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Objective Infections and graft-versus-host disease (GVHD) are the main causes of transplant-related mortality (TRM) of patients undergoing allo-SCT. The role of iron overload (IO) has been debated in this context. Studies, performed with non-specific surrogate markers of iron, suggest that IO predicts poor outcome after allo-SCT. Methods In this prospective study, we quantified pretransplant IO with MRI-based hepatic iron concentration (HIC) measurement; the degree of IO was used to predict infections, GVHD, and mortality after allo-SCT. Logistic univariate, multivariate, and Cox's regression analyses were performed. Results Iron overload was present in 78% of the patients (HIC>36 μmol/g). The median HIC was 98 μmol/g (range 5–348). There were no cases of cardiac iron excess. IO was significantly associated with severe infections during the early post-transplant period (for every 10 μmol/g increase OR: 1.15, 95% CI 1.05–1.26, P = 0.003). The odds for severe infections increased 6.5- (>125 μmol/g OR: 6.5, P = 0.013) to 14-fold (>269 μmol/g OR: 14.1, P = 0.040) with increasing HIC. IO was found to be associated with reduced risk of acute and chronic GVHD. Although TRM was due to infection-related deaths, IO was not associated with TRM or OS. Conclusion Pretransplant IO, measured with a direct MRI-based measurement, predicts severe infections in the early post-transplant period.

Achievement of complete response (CR) is a new goal of therapy for multiple myeloma (MM). By sensitive methods, the depth of response can be measured even among the patients in CR. We used a sensitive real-time quantitative polymerase chain reaction by allele-specific primers (qASO-PCR) to assess the level of minimal residual disease (MRD) in bone marrow of 37 patients with myeloma who had achieved CR/near-to-CR after autologous or allogeneic stem cell transplantation (SCT). Allele-specific primers could be successfully designed for 86% of patients. Three to six months after autotransplantation, the PCR target was not detectable in 53% of patients (16/30 patients), and the respective figure after allotransplantation was 71 % (5/7 patients); the median sensitivity of PCR assay was

In a randomised multicentre trial a combination of methylprednisolone, vincristine, lomustine, cyclophosphamide and melphalan (MOCCA) was compared with the same regimen omitting methylprednisolone after the first course (COLA) in previously untreated patients with multiple myeloma. The MOCCA arm showed a response rate of 72% among 79 patients and the COLA arm a response rate of 60% among 59 patients. This difference was not statistically significant. The median survival time was 56 months in the MOCCA arm and 61 months in the COLA arm. There was a slight increase of early deaths (within the first 6 months) in the MOCCA arm as compared with the COLA arm. We conclude that, in multidrug therapies, the continuation of corticosteroid at conventional dosage beyond the first course does not improve response rate or survival time in multiple myeloma.

A total of 178 bone marrow samples were taken for minimal residual disease (MRD) analysis after 34 stem cell transplantations for poor-risk chronic lymphocytic leukemia, and 86 of them were analyzed in parallel by flow cytometry and allele-specific oligonucleotide-PCR (ASO-PCR). ASO primer was successfully designed for all patients whose frozen diagnosis samples were available. Flow cytometry and ASO-PCR were concordant, i.e. both either positive or both negative, in 78% of the analyses. Flow cytometry did not detect MRD in any of the samples that were PCR-negative cases. In contrast, ASO-PCR detected MRD in samples that were negative for MRD by flow cytometry in 22% of the analyses. In one patient, the immunophenotype but not the IgV H gene sequence had changed during a course of the disease, and MRD could not be followed by flow cytometry. In the remaining cases, the discrepancy was due to a higher sensitivity of ASO-PCR. Autologous stem cell transplantation resulted in clinical complete response in 87% (20/23) of the patients. By flow cytometry, 35% (8/23) of autotransplanted patients became MRD-negative, but only 12.5% (2/16) PCR-negative (sensitivity of ASO-PCR

