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Background Diffuse large B-cell lymphoma (DLBCL) is a common indication for autologous stem cell transplantation (auto-SCT). Study design and methods This prospective noninterventional study aimed to evaluate the impact of mobilization characteristics and graft cellular content on hematologic recovery and outcome after auto-SCT among 68 patients with DLBCL. Results Better mobilization capacity as manifested by blood CD34+ cell count >32 × 106 /L and CD34+ cell yield of the first apheresis >2.75 × 106 /kg correlated with faster neutrophil (P = .005 and P = .017) and platelet (P = .002 and P 2.65 × 106 /kg) was associated with better 5-year overall survival (OS; 95% vs 67%, P = .012). The graft CD34+ CD133+ CD38- cell count >0.07 × 106 /kg was predictive of better 5-year OS (87% vs 63%; P = .008) and higher graft CD3+ cell count (>23.1 × 106 /kg) correlated also with better 5-year OS (80% vs 40%, P = .008). In multivariate analysis only disease status of CR I at auto-SCT was associated with better progression-free survival (P = .014) and OS (P = .039). Conclusion The mobilization capacity of CD34+ cells impacted on early hematologic recovery in patients with DLBCL after auto-SCT. Higher graft CD34+ cell count and both CD34+ CD133+ CD38- and CD3+ cells were also associated with better OS. The effect of optimal graft cellular composition on outcome in DLBCL should be evaluated in a randomized study.

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

BACKGROUND Autologous stem cell transplantation is an established treatment option for patients with multiple myeloma (MM) or non-Hodgkin?s lymphoma (NHL). STUDY DESIGN AND METHODS In this prospective multicenter study, 147 patients with MM were compared with 136 patients with NHL regarding the mobilization and apheresis of blood CD34+ cells, cellular composition of infused blood grafts, posttransplant recovery, and outcome. RESULTS Multiple myeloma patients mobilized CD34+ cells more effectively (6.3???106/kg vs. 3.9???106/kg, p?=?0.001). The proportion of poor mobilizers (peak blood CD34+ cell count 100?days) nonrelapse mortality (NRM; 6% vs. 0%, p?=?0.003). CONCLUSIONS Non-Hodgkin?s lymphoma and MM patients differ in terms of mobilization of CD34+ cells, graft cellular composition, and posttransplant recovery. Thus, the optimal graft characteristics may also be different.

Objectives: To investigate the protein expression of the epithelial-mesenchymal transition-inducing transcription factors (TFs) Twist, ZEB1 and Slug in peripheral T-cell lymphomas (PTCL) and their ...

The rare myelomas, immunoglobulin (Ig)D, IgM, and non-secretory, have been associated with poorer outcomes following treatment than the common myelomas (IgG, IgA, and light-chain only). We show that even with "novel" therapies, augmented with autologous transplantation, this remains true for IgD myeloma. In contrast, IgM and non-secretory myelomas have a prognosis similar to the usual myelomas.Background: The Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study has provided an opportunity to evaluate the real-world outcomes of patients with myeloma. The aim of this study was to compare the outcome according to the different subtypes of myeloma using CALM data. Patients: This study compared overall survival (OS), progression-free survival (PFS), and complete remission (CR) and the impact of novel versus non-novel drug containing induction regimens prior to autologous hematopoietic cell transplantation (HCT) of 2802 patients with "usual" and "rare" myelomas. Results: Our data suggest that IgM and non-secretory myeloma have superior PFS and OS compared with IgD myeloma and outcomes comparable to those for usual myeloma. Patients who received novel agent induction had higher rates of CR prior to transplant. Non-novel induction regimens were associated with inferior PFS but no difference in OS. Although not the primary focus of this study, we show that poor mobilization status is associated with reduced PFS and OS, but these differences disappear in multivariate analysis suggesting that poor mobilization status is a surrogate for other indicators of poor prognosis. Conclusion: We confirm that IgD myeloma is associated with the worst prognosis and inferior outcomes compared with the other isotypes. (C) 2021 Elsevier Inc. All rights reserved.

