Efficacy of conventional-dose cytarabine, idarubicin and thioguanine versus intermediate-dose cytarabine and idarubicin in the induction treatment of acute myeloid leukemia: Long-term results of the prospective randomized nationwide AML-2003 study by the Finnish Leukemia Group.

OBJECTIVES: AML-2003 study sought to compare the long-term efficacy and safety of IAT and IdAraC-Ida in induction chemotherapy of acute myeloid leukemia (AML) and introduce the results of an integrated genetic and clinical risk classification guided treatment strategy. METHODS: Patients were randomized to receive either IAT or IdAraC-Ida as the first induction treatment. Intensified postremission strategies were employed based on measurable residual disease (MRD) and risk classification. Structured questionnaire forms were used to gather data prospectively. RESULTS: A total of 356 AML patients with a median age of 53 years participated in the study. Long-term overall survival (OS) and relapse-free survival (RFS) were both 49% at 10 years. The median follow-up was 114 months. No significant difference in remission rate, OS or RFS was observed between the two induction treatments. Risk classification according to the protocol, MRD after the first and the last consolidation treatment affected the OS and RFS significantly (p < .001). CONCLUSIONS: Intensified cytarabine dose in the first induction treatment was not better than IAT in patients with AML. Intensification of postremission treatment in patients with clinical risk factors or MRD seems reasonable, but randomized controlled studies are warranted in the future.

Promising treatment results with blood brain barrier disruption (BBBD) based immunochemotherapy combined with autologous stem cell transplantation (ASCT) in patients with primary central nervous system lymphoma (PCNSL).

Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome has been poor. Patients with relapsed or refractory disease have a dismal prognosis. We performed retrospective analysis to evaluate results and tolerabilities of BBBD therapy in combination with high-dose therapy supported by autologous stem cell transplantation. We analysed 25 patients (age range: 40-71 years) who were treated in first or second line with BBBD therapy. When we started BBBD treatment, patients had relapsed or refractory PCNSL or they did not tolerate Bonn-like therapy. In recent years, some of the patients were treated in first line. We found promising response rates. Altogether 19 (76 %) of the patients achieved a complete response (CR). Two-year progression-free survival (PFS) and overall survival (OS) rates were 61 and 57 % respectively and the five-year OS was 47 %. Patients who were treated with a five-drug therapy had a very promising prognosis. The CR rate was 100 % in first-line therapy and 60 % in relapsed cases. These findings suggest that BBBD is a promising therapy for PCNSL, especially for patients in first line, but also for patients with relapsed or refractory disease after conventional chemotherapy, who commonly have a very poor prognosis. Treatment-related toxicity was generally manageable. Thus, BBBD followed by ASCT could be a treatment of choice in transplant-eligible patients with PCNSL.

Blood graft cellular composition and posttransplant recovery in non-Hodgkin's lymphoma patients mobilized with or without plerixafor: a prospective comparison.

BACKGROUND: Autologous stem cell transplantation is commonly used to treat non-Hodgkin's lymphomas (NHLs). Cellular composition of the blood grafts apparently has a role in the posttransplant hematologic and immune recovery. Plerixafor increases the mobilization of CD34+ cells and higher amounts of various lymphocyte subsets have been reported in the grafts. Limited prospective data are available in regard to graft cellular composition, hematologic and immune recovery, and patient outcomes in NHL patients who receive plerixafor added to chemomobilization. STUDY DESIGN AND METHODS: Forty-one patients with NHL participated in this prospective study. All patients received chemomobilization and 15 poor mobilizers also received plerixafor. CD34+ cell subsets and lymphocyte subsets of cell grafts, posttransplant hematologic and immune recovery, and outcome were evaluated. RESULTS: Blood grafts in the plerixafor group contained a significantly higher proportion of CD34+133+CD38- cells and more lymphocytes of all major subsets except B lymphocytes. Neutrophil engraftment was comparable and platelet recovery slightly slower in the plerixafor group. Natural killer cell recovery was significantly faster in patients mobilized with plerixafor. Otherwise hematologic and immune recovery as well as short-time outcome were comparable even though there was a trend for progression-free survival and overall survival benefit in the plerixafor group. CONCLUSIONS: In poorly mobilizing NHL patients, plerixafor added to chemomobilization is safe and effective. It also modifies the blood graft composition in many ways, some of which have been linked to better outcomes in previous studies. Larger sets of patients and longer follow-up are needed to see whether plerixafor-mobilized grafts are associated with superior outcome of the patients.