Objectives: Wilms tumour gene 1 (WT1) is overexpressed in leucocytes of most acute myeloid leukaemia (AML) patients. However, the clinical relevance of WT1 gene expression as minimal residual disease (MRD) marker in AML has been questioned. Methods: We determined the expression of WT1 gene in bone marrow (BM) mononuclear cells of 100 AML patients at diagnosis and compared it with other MRD markers during follow up in 16 patients using quantitative reverse transcription-polymerase chain reaction. Results: The median WT1 gene expression was 9.7% of K562 cell line WT1 expression (lower quartile 1.5%, upper quartile 29.9%, n = 100) at diagnosis and, 0.053% (lower quartile 0.022%, upper quartile 0.125%, n = 87) in molecular or immunophenotypic remission. Median WT1 expression in control BM was 0.029% (lower quartile 0.013%, upper quartile 0.061%, n = 22). The upper 99% percentile of remission samples was 0.3%, which was regarded as the cut-off of increased WT1 gene expression in AML and was exceeded in 87% of all AML patients at diagnosis. WT1 and the other MRD markers showed only minor differences in profiles during follow-up. WT1 expression at diagnosis with median value 9.7% as the cut-off level or as a continuous variable had no prognostic significance for 2-yr survival. Conclusions: The sensitivity of WT1 as a MRD marker was low due to the relatively high background WT1 gene expression in BM cells at remission and in subjects without haematological malignancies. Therefore, WT1 gene expression analysis would be beneficial only in those patients who do not have a more specific and sensitive MRD marker.

Data on the incidence and causes of late (>100 d) non-relapse mortality (NRM) in autologous stem cell transplant (ASCT) recipients is limited. We have analysed NRM in a cohort of 1,482 adult patients who received ASCT in 1990-2003 in six Finnish transplant centres. The most common diagnoses included non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (n = 132); Hodgkin's lymphoma (HL) (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). Until September 2005, 646 patients (44%) have died. Late NRM was observed in 68 patients (4.6% of ASCT recipients; 11% of all deaths). There were 38 males and 30 females with a median age of 58 yr (20-69) at the time of ASCT. The median time to NRM was 27 months from ASCT (3-112). The risk of NRM was highest in patients with CLL (9.5%) and those with HL (8.1%) followed by MM and NHL (4.9% and 4.8%, respectively). The risk of late NRM was comparable in patients who received total body irradiation (TBI) and those who received chemotherapy-only regimens (6.7% vs. 4.3%). Another malignancy was the most common cause of late NRM (24 patients, 35% of late NRM). Twelve patients (0.8% of ASCT recipients) have died due to secondary haematological malignancy. Altogether 22 patients (32% of late NRM) died from infectious causes. Malignancies and late infections are important causes of NRM after ASCT. These facts point out the importance of prolonged follow-up in ASCT recipients.

Invasive fungal infections (IFI) constitute a majorcomplication in allogeneic stem cell transplant(SCT) recipients, with an incidence of about 15%(1, 2). During the recent years, Aspergillus infec-tions have been predominant in this setting (1–4).In autologous stem cell transplant (ASCT)recipients, the risk of IFI has been considered tobe small when compared with allogeneic patients(5, 6). Several small single-centre series have shownan incidence of 1–2% or even less (7–11), althoughhigher figures have been observed especially inpatients receiving bone marrow support instead ofblood stem cells (12, 13). Recently, an incidence upto 5% for invasive aspergillosis (IA) in an autol-ogous setting has been reported from Seattle (14).The risk of Candida infections in autologous bonemarrow transplant recipients has been high in someearlier studies (15, 16).Several changes in autologous transplant pro-cedure have occurred during the last decade.These include the use of blood stem cells insteadof marrow cells, the use of granulocyte-colony-stimulating factor (G-CSF) after stem cell infu-sion, the use of manipulated stem cell grafts andfluconazole prophylaxis. In addition, improveddiagnosis of Aspergillus infections, includingJantunen E, Salonen J, Juvonen E, Koivunen E, Siitonen T, Lehtinen T,Kuittinen O, Leppa¨ S, Anttila V-J, Ita¨la¨ M, Wiklund T, Remes K,Nousiainen T. Invasive fungal infections in autologous stem celltransplant recipients: a nation-wide study of 1188 transplanted patients.Eur J Haematol 2004: 73: 174–178. Blackwell Munksgaard 2004.Abstract: Based on small single-centre series, the risk of invasive fungalinfections (IFI) has been considered small in autologous stem celltransplant (ASCT) recipients. Purpose: To analyse epidemiologicaland clinical features of (IFI) among ASCT recipients in Finland 1990–2001. Patients: During the study period, 1188 adult patients receivedhigh-dose therapy supported by ASCT in six centres. Altogether, 1112patients (94%) received blood progenitor cells. The graft was CD34+selected in 261 patients (22%). The major diagnostic groups werenon-Hodgkin’s lymphoma (n ¼ 417), multiple myeloma (n ¼ 395),breast cancer (n ¼ 132) and Hodgkin’s lymphoma (n ¼ 53).Results: Eighteen patients (1.5%) with IFI were identified. The inci-dence of proven or probable invasive aspergillosis was 0.8%, followedby candidaemia with an incidence of 0.3%. The median time to thediagnosis of IFI was 35 d (6–162) from the progenitor cell infusion. Infourteen patients (78%) IFI was diagnosed during lifetime and they weretreated with antifungal therapy for a median of 50 d. Nine patients(64%) were cured. Conclusions: IFI appears to be a rare event afterASCT and Aspergillus infections seem to be predominant. These epi-demiological features have an impact in planning prophylactic andempirical antifungal strategies in ASCT recipients.E. Jantunen

