients were analyzed for serum hyaluronan (HYA) at diagnosis. Median age was 68 years (range, 32 to 87 years). The distribution of Ig classes was typical (58% IgG, 21% IgA, 1% IgD, and 20% light chain disease). The patients comprised 58% in stage III, 33% in stage II, and 9% in stage I. The majority (82%) had HYA values within an intermediate range (10 to 120 micrograms/L), 13% had high values (>120 micrograms/L), and 5% had abnormally low values (0 to 9 micrograms/L). For the first time, a patient group with abnormally low HYA serum values is reported. An inverse correlation between survival and HYA serum level was found (P =.015). When tested separately, patients with abnormally low or high HYA values had significantly shorter median survival (21.1 and 19.7 months, respectively) than those with an intermediate HYA concentration (32. 6 months; P =.005). Patients with abnormally low or high HYA levels had more advanced disease as judged by staging and biochemical markers. Interestingly, there was an inverse correlation between the HYA value and the M-component concentration in serum. Fifty percent of patients with abnormally low HYA values had IgA myelomas. In conclusion, the serum concentration of HYA may be of prognostic value in selected cases of multiple myeloma. Further studies will be performed to elucidate possible explanations for our findings, especially those related to the HYA cell surface binding proteins.

[Chronic myeloid leukemia in health regions 1, 3, 4 and 5 during the period 1990-96]. / Kronisk myelogen leukemi i helseregion 1, 3, 4 og 5 i perioden 1990-96.

The aim of the present investigation was to obtain information about treatment, clinical course and outcome for all patients with chronic myeloid leukaemia through a six-year period in a defined part of Norway. A total number of 141 patients fulfilled the diagnostic criteria. This is equivalent to 0.9 patients per 100,000 per year. The median age was 62 years. More than 70% of the patients were primarily treated with hydroxyurea, either alone or combined with interferon. 40 out of 57 patients younger than 55 years underwent allogeneic stem cell transplantation. Median survival for all patients was 36 months with an estimated five-year survival rate of 33%. Patients older than 55 years had a median survival of 30 months with 16% alive after five years. The five-year survival rate for patients younger than 55 years was 56%, for transplanted patients 72%. 60 of 84 patients older than 55 years have died after 4 1/2 years median observation time. Two thirds of those died of leukaemia; one third of other causes. 23 of 57 patients younger than 55 years have died. 11 of them had had transplantations and most of them died from transplantation-related causes, while leukaemia was the dominating cause of death in the others.

[Empirical antibiotic treatment of patients with acute myelogenous leukemia]. / Empirisk antibiotikabehandling hos pasienter med akutt myelogen leukemi.

All febrile episodes (a total of 276) which occurred in 85 patients with acute myelogenous leukaemia treated in four Norwegian centres during the period 1990-1994 were studied retrospectively in order to assess the efficacy of antibiotic treatment. 72% of these episodes were initially treated with benzyl penicillin and aminoglycoside (standard treatment), while alternative empirical treatment was given in the remaining cases. The treatment was successful in 94% of the febrile episodes initially treated with standard treatment and in 96% of the episodes which received alternative antibiotics. For both types of treatment, a change to second line antibiotic regimen was made for various reasons in a majority of cases. The combination benzyl penicillin and aminoglycoside seems to be a safe empirical treatment for febrile neutropenia in patients with acute myelogenous leukaemia in our treatment centres, provided that the treatment is modified in patients with unsatisfactory clinical response.

[Decentralized high-dose cytostatic treatment with autologous stem cell support]. / Regionalisert høydose cellegiftbehandling med autolog stamcellestøtte.