Constant pattern of relapse in primary central nervous lymphoma patients treated with high-dose methotrexate combinations. A Finnish retrospective study.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor. MATERIAL AND METHODS: We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment. RESULTS: We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months. DISCUSSION: The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.

Engraftment and outcome after autologous stem cell transplantation in plerixafor-mobilized non-Hodgkin's lymphoma patients.

BACKGROUND: Plerixafor is used in combination with granulocyte-colony-stimulating factor to enhance the mobilization of hematopoietic stem cells. Limited data are available in regard to effects of plerixafor on posttransplant outcomes in chemomobilized patients who appear to mobilize poorly. STUDY DESIGN AND METHODS: Eighty-nine chemomobilized patients with non-Hodgkin's lymphoma (NHL) were included in this retrospective study. Thirty-three patients had received plerixafor preemptively (plerixafor group) and 56 patients served as controls. Posttransplantation outcomes including infections, hematologic recovery, and relapse were recorded. RESULTS: The median fold increase of CD34+ cells after the first plerixafor dose was 4.1 in patients mobilized with chemotherapy plus filgrastim and 7.2 in those mobilized with chemotherapy plus pegfilgrastim (p = 0.027). The median number of collected CD34+ cells was 3.5 × 10(6) CD34+ cells/kg in the plerixafor group and 4.2 × 10(6) CD34+ cells/kg in the control group (p = 0.076). Early engraftment was comparable between the groups (10 days for neutrophils >0.5 × 10(9) /L and 14 days for platelets >20 × 10(9) /L, respectively). Also late engraftment within 12 months was comparable except higher hemoglobin level at 3 months in the control group (121 g/L vs. 112 g/L, p = 0.009). Progression-free survival at 1 year after autologous stem cell transplantation (ASCT) was 79% in the plerixafor group and 86% in the control group (p = 0.399). CONCLUSIONS: Long-term engraftment and outcome after ASCT seem to be comparable in NHL patients receiving plerixafor compared to chemomobilized patients. These observations support the use of plerixafor in patients who mobilize poorly.

CD34+ cell subclasses and lymphocyte subsets in blood grafts collected after various mobilization methods in myeloma patients.

BACKGROUND: Cyclophosphamide (CY) combined with granulocyte-colony-stimulating factor (G-CSF) is commonly used to mobilize stem cells in multiple myeloma (MM). Plerixafor may also be used with G-CSF in patients who mobilize poorly or it may be added to chemomobilization to boost mobilization. Limited data are available on graft content collected after various mobilization methods. STUDY DESIGN AND METHODS: Blood grafts collected from 21 MM patients were retrospectively analyzed. We analyzed CD34+ subclasses and lymphocyte subsets from cryopreserved grafts collected on the next morning after plerixafor injection in nine MM patients mobilized with G-CSF with (n = 5) or without preceding CY (n = 4). As controls we had the first collections from 12 MM patients mobilized with low-dose CY with G-CSF. RESULTS: The proportion of the most primitive stem cells (CD34+CD133+CD38-) from all CD34+ cells in the graft was higher in the plerixafor-treated patients but there was no significant difference in the total number of these cells. The numbers of CD19+ B lymphocytes and natural killer cells were higher in patients collected after G-CSF plus plerixafor when compared to the patients mobilized with CY plus G-CSF. Early engraftment after high-dose melphalan was comparable between the groups. CONCLUSION: Plerixafor appears to have effects on blood stem cell graft composition in myeloma patients. A higher number of grafts should be evaluated in regard to cellular content and longer follow-up of the patients is needed to evaluate the potential clinical impact of graft content.

Blood graft lymphocyte subsets after plerixafor injection in non-Hodgkin's lymphoma patients mobilizing poorly with chemotherapy plus granulocyte-colony-stimulating factor.