Background: Autologous stem cell transplantation (auto-SCT) is a widely used treatment option in multiple myeloma (MM) patients. The optimal graft cellular composition is not known. Study design and methods: Autograft cellular composition was analyzed after freezing by flow cytometry in 127 MM patients participating in a prospective multicenter study. The impact of graft cellular composition on hematologic recovery and outcome after auto-SCT was evaluated. Results: A higher graft CD34+ cell content predicted faster platelet recovery after auto-SCT in both the short and long term. In patients with standard-risk cytogenetics, a higher graft CD34+ count (>2.5 × 10/kg) was linked with shorter progression-free survival (PFS; 28 vs. 46 months, p = 0.04), but there was no difference in overall survival (OS) (p = 0.53). In a multivariate model, a higher graft CD34+CD133+CD38− (>0.065 × 10/kg, p = 0.009) and NK cell count (>2.5 × 10/kg, p = 0.026), lenalidomide maintenance and standard-risk cytogenetics predicted better PFS. In contrast, a higher CD34+ count (>2.5 × 10/kg, p = 0.015) predicted worse PFS. A very low CD3+ cell count (≤20 × 10/kg, p = 0.001) in the infused graft and high-risk cytogenetics remained predictive of worse OS. Conclusions: Autograft cellular composition may impact outcome in MM patients after auto-SCT. More studies are needed to define optimal graft composition. publishedVersion

Follicular lymphoma (FL) is the most common indolent lymphoma. Currently there are many comparable treatment options available for FL. When selecting the most optimal therapy it is important to consider possible late effects of the treatment as well as survival. Secondary haematological malignancy (SHM) is a severe late effect of treatments, but the incidence of SHMs is still largely unknown. The goal of the present study was to determine the incidence of SHMs and how therapeutic decisions interfere with this risk. The study included 1028 FL patients with a median follow-up time of 5·6 years. The 5-year risk of SHM was 1·1% and the risk was associated with multiple lines of treatment (P = 0·016). The 5-year risk of SHM was 0·5% after the first-line treatment and 1·6% after the second-line. The standardized incidence ratio (SIR) was 6·2 (95% confidence interval 3·4-10·5) for SHM overall. This retrospective study found that the risk of SHM was low after first-line treatment in FL patients from the rituximab era. However, the risk of SHM increases with multiple lines of treatment. Therapeutic approaches should aim to achieve as long a remission as possible with first-line treatment, thereby postponing the added risk of SHM.

The study aim was to determine the benefit of the measurement of serum caspase-cleaved cytokeratin-18 (CK-18) fragment as a prognostic marker of febrile neutropenia (FN) in hematological patients. The study population consisted of 86 consecutive patients with FN who received intensive chemotherapy for hematological malignancy at the adult hematology ward of Kuopio University Hospital. Twenty-three patients (27%) had acute myeloid leukemia, and 63 patients (73%) were autologous stem cell transplant recipients. Serum caspase-cleaved CK-18 fragment M30, C-reactive protein (CRP) and procalcitonin (PCT) were measured at the onset of FN (d0), on day 1 (d1), and on day 2 (d2). Eight patients (9%) developed severe sepsis, including three patients with septic shock. Eighteen patients (21%) had a blood culture-positive infection. Serum CK-18 fragment peaked on the first day after fever onset in patients with severe sepsis. Higher CK-18 level was associated with severe sepsis, intensive care unit treatment, and fatal outcome, but not with blood culture positivity. In ROC curve analysis, d1 serum CK-18 fragment predicted severe sepsis with an area under the curve (AUC) of 0.767, CRP with an AUC of 0.764, and PCT with an AUC of 0.731. On d2, the best predictive capacity was observed for CRP with an AUC of 0.832. The optimal cutoff of caspase-cleaved CK-18 fragment M30 for predicting severe sepsis was 205 U/L on d1. In hematological patients, serum CK-18 fragment was found to be a potential prognostic marker of severe sepsis at early stages of FN.

Findings regarding the role of sex in follicular lymphoma (FL) are contradictory and the prognostic value of sex among patients with early progression of disease (POD) remains unclear. We collected real-life data from nine hospitals in Finland and Spain including 1020 FL patients to study the influence of sex on disease outcome. The median follow-up duration was 67 months (range 0–226 months). Female patients showed better progression-free survival (PFS) (hazard ratio [HR], 0.720; 95% confidence interval [CI], 0.588–0.881), disease-specific survival (DSS) (HR, 0.653; 95% CI, 0.448–0.951), and overall survival (OS) (HR, 0.653; 95% CI, 0.501–0.853) than male patients. However, there were no significant sex differences in prognosis in patients with early POD. This study strengthens the understanding that male sex is an adverse prognostic factor for FL. However, this difference does not apply to patients with early POD. publishedVersion

