Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group.

OBJECTIVE: We investigated the efficacy and safety of carfilzomib-containing induction before salvage high-dose melphalan with autologous stem-cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma. METHODS: This randomised, open-label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re-induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 â†’ 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86). RESULTS: Median time to progression (TTP) after randomisation was 25.1 months (22.5-NR) in the carfilzomib-dexamethasone maintenance group and 16.7 months (14.4-21.8) in the control group (HR 0.46, 95% CI 0.30-0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections. CONCLUSION: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well-tolerated with manageable toxicity.

Contactless online characterization of large-area conductive thin films by thermography and induction.

Testing and characterization techniques intended for traditional electronics production are rarely compatible with modern large-area, thin film electronics manufacturing processes such as roll-to-roll fabrication. Online quality monitoring of conductive thin films is necessary for upscaling and maintaining high-yield production. Thermography has already shown its usefulness in these kinds of applications, but has suffered from the lack of proper non-contact electrical heating. Now a fully contactless quality inspection technique based on thermal imaging and induction heating is implemented and evaluated. This approach is capable of discovering defected areas and estimating conductivity degradation online with full coverage over conductive thin films.

Thermography based online characterization of conductive thin films in large-scale electronics fabrication.

Flexible electronics is an emerging thin film based technology enabling completely new types of products and applications compared to conventional electronics. Since the quality of films defines the functionality of fabricated devices, the lack of suitable online manufacturing quality assessment tools has been identified to be a critical bottleneck while upscaling the volume and the yield of thin film electronics manufacturing. In order to solve that problem, a synchronized thermography (ST) based online measurement system was built. Applicability of proposed roll-to-roll compatible ST based system was demonstrated by characterizing a moving plastic film with conductive indium tin oxide on top. Obtained results show that ST can be utilized for online homogeneity characterization and sheet resistance estimation of large area thin films which are not possible with other existing methods.

A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation.

Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality. There was no significant difference in the cumulative incidence of acute graft-versus-host disease of grades II-IV (41% vs. 51%; P=0.19) or grades III-IV (13% vs. 7%; P=0.09) between the groups. Time to neutrophil engraftment (18 days vs. 17 days; P=0.24) was similar, but time to platelet engraftment was longer in cyclosporine/methotrexate patients (14 vs. 12 days; P<0.01). No significant differences in incidence of oropharyngeal mucositis, time to full donor chimerism, or number of cytomegalovirus infections were seen between the two treatment arms, and transplant-related toxicities were equally distributed. Triglyceride (P=0.005) and cholesterol (P=0.009) levels were higher in tacrolimus/sirolimus patients. Transplant-related mortality (18% vs. 12%; P=0.40) and 5-year overall survival (72% vs. 71%; P=0.71) were similar. Five-year relapse-free survival in patients with malignant diagnoses was 65% in the cyclosporine/methotrexate group and 63% in the tacrolimus/sirolimus group (P=0.73). We conclude that tacrolimus/sirolimus remains a valid and safe alternative to cyclosporine/methotrexate as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation, with comparable transplant-related outcomes. The trial was registered at clinicaltrials.gov identifier: 00993343.

Blood graft cellular composition and posttransplant outcomes in myeloma patients mobilized with or without low-dose cyclophosphamide: a randomized comparison.