BACKGROUND: A combination of chemotherapy plus granulocyte-colony-stimulating factor (G-CSF) (chemomobilization) is commonly used to mobilize CD34+ cells to circulation. Plerixafor, a chemokine CXCR4 antagonist, increases the mobilization of CD34+ cells and may also have effect on graft composition. STUDY DESIGN AND METHODS: We have analyzed lymphocyte subsets in grafts collected on the next morning after plerixafor injection in 13 chemomobilized patients with non-Hodgkin's lymphoma (NHL) mobilizing poorly. As controls we had the first leukapheresis products from 11 NHL patients mobilized with chemotherapy plus G-CSF. The analyses were performed from cryopreserved apheresis products. RESULTS: The median counts of both total CD3+ T cells and natural killer (NK) cells (CD3-CD16/56+) in the graft were significantly higher in plerixafor-treated group compared to the control group. Both helper T-lymphocytes (CD3+CD4+) and suppressor T-lymphocytes (CD3+CD8+) were significantly increased in the plerixafor-treated group so that CD4+/CD8+ ratio in the graft did not differ between the groups. CD19+ cells were evident only at very small amounts in few patients in both groups, and the CD34+ cell content of the graft did not differ between the groups. Engraftment after high-dose therapy was comparable between the groups. CONCLUSION: Plerixafor added to chemomobilization in poor mobilizers seems to mobilize more T cells and NK cells than chemomobilization. Larger patient numbers and longer follow-up is needed in regard to evaluate posttransplant complications and risk of relapse in patients receiving plerixafor due to poor mobilization.

Blood graft composition after plerixafor injection in patients with NHL.

BACKGROUND: Plerixafor is used to mobilize CD34(+) hematopoietic stem cells from bone marrow to circulation. Limited data are available in regard to graft cellular content collected after plerixafor. OBJECTIVES: The aim of this study was to assess effects of plerixafor added to chemomobilization on graft CD34(+) cell subclasses, lymphocyte subsets, engraftment, and post-transplant course in non-Hodgkin lymphoma (NHL) patients. METHODS: Thirty-four patients with NHL were included. All patients received chemotherapy plus G-CSF to mobilize stem cells. Nineteen patients received plerixafor pre-emptively owing to poor mobilization or poor collection yields. The rest of the patients constituted the control group. Flow cytometric analyzes were performed from cryopreserved graft samples. Also, data on post-transplant engraftment and outcome were collected. RESULTS: The proportion of primitive stem cells (CD34(+)  CD133(+)  CD38(-) ) was significantly higher after the plerixafor injection when compared to the first collection in the control group. The amount of T cells (CD3(+) ), helper (CD3(+)  CD4(+) ) T subsets, and suppressor (CD3(+)  CD8(+) ) T subsets in the graft was all significantly higher in the plerixafor group. Also, the amount of NK cells (CD3(-)  CD16/56(+) ) was higher. Engraftment after high-dose therapy was comparable between the groups, but leukocyte and platelet count at 6 months were higher in patients receiving plerixafor-mobilized grafts. CONCLUSION: Plerixafor, when used pre-emptively in addition to chemomobilization, seems to mobilize more primitive CD34(+) stem cells, T lymphocytes, and NK cells. Whether these differences are associated with immune reconstitution, long-term engraftment, or patient outcomes needs to be evaluated in larger patient groups with longer follow-up.

High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients.

We evaluated pentraxin 3 as a marker for complications of neutropenic fever in 100 hematologic patients receiving intensive chemotherapy. Pentraxin 3 and C-reactive protein were measured at fever onset and then daily to day 3. Bacteremia was observed in 19 patients and septic shock in 5 patients (three deaths). In comparison to C-reactive protein, pentraxin 3 achieved its maximum more rapidly. Pentraxin 3 correlated not only with the same day C-reactive protein but also with the next day C-reactive protein. High pentraxin 3 on day 0 was associated with the development of septic shock (P=0.009) and bacteremia (P=0.046). The non-survivors had constantly high pentraxin 3 levels. To conclude, pentraxin 3 is an early predictor of complications in hematologic patients with neutropenic fever. High level of pentraxin 3 predicts septic shock and bacteremia already at the onset of febrile neutropenia. (ClinicalTrials.gov Identifier: NCT00781040.).