Autologous stem cell transplantation (auto-SCT) is an established treatment option in patients with non-Hodgkin lymphoma (NHL). In this prospective multicenter study, the effect of infused blood graft cellular composition on post-transplant outcome was analyzed in 129 NHL patients. Higher graft CD34

Objectives To evaluate quick Sequential Organ Failure Assessment (qSOFA) score during febrile neutropenia (FN) in adult patients receiving intensive chemotherapy for acute myeloid leukemia (AML). Methods qSOFA score, as well as the association of qSOFA score with ICU admission, infectious mortality, blood culture findings, and C-reactive protein (CRP) measurements during FN were assessed among 125 adult AML patients with 355 FN periods receiving intensive chemotherapy in a tertiary care hospital from November 2006 to December 2018. Results The multivariate model for qSOFA score ≥ 2 included CRP ≥ 150 mg/L on d0-2 [OR 2.9 (95% CI 1.1-7.3), P = .026], Gram-negative bacteremia [OR 2.7 (95% CI 1.1-6.9), P = .034], and treatment according to AML-2003 vs more recent protocols [OR 2.7 (95% CI 1.0-7.4), P = .047]. Age or gender did not gain significance in the model. qSOFA score ≥ 2 was associated with ICU treatment and infectious mortality during FN with sensitivity and specificity of 0.700 and 0.979, and 1.000 and 0.971, respectively. Conclusion qSOFA offers a useful tool to evaluate the risk of serious complications in AML patients during FN.

Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups.

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

Autologous stem cell transplantation (auto-SCT) is a treatment approach in non-Hodgkin lymphoma (NHL) patients. The options for mobilization of CD34The present prospective nonrandomized study compared LIPEG 6 mg (n = 40) with pegfilgrastim (PEG) 6 mg (n = 37) in the mobilization of blood CD34Significantly higher blood CD34The mobilization of blood grafts with LIPEG added to chemotherapy was associated with higher CD34

Recognizing the significant biological and clinical heterogeneity of mature T cell and natural killer (NK)/T cell lymphomas, the American Society for Blood and Marrow Transplantation invited experts to develop clinical practice recommendations related to the role of autologous hematopoietic cell transplantation (auto-HCT) and allogeneic HCT (allo-HCT) for specific histological subtypes. We used the GRADE methodology to aid in moving from evidence to decision making and ultimately to generating final recommendations. Auto-HCT in front-line consolidation is recommended in peripheral T cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma–anaplastic lymphoma kinase (ALCL-ALK)-negative, NK/T cell (disseminated), enteropathy-associated T cell lymphoma (EATL), and hepatosplenic lymphomas. Auto-HCT in relapsed-sensitive disease is recommended for NK/T cell (localized and disseminated), EATL, subcutaneous panniculitis-like T cell, and ALCL-ALK–positive lymphomas. Auto-HCT is also recommended for PTCL-NOS, AITL, and ALCL-ALK–negative lymphomas if not performed as front-line therapy. Auto-HCT in refractory (primary or relapsed) disease is not recommended for any of the histological subtypes discussed. Allo-HCT in front-line consolidation is recommended for NK/T cell (disseminated), adult T cell leukemia/lymphoma (ATLL; acute and lymphoma type), and hepatosplenic lymphomas. Allo-HCT for relapsed-sensitive disease is recommended for PTCL-NOS, AITL, ALCL-ALK–negative, ALCL-ALK–positive, NK/T cell (localized and disseminated), ATLL (acute, lymphoma type, smoldering/chronic), mycosis fungoides/Sezary syndrome (advanced stage IIB-IVB or tumor stage/extracutaneous), EATL, subcutaneous panniculitis-like T cell, and hepatosplenic lymphoma. Allo-HCT in refractory (primary or relapsed refractory) disease is recommended for any aforementioned histological subtypes. Emerging novel therapies will likely be incorporated into the pretransplantation, peritransplantation, and post-transplantation algorithms (auto-HCT or allo-HCT) with the goals of optimizing efficacy and improving outcomes. We acknowledge that there are unique clinical scenarios not covered by these recommendations that may require individualized decisions.