Multiple myeloma (MM) is considered to be an essentially incurable haematological malignant disease, probably because of the existence of resistant clonal precursor cell with self-renewal capacity. Recent data have indicated that the myeloma cell hierarchy includes circulating clonal memory B cells, which differ considerably from the classical end-stage plasma cells, infiltrating the bone marrow. The pathophysiological significance of these cells is unknown, but hypothetically they may serve as ‘sleeping’ myeloma stem cells responsible for and ‘feeding’ post-treatment relapse and progression. The present study evaluates the toxicity and feasibility of fludarabine, added to the VAD-induction regimen in MM, and investigates the effect on the myeloma cell hierarchy. Nineteen patients were randomised to receive either four cycles of VAD (n = 9) or two cycles of VAD, followed by two cycles of VAD combined with 5 days fludarabine 25 mg/m2/day i.v. (n = 10). Toxicity evaluation showed more profound neutropenia in the fludarabine-treated patients and two infectious episodes in each study arm: three were fever of unknown origin while one, in the fludarabine-arm, was a local skin infection at the insertion site of the central venous line. Nine of the fludarabine-treated patients responded to treatment (two complete remission, seven partial remission), compared with five responders (all PR) in the control-arm. The effects on the blood circulating myeloma compartments identified an increased reduction of CD19+ B cells and myeloma plasma cells in the fludarabine-arm. In conclusion, adding fludarabine to VAD induction in multiple myeloma is feasible and may be clinically effective by reducing the myeloma clone.

Objectives: This prospective multicentre study was conducted to assess the efficacy of the monoclonal anti-CD20 antibody rituximab in patients with chronic lymphocytic leukaemia (CLL). Secondary ob ...

Since high levels of serum IL-6 predict a poor prognosis of patients with multiple myeloma (MM), we investigated if a related cytokine, oncostatin M (OSM), correlates with clinical or biochemical findings or has prognostic significance in patients with MM. Among 82 newly diagnosed MM patients, OSM was detected in the sera in 45 (55%). Serum OSM had a borderline statistical correlation with serum IL-6 (r = 0.198, p = 0.074) and C-reactive protein (r = 0.199, p = 0.074) concentrations. However, OSM did not have prognostic significance alone or in combination with other factors. The median survival of patients with detectable serum OSM concentration was 41 months (range 2-124 months) and of OSM negative patients 35 months (1-75 months). Serum OSM concentration was not associated with clinical factors or severity of bone disease at diagnosis. We conclude that serum OSM concentration is not a prognostic factor in MM patients.

Objectives Previous studies indicate that 40–50% of patients with chronic myeloid leukemia in prolonged complete molecular remission may discontinue imatinib therapy without imminent relapse. The combination of pegylated interferon-alpha (Peg-IFN-α2b) and imatinib may increase the rate of successful discontinuation. Methods In this pilot study, we prospectively stopped imatinib from patients (n = 12) who had achieved major molecular response (MMR) after ≥12 months of treatment with either imatinib or imatinib+Peg-IFN-α2b. Molecular monitoring was carried out monthly for BCR-ABL1. In addition, analyses of lymphocyte immunophenotype, function, and plasma cytokines were performed. Results In the monotherapy group, 5/6 patients lost MMR within 4 months. One patient remains to date in MR4.0 61 months after discontinuation. In the combination therapy group, 2/6 patients relapsed within 4 months while still receiving Peg-IFN-α2b. Four of six patients were able to discontinue both treatments, but three of these patients relapsed after 3 months. One patient is still in sustained MR4.0 at 58 months off all treatment. All relapsed patients re-responded to imatinib. The two successfully discontinued patients had either an increased number of NK-cells or functionally active T-cells. Conclusions A higher frequency of relapsed patients in our study in comparison with other studies may be due to the shorter duration of imatinib treatment prior to discontinuation. However, in selected patients with an active immune system, even a short duration of TKI therapy (