BACKGROUND: Autologous stem cell transplantation is a standard treatment in multiple myeloma (MM). Blood grafts are usually collected after mobilization with granulocyte-colony-stimulating factor (G-CSF) alone or in a combination with cyclophosphamide (CY). There is limited knowledge of the possible effects of different mobilization regimens on blood graft characteristics and posttransplant outcomes. STUDY DESIGN AND METHODS: Thirty-eight patients with MM were included in this study. The patients were randomly assigned at registration to mobilization with either low-dose CY plus G-CSF (Arm A) or G-CSF alone (Arm B) and received three cycles of lenalidomide, bortetzomib, and dexamethasone induction. Flow cytometry analysis of lymphocyte subsets in the blood grafts after cryopreservation was performed. Hematologic and immune recovery were evaluated up to 12 months posttransplant. RESULTS: The blood grafts in Arm A contained significantly more CD34+ cells but in Arm B there was a greater proportion of CD34+CD38- cells and higher numbers of T and B lymphocytes as well as natural killer (NK) cells. The engraftment was comparable but lymphocyte count at 15 days posttransplant was higher in Arm B (0.8 × 10(9) /L vs. 0.5 × 10(9) /L, p = 0.033). At 3 and 6 months posttransplant the total number of NK cells was also higher in G-CSF-mobilized patients. There was no difference in progression-free survival between the study arms. CONCLUSION: CY plus G-GSF yields more CD34+ cells but seems to diminish lymphocyte and NK cell counts in the grafts and hampers immune recovery after transplantation. Thus G-CSF alone might be a preferred mobilization method due to more rapid immune recovery posttransplant.

Cost analysis of a randomized stem cell mobilization study in multiple myeloma.

Upfront autologous stem cell transplantation (ASCT) is the standard therapy for younger multiple myeloma (MM) patients. MM patients usually undergo stem cell mobilization with cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF), or with G-CSF alone. A limited number of randomized studies are available comparing costs of different mobilization strategies. Eighty transplant-eligible patients aged up to 70 years with untreated MM were included in this prospective study. The patients were treated with RVD induction for three 21-day cycles and randomized 1:1 at inclusion into one of the two mobilization arms CY 2 g/m(2) + G-CSF [arm A] vs. G-CSF alone [arm B]. Plerixafor was given according to a specific algorithm if needed. Sixty-nine patients who received mobilization followed by blood graft collection were included in the cost analysis. The median total costs of the mobilization phase were significantly higher in arm A than in arm B (3855 € vs. 772 €, p ≤ 0.001). The cumulative median cost of the mobilization and collection phases was significantly lower in arm B than in arm A (8524 € vs. 11,622 €, p = 0.012). There was no significant difference between the arms in the total median costs of ASCT (n = 59) (34,997 € in arm A vs. 31,981 € in arm B, p = 0.118). Mobilization with G-CSF alone seems to be a preferable mobilization method for MM patients in terms of mobilization and apheresis costs. In addition, it requires less hospital resource utilization.

[Prophylactic platelet transfusions]. / Trombosyyttisiirrot verenvuotojen ehkäisyssä.

The consumption of platelet products in Finland is exceptionally high. For the most part, platelets are transfused pre-operatively to thrombocytopenic patients in order to prevent hemorrhage. Most of the minor procedures could, however, be conducted even if the patients'platelet levels would be lower than usual. In cardiac surgery, platelets are used because of the hemorrhagic diathesis associated with platelet inhibitors. Platelet inhibitors will, however, also bind to transfused platelets, whereby instead of prophylactic platelet transfusions it would be more sensible to leave the thorax open and not carry out ineffective platelet transfusions until the effect of the inhibitors has run out. We outline the prophylactic use of platelets based on recent international clinical practice guidelines.

Treatment of adult acute myeloid leukemia.

The aim of this study was to analyze the treatment results of 180 adult AML patients treated at Turku University Hospital from 2002 to 2012. 124 patients received intensive therapy according to the protocol of the Finnish Leukemia Group. 86% of them achieved remission. 46 patients underwent allogeneic stem cell transplantation which was beneficial for high and intermediate risk disease. 60 - 70% of patients under 60 years old can be cured. The genetic profile of the disease, patient age and treatment response had a significant impact on survival. Our treatment results are comparable with data in literature.

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial.

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the ≥ VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006).

We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100 mg QD or imatinib 400 mg QD and report outcome as an intention-to-treat analysis with 36 months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR(3.0) was reached at 3 months in 36% vs. 8% (P = 0.02), at 12 months in 81% vs. 46% (P = 0.02) and at 18 months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR(4.5) was consistently superior in the dasatinib group at all time points from 6 months onwards, reaching 61% vs. 21% (P < 0.05) at 36 months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.