Filgrastim is usually combined with chemotherapy to mobilize hematopoietic progenitor cells in non-Hodgkin lymphoma (NHL) patients. Limited information is available on the efficacy of a preemptive plerixafor (PLER) injection in poor mobilizers after chemotherapy and pegfilgrastim. In this prospective study, 72 patients with NHL received chemotherapy plus pegfilgrastim, and 25 hard-to-mobilize patients received also PLER. The usefulness and efficacy of our previously developed algorithm for PLER use in pegfilgrastim-containing mobilization regimen were evaluated as well as the graft cellular composition, hematological recovery, and outcome after autologous stem cell transplantation (auto-SCT) according to the PLER use. A median 3.4-fold increase in blood CD34+ cell counts was achieved after the first PLER dose. The minimum collection target was achieved in the first mobilization attempt in 66/72 patients (92%) and 68 patients (94%) proceeded to auto-SCT. An algorithm for PLER use was fulfilled in 76% of the poor mobilizers. Absolute numbers of T-lymphocytes and NK cells were significantly higher in the PLER group, whereas the number of CD34+ cells collected was significantly lower. Early neutrophil engraftment was slower in the PLER group, otherwise hematological recovery was comparable within 12 months from auto-SCT. No difference was observed in survival according to the PLER use. Chemotherapy plus pegfilgrastim combined with preemptive PLER injection is an effective and convenient approach to minimize collection failures in NHL patients intended for auto-SCT. A significant effect of PLER on the graft cellular composition was observed, but no difference in outcome after auto-SCT was detected.

Introduction: Patients with follicular lymphoma (FL) have classically had a higher risk of solid cancers than the general population, but there is little data available in patients diagnosed and tr...

Commonly used indicators of sepsis are nonspecific and insufficient for predicting the course of febrile neutropenia (FN) in hematological patients. We analyzed data from 91 adult FN patients who received intensive chemotherapy for acute myeloid leukemia or autologous stem cell transplantation. Compared to patients with non-severe sepsis, patients with severe sepsis had significantly higher serum levels of tissue inhibitor of metalloproteinases-1 on the day of first occurrence of fever (day 0: 172 vs. 112 µg/L

Lymphomas constitute the second most common indication for autologous hematopoietic cell transplantation (AHCT). Graft infusion is followed by a rapid hematological recovery and slower immune recovery. The number of natural killer cells and CD3

AimsOxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown.MethodsDiagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome.ResultsNuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival.ConclusionsNrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group.

Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS. Electronic supplementary material The online version of this article (10.1007/s00277-019-03815-7) contains supplementary material, which is available to authorized users.

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.

A combination of granulocyte colony-stimulating factor (G-CSF) and chemotherapy or G-CSF alone are the most common mobilization regimens for autotransplantations. Plerixafor is used for mobilization of CD34(+) cells with G-CSF in non-Hodgkin lymphoma (NHL) and myeloma (MM) patients.The available phase II and III data on plerixafor has been reviewed. The efficacy of plerixafor in the mobilization of CD34(+) cells in predicted poor mobilizers as well as in patients who had failed a mobilization has been evaluated. The pre-emptive use of plerixafor as well as studies on cost-effectiveness are covered. Also effects in the composition of the collected grafts along with the data on long-term outcome of plerixafor-mobilized patients is discussed. Expert commentary: Plerixafor combined with G-CSF mobilizes CD34(+) cells more efficiently than G-CSF alone in patients with NHL or MM. In phase III studies, engraftment after high-dose therapy has been comparable to G-CSF mobilized patients. The pre-emptive use of plerixafor added to mobilization with chemotherapy plus G-CSF or with G-CSF alone has gained more popularity. This approach may be more cost-effective than the routine use of this drug. The changes observed in the composition of grafts after plerixafor injection may have implications for post-transplant events.