Achievement of complete response (CR) is a new goal of therapy for multiple myeloma (MM). By sensitive methods, the depth of response can be measured even among the patients in CR. We used a sensitive real-time quantitative polymerase chain reaction by allele-specific primers (qASO-PCR) to assess the level of minimal residual disease (MRD) in bone marrow of 37 patients with myeloma who had achieved CR/near-to-CR after autologous or allogeneic stem cell transplantation (SCT). Allele-specific primers could be successfully designed for 86% of patients. Three to six months after autotransplantation, the PCR target was not detectable in 53% of patients (16/30 patients), and the respective figure after allotransplantation was 71% (5/7 patients); the median sensitivity of PCR assay was0.002%. The proportion of patients without detectable PCR target was 22% of all autotransplanted patients. A threshold level of 0.01% in the qASO-PCR assay 3-6 months after SCT was found to be a useful cut-off limit to divide the patients into two prognostic groups: MRD low/negative vs. MRD high. Low/negative MRD after SCT was a significant predictive factor for the prolongation of progression free (70 vs. 19 months; P = 0.003) and suggestively also for overall survival. We conclude that not only CR but also its depth is important for the long-term outcome in MM.

Objective: To investigate the long-term outcome of idarubicin- and cytarabine-based intensive chemotherapy in adult acute myeloid leukaemia (AML). Patients and methods: A total of 327 consecutive patients with de novo AML (promyelocytic leukaemia excluded) aged 16–65 yr were recruited into the study between September 1992 and December 2001. The latest follow-up data were collected in October 2006. After remission achievement with the first (conventional cytarabine) or second (high-dose cytarabine) chemotherapy cycle, three intensive consolidation courses each containing high- or intermediate-dose cytarabine were given. Results: A total of 268 patients (82%) achieved complete remission (CR). CR rate was 82% and 84% for patients

Objectives: To evaluate early (

Objectives: To analyse outcome and prognostic factors in non-Hodgkin's lymphoma (NHL) patients who progress after autologous stem cell transplantation (ASCT). Patients: Altogether 115 consecutive NHL patients transplanted in 1991–2000 were studied. Histology included diffuse large B cell (n = 52), follicular (n = 26), mantle cell (n = 15), T cell (n = 16) and other subtypes (n = 6). The median time from ASCT to the progression was 7 months. Ninety-six patients (83%) received salvage treatment. Results: Twenty-four patients (25%) achieved complete remission and 30 (31%) partial remission. The median overall survival was 8 months (range 0–98+) and the projected 4-year survival 21%. In multivariate analysis factors predicting treatment response after the progression included the use of rituximab (P = 0.036), histology other than diffuse large B cell (P = 0.001) and International Prognostic Index ≤2 at progression (P

A randomised multicentre study was conducted among patients over 65 yr of age with newly diagnosed acute myeloid leukaemia (AML) to compare oral treatment with etoposide 80 mg/m 2 and thioguanine 100 mg/m 2 twice daily on5 d and idarubicin 15 mg/m 2 on 3 d (ETI) to a mainly i.v. combination of cytarabine 100 mg/m 2 twice daily on 5 d, idarubicin 12 mg/m 2 x 1 , and thioguanine (TAI). Ninety-two patients were enrolled. Their median age was 72 yr. range 65 84 yr. Sixty-five patients had de novo AML, 21 AML subsequent to myelo-dysplastic syndrome, and six treatment-related AML. They received at first a 6-d i.v. treatment with cytarabine and idarubicin. After the first treatment, 68 patients were randomised to receive two cycles of ETI (n = 36) or TAI (n = 32) and thereafter maintenance with mercaptopurine and methotrexate. Of the 92 patients, 52 (57%) achieved remission at some stage. The median survival was 10 months. There were no significant differences between the patients randomised to ETI or TAI in the remission rate (67% vs. 72%), survival (12 months from randomisation in both arms), event-free survival or relapse rate. The patients randomised to receive ETI spent significantly fewer days at hospital during the two randomised cycles (20 vs. 41 d, P = 0.010), and they had fewer days with infusions, shorter neutropenias and thrombocytopenias and fewer and less severe infections. In conclusion, treatment with oral ETI resulted in a similar antileukaemic effect as obtained with mainly i.v. TAI, with less toxicity and reduced need for hospitalisation.