Efficacy of pre-emptively used plerixafor in patients mobilizing poorly after chemomobilization: a single centre experience.

A significant proportion of patients with lymphoid malignancies are hard-to-mobilize with a combination of chemotherapy plus granulocyte colony-stimulating factor (G-CSF) (chemomobilization). Plerixafor is a novel drug used to improve mobilization of blood stem cells. However, it has been studied mainly in association with G-CSF mobilization. We evaluated the efficacy of 'pre-emptive' use of plerixafor after chemomobilization in patients who seem to mobilize poorly. During a 15 month period, altogether 63 patients with lymphoid malignancies were admitted to our department for blood stem cell collection. Sixteen patients (25%) received plerixafor after the first mobilization due to the low blood (B) CD34(+) cell counts (n = 12) or poor yield of the first collection (n = 4). The median number of plerixafor injections was 1 (1-3). The median B-CD34(+) count after the first plerixafor dose was 39 × 10(6) /L (<1-81) with the median increase of fivefold. Stem cell aphaereses were performed in 14/16 patients (88%) receiving plerixafor and a median of 2.9 × 10(6) /kg (1.6-6.1) CD34(+) cells were collected with a median of one aphaeresis (1-3). Altogether 13/16 patients mobilized with a combination of chemomobilization and plerixafor received high-dose therapy with stem cell support and all engrafted. Pre-emptive use of plerixafor after chemomobilization is efficient and safe and should be considered in poor mobilizers to avoid collection failure. In patients with low but rising B-CD34(+) counts, the use of plerixafor might be delayed as late mobilization may occur. Further studies are needed to optimize patient selection and timing of plerixafor.

Pentraxin 3 predicts complicated course of febrile neutropenia in haematological patients, but the decision level depends on the underlying malignancy.

OBJECTIVES: This study aimed at assessing the cut-off levels for pentraxin 3 (PTX3) in predicting complications of neutropenic fever (bacteraemia, septic shock) in haematological patients. METHODS: A prospective study during 2006-2009 was performed at haematology ward in Kuopio University Hospital. A patient was eligible for the study if having neutropenic fever after intensive therapy for acute myeloid leukaemia (AML) (n = 32) or non-Hodgkin lymphoma (NHL) (n = 35). Blood cultures were taken, and maximal PTX3 and C-reactive protein (CRP) were evaluated during d0 to d3 from the beginning of fever onset. RESULTS: The level of PTX3 was associated with both the underlying malignancy and the presence of complications, with highest level in NHL patients with complicated course of febrile neutropenia and lowest in AML patients with non-complicated course. The cut-off level of PTX3 to predict complications was ten-fold in patients with NHL (115 µg/L) in comparison with patients with AML (11.5 µg/L). In combined analysis based on separate cut-offs, PTX3 predicted complications of febrile neutropenia with sensitivity of 0.86, specificity of 0.83, positive predictive value of 0.57 and negative predictive value of 0.96. CONCLUSIONS: PTX3 was superior to CRP in predicting complicated course of febrile neutropenia, but only when the effect of the underlying malignancy had been taken into account.

Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia.