[Hemolysis and metastatic cancer in an elderly man]. / Iäkkään miehen hemolyysi ja levinnyt syöpä.

Sometimes correct diagnoses is reached after many years and even after decades. Our patient had for decades suffered from a hemolytic disease, life-threatening, metastatic cancer at the age of almost 90 years was also suspected. The patient was finally diagnosed as having mild hereditary spherocytosis and the associated paraspinal extramedullar hematopoiesis as well as an osteoporotic vertebral fracture caused by osteoporosis.

Improved survival with ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a randomized study.

We report the long-term results of a prospective randomized study on the use of ursodeoxycholic acid (UDCA) for prevention of hepatic complications after allogeneic stem cell transplantation. Two hundred forty-two patients, 232 with malignant disease, were randomized to receive (n = 123) or not to receive (n = 119) UDCA from the beginning of the conditioning until 90 days post-transplantation. The results were reported after 1-year follow-up. UDCA administration reduced significantly the proportion of patients developing high serum bilirubin levels as well as the incidence of severe acute graft-versus-host disease (GVHD), liver GVHD, and intestinal GVHD. In the UDCA prophylaxis group, nonrelapse mortality (NRM) was lower and overall survival better than in the control group. After a 10-year follow-up, the difference in the survival and NRM in favor of the UDCA-treated group, seen at 1 year, was maintained (survival 48% versus 38%, P = .037; NRM 28% versus 41%, P = .01). A landmark analysis in patients surviving at 1 year post-transplantation showed no significant differences between the study groups in the long-term follow-up in chronic GVHD, relapse rate, NRM, disease-free survival, or overall survival. These long-term results continue to support the useful role of UDCA in the prevention of transplant-related complications in allogeneic transplantation.

Imatinib and pegylated IFN-α2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response.

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 MR(4.0) 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 MR(4.0) 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 (<2 yr) may allow for therapy discontinuation but this needs to be confirmed in larger prospective studies.

[Adult acute lymphoblastic leukemia - 20-year treatment results at TYKS]. / Aikuisten akuutti lymfaattinen leukemia - 20 vuoden hoitotulokset TYks:ssa.

Approximately 30 cases of adult acute lymphoblastic leukemia (ALL) emerge in Finland yearly. In literature 35 to 40% of those under the age of 60 are reported to recover from their illness. Of the 67 adult ALL patients treated at the Turku University Hospital from 1990 to 2010, 96% achieved remission. The five-year survival rate was 53%. After remission, an allogeneic stem cell transplant was performed for 22 patients (37%), with 38 patients (63%) continuing on cytotoxic drugs. There was no difference in survival between modes of treatment or risk groups.

Health-related quality of life and quality-adjusted progression free survival for carfilzomib and dexamethasone maintenance following salvage autologous stem-cell transplantation in patients with multiple myeloma: a randomized phase 2 trial by the Nordic Myeloma Study Group.