In the past high-dose chemotherapy with autologous stem cell support in the treatment of certain types of cancer, was centralized to two hospitals in Norway. Almost three years ago it was decided that the treatment should be offered by all five university hospitals. In the northernmost university hospital of Norway, Tromsø, peripheral stem cells were harvested from 29 patients after successful mobilization with chemotherapy and granulocyte colony-stimulating factor (G-CSF). After high-dose chemotherapy, more than 2 x 10(6) CD34-positive stem cells/kg were transplanted in 24 patients and a sign of reconstitution of bone marrow function was achieved with mean time for neutrophils > 0.5x10(9)/l, 9.8 days and for platelets > 20x10(9)/l, 10.8 days. No treatment-related deaths have occurred. Transplantation of selected CD34-positive stem cells has been performed in one patient. Recovery was comparable to the recovery of patients who had undergone transplantation with unselected products. This indicates that even small centres performing as few as ten procedures per year may offer high-dose chemotherapy with autologous stem cell support safely and successfully.

[Future requirements for hematologists]. / Fremtidig behov for spesialister i blodsykdommer.

Today there are not enough specialists in haematology in Norway. During the period 1990-1995 2.5 specialists in haematology qualified per year. In order to meet future requirements for haematologists at Norwegian municipal and university hospitals, it has been estimated by the Norwegian Society for Haematology that the number of specialists qualifying per year should be increased to ten for the next ten years.

Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients.

Treatment with erythropoietin (epo) may improve the anemia of myelodysplastic syndromes (MDS) in approximately 20% of patients. Previous studies have suggested that treatment with the combination of granulocyte colony-stimulating factor (G-CSF) and epo may increase this response rate. In the present phase II study, patients with MDS and anemia were randomized to treatment with G-CSF + epo according to one of two alternatives; arm A starting with G-CSF for 4 weeks followed by the combination for 12 weeks, and arm B starting with epo for 8 weeks followed by the combination for 10 weeks. Fifty evaluable patients (10 refractory anemia [RA], 13 refractory anemia with ring sideroblasts [RARS], and 27 refractory anemia with excess blasts [RAEB]) were included in the study, three were evaluable only for epo as monotherapy and 47 for the combined treatment. The overall response rate to G-CSF + epo was 38%, which is identical to that in our previous study. The response rates for patients with RA, RARS, and RAEB were 20%, 46%, and 37%, respectively. Response rates were identical in the two treatment groups indicating that an initial treatment with G-CSF was not neccessary for a response to the combination. Nine patients in arm B showed a response to the combined treatment, but only three of these responded to epo alone. This suggests a synergistic effect in vivo by G-CSF + epo. A long-term follow-up was made on 71 evaluable patients from both the present and the preceding Scandinavian study on G-CSF + epo. Median survival was 26 months, and the overall risk of leukemic transformation during a median follow-up of 43 months was 28%. Twenty patients entered long-term maintenance treatment and showed a median duration of response of 24 months. The international prognostic scoring system (IPSS) was effective to predict survival, leukemic transformation, and to a lesser extent, duration of response, but had no impact on primary response rates.

[Chronic lymphatic leukemia. A population-based study of symptoms, findings, complications and choice of treatment]. / Kronisk lymfatisk leukemi. En populasjonsbasert undersøkelse av symptomer, funn, komplikasjoner og behandlingsvalg.

224 patients with a recent diagnosis of chronic lymphocytic leukemia, confirmed by immune phenotype, were studied with a mean follow-up of 16 months. The median age was 72 years and the ratio of men to women was 1.51. An incidental diagnosis because of leukocytosis was made in 75% of the patients; in only 22% was the diagnosis related to symptoms. 80% were in stage A, 7.5% in stage B, and 12.5% in stage C. A relation was found between advanced stage and the number of lymphocytes in the blood, the percentage of lymphocytes in the bone marrow, WHO performance status, bacterial infection and disease-related mortality. Thus, six patients in stage C (21%) died because of infection (septicaemia or pneumonia), as opposed to only one out of 196 patients in stages A and B. The incidence of bacterial infection was 64% in stage C, as compared to 8.3% in stage A. Treatment with chlorambucil, started in 59 patients, was in accordance with the guidelines of the national programme for 52 of them. In contrast, a strict indication for prednisone (autoimmune cytopenia) was found in only 42% of 42 patients given this treatment.