OBJECTIVE: To compare semi-quantitative procalcitonin with C-reactive protein in predicting bacteraemia in haematological patients with neutropenic fever. METHODS: A total of 77 patients treated with intensive chemotherapy for haematological malignancy at Kuopio University Hospital were candidates for study entry. Eleven of these patients did not fulfil the criteria for neutropenic fever, and 66 patients were finally included. Nineteen patients had acute myeloid leukaemia and 47 had received high-dose chemotherapy supported by autologous stem cell transplant. Ninety neutropenic fever episodes in these 66 patients fulfilled the study entry criteria, with microbiological cultures, procalcitonin and C-reactive protein measurements available. Serum procalcitonin and C-reactive protein were analyzed at the onset of each neutropenic fever episode on day 0, and then daily from days 1 to 4. RESULTS: Bacteraemia was observed in 21 episodes (23%) and the criteria for severe sepsis were fulfilled in 13 episodes (14%). Half of the bacteraemic episodes were caused by Gram-negative bacteria. The kinetics of procalcitonin and C-reactive protein were similar, with increasing levels for 2 to 4 days after the onset of fever. The procalcitonin level on days 1, 2, 3 and 4 was associated with bacteraemia and Gram-negative bacteraemia, but not with the development of severe sepsis. On day 1, a procalcitonin level above 0.5 ng/ml had a sensitivity of 57% and 70% and specificity of 81% and 77% to predict bacteraemia and Gram-negative bacteraemia, respectively. CONCLUSIONS: An elevated level of procalcitonin within 24 h after the onset of neutropenic fever predicts bacteraemia and Gram-negative bacteraemia in haematological patients.

Serial plasma lactate measurements in haematological patients with neutropenic fever.

Elevated plasma lactate and impaired lactate clearance have been associated with poor outcome in patients with severe sepsis. No data are available on the kinetics or prognostic value of plasma lactate in haematological patients with neutropenic fever. A total of 70 haematological patients with 94 episodes of neutropenic fever were included into this prospective study during the period 2006-2008. The median age of the patients was 56 (range 18-70) y. Nineteen patients received therapy for acute myeloid leukaemia and 51 patients received autologous stem cell transplantation. At the onset and on days 1, 2, and 3 of each neutropenic fever episode, plasma lactate and serum C-reactive protein were determined. Criteria for severe sepsis were fulfilled in 13 neutropenic episodes. An elevated plasma lactate level was infrequent at the start of neutropenic fever (5%). There was no association of lactate level with the development of severe sepsis. Two patients died of septic shock, 1 patient with an exceptionally high and increasing level of lactate and the other patient with a normal lactate level. An elevated plasma lactate level at the start of neutropenic fever is not common and does not indicate severe sepsis, but high lactate and an impaired lactate decrease may signify a fatal course in neutropenic fever.

Changes in the microbiological epidemiology of febrile neutropenia in autologous stem cell transplant recipients.

BACKGROUND: The aim of the study was to explore the incidence, microbiological etiology and outcome of febrile neutropenia among adult hematological patients following autologous stem cell transplantation (ASCT). METHODS: The study population consisted of patients who received ASCT between 1 December 2006 and 30 November 2012. The epidemiology was compared to a retrospective series covering eleven previous years at the same institution. Non-Hodgkin lymphoma (NHL) patients, who had been identified as a risk group in the retrospective study, received ciprofloxacin prophylaxis from January 2008. RESULTS: Altogether, 142 out of 178 of the included patients (80%) developed febrile neutropenia. The blood cultures were positive in 24 cases (17%). Of all bacteremia's, 88% were caused by Gram-positive and 12% by Gram-negative bacteria. The number of Gram-negative bacteremia were significantly lower in the prospective study compared to the retrospective study (3/142, 2.1% vs. 23/265, 8.7%, p = .01). Pseudomonas aeruginosa was prevalent in the retrospective series but not discovered in the present series. Enterococcus faecium was found more frequently in the prospective study (6/142, 4.2 vs. 2/265, 0.8%, p = .02). The infectious mortality among patients with febrile neutropenia was 4/142 (2.8%) in the present series and 9/265 (3.4%) in those who received ASCT in 1996-2006. CONCLUSION: Most patients who received ASCT developed febrile neutropenia and a minority had bacteraemia. In comparison to the earlier time period, the incidence of Gram-negative bacteraemias decreased, probably due to ciprofloxacin prophylaxis in NHL patients, but simultaneously the incidence of Enterococcus bacteraemias increased. Infectious mortality during febrile neutropenia was low in both series.

Bloodstream infections in acute myeloid leukemia patients treated according to the Finnish Leukemia Group AML-2003 protocol - a prospective nationwide study.