BACKGROUND: Decisions regarding maintenance therapy in patients with multiple myeloma should be based on both treatment efficacy and health-related quality of life (HRQL) consequences. In the CARFI trial, patients with first relapse of multiple myeloma underwent salvage autologous stem cell transplantation (salvage ASCT) before randomization to carfilzomib-dexamethasone maintenance therapy (Kd) or observation. The primary clinical endpoint was time to progression, which was extended by 8 months by Kd. The aim of this paper is to present the all HRQL endpoints of the CARFI trial including the HRQL effect of Kd maintenance therapy relative to observation. The primary HRQL endpoint was assessed by EORTC QLQ-C30 Summary score (QLQ-C30-sum) at 8 months follow-up. A key secondary HRQL endpoint was quality-adjusted progression-free-survival (QAPFS). METHODS: HRQL was assessed with EORTC QLQ-C30, EORTC QLQ-MY20 and FACT/GOG-Ntx at randomization and every second month during follow-up. HRQL data were analyzed with linear mixed effect models until 8 months follow-up. QAPFS per individual was calculated by multiplying progression-free survival (PFS) by two quality-adjustment metrics, the QLQ-C30-sum and EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D). The QAPFS per treatment group was estimated with the Kaplan-Meier method. P < 0.05 was used for statistical significance, and a between-group minimal important difference of 10 points was interpreted as clinically relevant for the QLQ-C30-sum. RESULTS: 168 patients were randomized. HRQL questionnaire compliance was 93%. For the QLQ-C30-sum, the difference of 4.62 points (95% confidence interval (CI) -8.9: -0.4, p = 0.032) was not clinically relevant. PFS was 19.3 months for the Kd maintenance group and 16.8 months for the observation group; difference = 2.5 months (95% CI 0.5; 4.5). QAPFS based on the QLQ-C30-sum for the Kd maintenance group was 18.0 months (95% CI 16.4; 19.6) and for the observation group 15.0 months (95% CI 13.5; 16.5); difference = 3.0 months (95% CI 0.8-5.3). QAPFS based on the QLU-C10D for the Kd maintenance group was 17.5 months (95% CI 15.9; 19.2) and 14.0 months (95% CI 12.4; 15.5) for the observation group; difference = 3.5 months (95% CI 1.1-5.9). CONCLUSIONS: Kd maintenance therapy after salvage ASCT did not adversely affect overall HRQL, but adjustment for HRQL reduced the PFS compared to unadjusted PFS. PFS of maintenance therapy should be quality-adjusted to balance the benefits and HRQL impact.

Reduced Intensity transplantation vs chemotherapy in CR1. A prospective, pseudorandomized study in 50-70 year old AML patients.

The aim of this prospective, international multicenter, pseudorandomized study comparing RICT HCT to standard-of-care chemotherapy in intermediate- or high-risk AML patients 50-70 years using the donor versus no-donor concept. Part 1 included only patients with potential family donors (RD) at the date of HLA-typing of the first potential sibling or CR-date, if later. Part 2 allowed the inclusion of patients without a possible sibling donor using the start of an unrelated donor (URD) search as inclusion date. 360 patients were registered and 309 analyzed. The median follow-up was 47 months (1-168). There was no difference in overall survival (OS) between the RD (n = 124) and the Control (n = 77) groups (p = 0.50, 3-year OS RD: 0.41(95% CI; 0.32-0.50); Controls: 0.49 (95% CI; 0.37-0.59)). The main cause of death was relapse (67% RD; 88% Controls). In Part 2, the 3-year OS was 0.60 (95% CI 0.50-0.70) for URD-HCT (n = 86) and 0.37 (95% CI 0.13-0.62) for Controls (n = 20), respectively (p = 0.10). When analyzing transplanted patients (Part 2), the OS at 3-years was higher for URD-HCT than RD-HCT (0.67 (0.55-0.76) vs. 0.42 (0.26-0.57; p = 0.005). This study doesn't support elderly HLA-identical siblings as donors for older AML patients undergoing a RICT allogeneic HCT in first CR.

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia.

Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b (Peg-IFN-α2b) 50 µg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-α2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-α2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-α2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.

Prognostic impact of pretransplant iron overload measured with magnetic resonance imaging on severe infections in allogeneic stem cell transplantation.

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.

[Stem cell transplantation in myelofibrosis]. / Allogeeninen kantasolusiirto myelofibroosin hoidossa.

Allogeneic hematopoietic stem cell transplantation (ASCT) offers the only potentially curative therapy for myelofibrosis, a malignant myeloproliferative disease. The transplant-related mortality is still high, 10-48%, but use of reduced-intensity conditioning is less toxic and allows transplantation to be performed up to 65-70 years of age. Fabourable treatment response will be attained at least in a third of patients, in another third the disease will progress, and nearly one third will succumb due to transplant complications. Thirteen patients with myelofibrosis underwent ASCT at our institution between 1999 and 2009. The outcome of the patients treated with reduced-intensity conditioning corresponds well with those reported in the literature.

Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma.

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 <0.002%. 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.