Multiple myeloma (MM) is considered to be an essentially incurable haematological malignant disease, probably because of the existence of resistant clonal precursor cell with self-renewal capacity. Recent data have indicated that the myeloma cell hierarchy includes circulating clonal memory B cells, which differ considerably from the classical end-stage plasma cells, infiltrating the bone marrow. The pathophysiological significance of these cells is unknown, but hypothetically they may serve as 'sleeping' myeloma stem cells responsible for and 'feeding' post-treatment relapse and progression. The present study evaluates the toxicity and feasibility of fludarabine, added to the VAD-induction regimen in MM, and investigates the effect on the myeloma cell hierarchy. Nineteen patients were randomised to receive either four cycles of VAD (n = 9) or two cycles of VAD, followed by two cycles of VAD combined with 5 days fludarabine 25 mg/m2/day i.v. (n = 10). Toxicity evaluation showed more profound neutropenia in the fludarabine-treated patients and two infectious episodes in each study arm: three were fever of unknown origin while one, in the fludarabine-arm, was a local skin infection at the insertion site of the central venous line. Nine of the fludarabine-treated patients responded to treatment (two complete remission, seven partial remission), compared with five responders (all PR) in the control-arm. The effects on the blood circulating myeloma compartments identified an increased reduction of CD19+ B cells and myeloma plasma cells in the fludarabine-arm. In conclusion, adding fludarabine to VAD induction in multiple myeloma is feasible and may be clinically effective by reducing the myeloma clone.

Leukocyte functions were studied in 22 patients with chronic lymphocytic leukaemia (CLL) and were related to the patients' susceptibility to infections. In CLL patients with a history of infections, compared with CLL patients without infections or healthy controls, there were significant impairments of most granulocyte functions; random migration, N-formyl-methionylleucylphenylalanine (fMLP) and C5a stimulated chemotaxis and chemiluminescence response were decreased. No differences in these functions between CLL patients without infections and healthy controls were observed. Phagocytosis and intracellular killing of granulocytes were intact in all patients with CLL. By univariate analysis, neutrophil count and serum IgG level also predicted susceptibility to infections. By multivariate analyses, granulocyte chemotaxis and chemiluminescence remained as statistically significant predictors of infections. The lymphocyte functions (mitogen-induced lymphocyte proliferation and immunoglobulin production in vitro) were equally impaired in all patients with CLL and differed significantly from the respective functions in healthy control subjects. We conclude that impairments in granulocyte functions contribute to susceptibility to infections in CLL.

To review our policy of prophylactic treatment with intravenous immunoglobulin (i.v.IG) in chronic lymphocytic leukemia (CLL), we analyzed the infection history, serum IgG levels (S-IgG) and disease stage of 146 patients who were treated and followed at our institution in 1980-1989. S-IgG was available for 98 patients: 55% were hypogammaglobulinemic and 56% had had at least one severe infection. There were significant associations between S-IgG and the occurrence of infections (p less than 0.01) and disease stage (p less than 0.02). There was also a significant association between disease stage and occurrence of infections (p less than 0.001). Severe infections tended to accumulate in patients with subnormal S-IgG and advanced disease stage. Totally, 292 infections were recorded, and the incidence of moderate to severe infections was 0.47 per patient year. Infection mortality was high: 42 patients died of a severe infection (46% of all causes of death). Patients with a low S-IgG and advanced disease stage are the most susceptible to death from infection and would be most likely to benefit most from i.v.IG prophylaxis; however, the cost of this therapy is so high that strict individual consideration still remains crucial for treatment decisions.

108 consecutive patients with de novo acute myeloid leukaemia at ages 15 to 59 years were treated in a prospective controlled multicentre trial. Induction with combination TAD resulted in a complete remission in 85 cases (79%). After a cyclic consolidation programme for 6 months, 73% of the remissions continued. The maintenance therapy was at random either nothing, or alpha interferon, or monthly 5 day courses with thioguanine and cytarabine. The median duration of all remissions was 13 months; that of those in the control and interferon arms 15 months each, and in the chemotherapy arm 18 months. The median survival of all the 108 patients was 16 months; that of those in the control arm 20 months, in the interferon arm 33 months and in the chemotherapy arm 26 months. At 5 yr, 31%, 22% and 31%, respectively, were alive. The survival curves did not differ from each other significantly. Maintenance treatment after an intensive induction and a moderately intensive consolidation was of no benefit in this study. Interferon did not improve the prognosis.