In search of a biomarker for complicated course of febrile neutropenia (FN), plasma IL-18 was measured in 92 hematological patients after intensive chemotherapy at the beginning of FN (days 0-3). Complicated course was defined as blood culture positivity or septic shock. IL-18 varied according to background hematological malignancy and showed an inverse correlation with leukocyte count. IL-18 was not associated with complicated course of FN, defined as blood culture positivity or septic shock, in the whole study group, but an association was observed on d1 and d2 after the onset of FN in the subgroup of autologous stem cell transplant recipients with non-Hodgkin lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. The standard therapy for DLBCL is R-CHOP. The current 5-year overall survival is 60% to 70% using standard frontline therapy. However, the use of doxorubicin and its cardiotoxicity is a major clinical problem and preexisting cardiac disease may prevent the use of doxorubicin. Age greater than 65 years is a significant risk factor for anthracycline-induced cardiotoxicity, and therefore, the use of R-CHOP is often withheld from elderly patients. The feasibility of replacing doxorubicin with either epirubicin or etoposide in patients who have risk factors for heart complications is analyzed here. Clinical data of 223 DLBCL patients were retrospectively collected from hospital records. Fifty-five patients were treated with R-CHOP, 105 with R-CIOP (epirubicin instead of doxorubicin), 17 with R-CEOP (etoposide instead of doxorubicin), and 31 with R-CHOEP. Matched-pair analysis was carried out between 30 patients treated with R-CEOP and R-CHOP. For all patients, the 2-year progression-free survival (PFS) was 73.6%. In patients treated with R-CHOP, the 2-year PFS was 84.2%, with R-CIOP 64.4%, with R-CEOP 87.7%, and with R-CHOEP 83.2%. In matched-pair analysis, the 2-year PFS was 92.3% with R-CHOP and 86.2% with R-CEOP. The 2-year disease specific survival was 100% with R-CHOP and 86.2% with R-CEOP. In conclusion, R-CEOP offers reasonable PFS and disease specific survival in the treatment of DLBCL and good disease control can be achieved in elderly patients. Elderly patients with impaired cardiac function could benefit from the use of R-CEOP instead of R-CHOP. The results with R-CIOP were unsatisfactory, and we do not recommend using this protocol in elderly patients with cardiac disease.

The composition of autologous blood grafts after cryopreservation, post-transplant hematological recovery up to 1 year and immune recovery up to 6 months as well as outcome was analyzed in 87 patients with multiple myeloma (MM). The patients receiving added plerixafor due to poor mobilization (11%) were compared to those mobilized with G-CSF or cyclophosphamide (CY) plus G-CSF. The use of plerixafor was found to significantly affect the graft composition as there was a significantly higher proportion of the more primitive CD34+ cells, higher number of T and B lymphocytes as well as NK cells in the grafts of patients who received also plerixafor. The hematological recovery after auto-SCT was comparable between the groups. The recovery of CD3+CD4+ T cells was faster in plerixafor mobilized patients at 1 and 3 months post-transplant. There were no significant differences in progression-free (PFS) or overall survival (OS) according to the plerixafor use.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with diverse outcomes. Concurrent translocation of MYC and BCL-2 and/or BCL-6, and concurrent immunohistochemical (IHC) high expression of MYC and BCL-2, have been linked to unfavorable treatment responses. TP53-mutated DLBCL has also been linked to worse outcome. Our aim was to evaluate the aforementioned issues in a cohort of 155 patients uniformly treated with R-CHOP-like therapies. We performed direct sequencing of TP53 exons 5, 6, 7 and 8 as well as fluorescence in-situ hybridization (FISH) of MYC, BCL-2 and BCL-6, and IHC of MYC, BCL-2 and BCL-6. In multivariate analysis, TP53 mutations in L3 and loop-sheet helix (LSH) associated with a risk ratio (RR) of disease-specific survival (DSS) of 8.779 (p = 0.022) and a RR of disease-free survival (DFS) of 10.498 (p = 0.011). In IHC analysis BCL-2 overexpression was associated with inferior DFS (p = 0.002) and DSS (p = 0.002). DLBCL with BCL-2 and MYC overexpression conferred inferior survival in all patients (DSS, p = 0.038 and DFS, p = 0.011) and in patients with non-GC phenotype (DSS (p = 0.013) and DFS (p = 0.010). Our results imply that in DLBCL, the location of TP53 mutations and IHC analysis of BCL-2 and MYC might have a role in the assessment of prognosis.