BACKGROUND: Infections greatly influence the outcome of acute myeloid leukemia (AML) patients receiving intensive treatment. The aim of this study was to establish the incidence, microbial etiology, risk factors and prognosis of bloodstream infections (BSIs) in patients with AML and compare the results with the previous treatment protocol (AML-92). METHODS: Registery data were gathered prospectively from 357 patients aged 16-65 years recruited on the AML-2003 treatment protocol between November 2003 and November 2011 during different treatment cycles. RESULTS: Blood culture data were available on 977 treatment episodes, in which there were 503 BSIs (51%). The overall incidence rate (IR) for BSIs (per 1000 hospital days) was 16.7. Twenty patients (5.6%) died due to an infection and 16 of them (80%) had a BSI. The most commonly detected microbes (polymicrobial episodes included) in blood cultures were coagulase-negative staphylococci (CoNS, 24.7%), viridans group streptococci (VGS, 19.1%), enterococci (13.9%) and Enterobacteriacae group (25.9%). The etiology of BSIs varied greatly from treatment cycle to cycle. CONCLUSIONS: Enterococcal BSIs have increased compared to our previous treatment protocol, and they represent significant pathogens in blood cultures. Infection-related mortality has decreased despite the increase in the IR of BSIs. Enterococci seem to be an increasingly prominent pathogen underlying BSIs in the AML patients, especially during induction therapy (20%).

Early immune recovery after autologous transplantation in non-Hodgkin lymphoma patients: predictive factors and clinical significance.

Limited data is available about the factors affecting early immune recovery or its clinical significance after autologous stem cell transplantation (auto-SCT). We prospectively analyzed factors affecting early immune recovery and outcome among 72 non-Hodgkin lymphoma (NHL) patients. Absolute lymphocyte count 15 d after auto-SCT (ALC-15) ≥ 0.5 × 10(9)/L was associated with the use of plerixafor (p = 0.004), the number of CD34(+) cells (p = 0.015), and CD34(+) CD38(-) cells (p = 0.005) in the grafts. ALC-15 ≥ 0.5 × 10(9)/L was associated with improved overall survival (p = 0.021). In patients with aggressive histology, ALC-15 ≥ 0.5 × 10(9)/L was beneficial in regard to both progression-free survival (p = 0.015) and overall survival (p = 0.002). Early immune recovery seems to be important in transplanted patients with NHL and, therefore, an easy and affordable method for disease-related risk analysis. Patients with aggressive histology and slow immune recovery may need additional post-transplant treatment.

Colonization of hospital water systems by legionellae, mycobacteria and other heterotrophic bacteria potentially hazardous to risk group patients.

Occurrences of legionellae and nontuberculous mycobacteria were followed in water systems of a tertiary care hospital where nosocomial infections due to the two genera had been verified. The aim was to examine whether their occurrence in the circulating hot water can be controlled by addition of a heat-shock unit in the circulation system, and by intensified cleaning of the tap and shower heads. One hot water system examined had an inbuilt heat-shock system causing a temporary increase of temperature to 80 degrees C, the other was an ordinary system (60 degrees C). The heat-shock unit decreased legionella colony counts in the circulating hot water (mean 35 cfu/l) compared to the ordinary system (mean 3.6 x 10(3) cfu/l). Mycobacteria constantly present in the incoming cold water (mean 260 cfu/l) were never isolated from the circulating hot water. Water sampled at peripheral sites such as taps and showers contained higher concentrations of legionellae, mycobacteria, and mesophilic and Gram-negative heterotrophs than the circulating waters. The shower water samples contained the highest bacterial loads. The results indicate the need to develop more efficient prevention methods than the ones presently used. Prevention of mycobacteria should also be extended to incoming cold water.

Concomitant impairment of left ventricular systolic and diastolic function during doxorubicin therapy: a prospective radionuclide ventriculographic and echocardiographic study.