[Chronic lymphatic leukemia. Immunophenotyping as an aid to correct diagnosis]. / Kronisk lymfatisk leukemi. Immunfenotyping som hjelpemiddel for riktig diagnose.

The purpose of the study was to examine the validity of the primary diagnosis in chronic lymphocytic leukemia based on clinical and morphological criteria, and to examine the role of immune phenotyping for correct diagnosis in an unselected population-based group of patients. Over a 2-year period leukemic cells from 222 of 235 patients in Norway with a recent clinical diagnosis of chronic lymphocytic leukemia (CLL) were immune phenotyped in order to find cases erroneously diagnosed as CLL. Median age was 72.5 years, and the ratio of men to women was 1.47. At the time of diagnosis, 77% of the patients were in Binet stage A and 23% in stage B or C. Immune phenotyping, in some patients followed by lymph node or bone marrow biopsy, showed a different diagnosis in 11 (5%) of 222 patients: prolymphocytic leukemia, four patients (three B-cell and one T-cell); morbus Waldenstrøm, one patient; T-cell CLL, one patient; hairy cell leukemia, one patient; mycosis fungoides, one patient; mantle cell lymphoma, one patient; monocytoid B-cell lymphoma, one patient and immunoblastic lymphoma one patient. In eight of these 11 patients, the clinical features or morphology, or both, were atypical for CLL, but this was not recognized at the time of diagnosis. Thus, immune phenotyping is valuable for correct diagnosis in a small subgroup of patients with chronic B- or T-cell leukemia, and it is essential in patients with modest lymphocytosis (lymphocytes < 10. 10(9)/1).

Survival in 86 patients, aged 15-60, with primary acute myelogenous leukemia, treated with a common program in the Norwegian health regions I, III, IV and V in the period 1990-1995.

Eighty-six patients between 15 and 60 yr with primary acute myelogenous leukemia in health regions I, III, IV and V in Norway were treated according to a common protocol from 21 January 1990 until 1 September 1995 (until 1 January 1993 for health region IV). Seventy-one percent of the patients reached complete remission (CR) and went on to receive consolidation treatment. In addition to chemotherapy, 18 patients under the age of 52, i.e. 28% of all patients in this age group, received allogeneic bone marrow transplantation. A follow-up analysis was performed by 1 September 1996. The median overall survival was 15 months, estimated 3-yr survival 30% and estimated survival at 5 yr was 26%. The median duration of 1st CR was 19 months, and the leukemia-free survival at 3 yr was 29%. At follow-up 26/86 patients were alive, 18 in 1st CR (4 after BMT) and 8 in 2nd CR (5 after BMT in 2nd, 1 after BMT in early 1st relapse). These results are comparable to many previously published studies, but may be inferior to the results obtained with more intensive consolidation treatment, including high dose Ara C.

[Treatment with growth factors and cytokines in hematologic diseases]. / Behandling med vekstfaktorer og cytokiner ved hematologiske lidelser.

The Norwegian Society of Haematology has worked out guidelines for the use of granulocyte-colony stimulating factor and granulocyte-monocyte colony stimulating factor and interferon alpha in clinical haematological practice. We recommend not using growth factors as a routine to prevent or to treat fever in patients with granulocytopenia induced by cytostatics, or patients with myelodysplastic syndromes. At present such treatment should be restricted to clinical trials. The same conclusion was reached in regard to use of erythropoietin in the case of myelodysplastic syndromes. Harvesting of stem cells from peripheral blood is a well documented indication for administration of growth factors. Interferon alpha as maintenance treatment for cases of multiple myeloma and low grade malignant lymphoma delays progression of the disease but does not improve chance of survival. There is no documentation of improved quality of life. Use of interferon alpha is not justified as a routine treatment for multiple myeloma. In chronic myelogenous leukemia, interferon alpha seems to be equal to or better than hydroxyurea, and may be considered for patients who cannot undergo allogeneic bone marrow transplantation.