Thirty adult lymphoma patients were studied prospectively with serial radionuclide ventriculography (RVG) and echocardiography (ECHO) to investigate whether changes in left ventricular (LV) diastolic function precede the impairment of LV systolic function during doxorubicin therapy. The patients received 8-10 cycles of CHOP to a cumulative doxorubicin dose of 400-500 mg/m2. RVG and ECHO were performed at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg/m2. Left ventricular ejection fraction (LVEF) decreased from 58 +/- 1.3 to 49.6 +/- 1.7% (p < 0.001) and from 58 +/- 1.7 to 52.5 +/- 1.3% (p = 0.036) as assessed with RVG and 2D ECHO, respectively. Of the diastolic ECHO doppler indices peak E wave velocity decreased from 63.3 +/- 3.2 to 51.3 +/- 2.6 cm/s (p = 0.008) and LV filling during the first 1/3 of diastole (1/3FF) from 42.2 +/- 1.7 to 36.5 +/- 2.0% (p < 0.001). The decrease in LVEF was statistically significant after the cumulative doxorubicin dose of 200 mg/m2 as assessed with RVG and after 400 mg/m2 as assessed with 2D ECHO. The decrease in 1/3FF reached the statistical significance after the cumulative doxorubicin dose of 400 mg/m2 and the decrease in peak E wave velocity after 500 mg/m2. This study shows that during doxorubicin therapy there are significant changes both in systolic and diastolic LV function. In addition, these changes manifest at relatively low cumulative doxorubicin doses and occur concomitantly. Thus, the assessment of diastolic function provides no advantage over monitoring systolic function during doxorubicin therapy.

Economic evaluation of sequential treatments for follicular non-hodgkin lymphoma.

BACKGROUND: The cost-effectiveness analyses of follicular lymphoma (FL) treatments have focused on the second-line rituximab maintenance in patients with relapsed FL. The assessment of full FL treatment chain has been lacking. OBJECTIVE: The aim of this study was to assess the cost-effectiveness of FL treatment sequences. METHODS: Transitions between progression-free first-line treatment (PF1), progression-free second-line treatment (PF2), progression, and death health states were simulated with a probabilistic Markov model with half-cycle correction. At first, patients were assumed to be receiving rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) induction. The first-line RCHOP induction responders continued without (RCHOP) or with (RCHOPR) the first-line rituximab-maintenance treatment. In the case of PF1 failure, patients received RCOPR/bendamustine or RCOPR/COP according to the European Society for Medical Oncology guidance. In the case of PF2 failure, patients were expected to receive the best supportive care (BSC). The survivals and adverse events were estimated with direct and indirect comparisons. Health outcomes and Finnish payer (drug, drug administration, monitoring, test, progression, serious adverse event) costs valued in 2010 euros were discounted with 3% per annum. RESULTS: The mean discounted lifetime overall survival with FL was 9.6 to 11.5 years, quality-adjusted survival was 7.2 to 8.8 quality-adjusted life-years (QALYs), progression-free time was 7.7 to 10.2 years, and costs were €153,425 to €168,549, depending on the treatment sequence. The incremental cost-effectiveness ratios for RCHOPR→RCOPR/bendamustine→BSC, RCHOPR→RCOPR/COP→BSC, and RCHOP→RCOPR/bendamustine→BSC were €9575/€8014/€5900, €9881/€8310/€6013, and €8812/€7194/€5808, respectively, per QALY/life-year/progression-free year gained in comparison with RCHOP→RCOPR/COP→BSC. According to the cost-effectiveness acceptability frontier, the treatment of 61.8% to 72.7% patients with RCHOPR→RCOPR/bendamustine→BSC was cost effective at €20,000 to €30,000/QALY gained (expected value of perfect information [EVPI], €1287 to €1976/patient). The relative results were found to be robust in sensitivity analyses, and, in the direct comparison that included only head-to-head data, the first-line rituximab maintenance had 93.1% cost-effectiveness probability at €20,000/QALY gained (EVPI, €282/patient). CONCLUSION: Sequences that included first-line rituximab maintenance is and second-line bendamustine are potentially cost effective in the treatment of FL. LIMITATIONS: Because of data available, health outcomes of the first-line rituximab induction were excluded, the second-line patients on COP were assumed to incur the cost of COP, and the efficacy and adverse events of CHOP and the efficacy and adverse events of bendamustine were estimated indirectly according to a comparison of rituximab+bendamustine and RCHOP, and treatment benefits were truncated.