Background. Novel potential small molecular biomarkers for sepsis were analyzed with nontargeted metabolite profiling to find biomarkers for febrile neutropenia after intensive chemotherapy for hematological malignancies. Methods. Altogether, 85 patients were included into this prospective study at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The plasma samples for the nontargeted metabolite profiling analysis by liquid chromatography-mass spectrometry were taken when fever rose over 38° and on the next morning. Results. Altogether, 90 differential molecular features were shown to explain the differences between patients with complicated (bacteremia, severe sepsis, or fatal outcome) and noncomplicated courses of febrile neutropenia. The most differential compounds were an androgen hormone, citrulline, and phosphatidylethanolamine PE(18:0/20:4). The clinical relevance of the findings was evaluated by comparing them with conventional biomarkers like C-reactive protein and procalcitonin. Conclusion. These results hold promise to find out novel biomarkers for febrile neutropenia, including citrulline. Furthermore, androgen metabolism merits further studies.

Central nervous system (CNS) relapse occurs in around 5% of diffuse large B-cell lymphoma (DLBCL) cases. No biomarkers to identify high-risk patients have been discovered. We evaluated the expression of lymphocyte-guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi-square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement (P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL.

Aims Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction of risk of relapse is based on clinical markers. There is a need for more accurate biomarkers to select patients for more aggressive first-line treatments. Peroxiredoxins (Prxs) are a family of potent antioxidant proteins. Their prognostic role in DLBCL is unknown. Methods Altogether, 103 diagnostic biopsy samples from patients with DLBCL were immunohistochemically stained for Prxs I, II, III, V and VI. Results Strong Prx VI expression was associated with the presence of B-symptoms. There were no other significant associations with traditional risk factors. Five-year disease-specific survival was 68.6% in patients with high cytoplasmic Prx VI intensity vs 97.0% in those with low intensity. In multivariate analysis, high Prx VI expression (HR 12.846, 95% CI 1.722 to 95.807, p=0.013) was an independent risk factor of lymphoma-associated death not related to International Prognostic Index score (HR 2.514, 95% CI 1.040 to 6.073, p=0.041). Conclusions High intensity of cytoplasmic Prx VI expression in pretreatment DLBCL samples predicts worse outcome in patients with DLBCL. Whether Prx VI is associated with chemoresistance, and therefore a poorer outcome, needs to be evaluated. If Prx VI is a predictive marker and it proves causality, it would be crucial to study Prx VI ability to become a target enzyme for treatment.

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).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.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.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%).

Cerebral venous thrombosis (CVT) covers up to a third of all venous thromboses (VTs) detected in patients with acute lymphoblastic leukemia (ALL). It usually hampers patients' lives and may also endanger efficient leukemia treatment. Although many factors have been suggested to account for an elevated risk of VTs in patients with ALL, there still is a lack of studies focusing on CVTs and especially in the setting of adult ALL patients. We studied in our retrospective population-based cohort the occurrence, characteristics, as well as risk factors for VTs in 186 consecutively diagnosed Finnish adult ALL patients treated with a national pediatric-inspired treatment protocol ALL2000. In the risk factor analyses for VTs we found a distinction of the characteristics of the patients acquiring CVT from those with other kinds of VTs or without thrombosis. In contrast to previous studies we were also able to compare the effects of asparaginase in relation to CVT occurrence. Notably, more than half of the CVTs were diagnosed prior the administration of asparaginase which accentuates the role of other risk factors on the pathophysiology of CVT compared to truncal or central venous line (CVL) VTs in adult ALL patients.

Sir,We read with great interest the paper by Campos et al. [1], who described an endemic outbreak of vancomycin-resistant Enterococcus faecium (VRE). VRE is not a common microbiological finding in ...

Asymmetric dimethylarginine (ADMA) has been recognized as an independent prognostic factor for sepsis mortality in intensive care units. No data are available on kinetics or prognostic value of ADMA in hematological patients. We evaluated the ability of ADMA to act as a predictor for complicated course of febrile neutropenia, defined as bacteremia and/or septic shock in adult hematological patients receiving intensive chemotherapy. This prospective study included 87 adult hematological patients with febrile neutropenia after an intensive chemotherapy for acute myeloid leukemia (AML) or after an autologous stem cell transplantation (ASCT). Plasma ADMA and serum C-reactive protein (CRP) levels were measured from the onset of fever (d0) and for 2 days (d1-d2) thereafter. The levels of ADMA were stable or had only minimal changes during the study period. There was no difference between the levels at any time-point in patients having complicated course compared to those without it. On the other hand, CRP levels were significantly higher on d1 (p = 0.016) in patients with bacteremia and/or septic shock than in those without. ADMA was not able to differentiate hematological patients with a complicated course from those without complications. Elevated ADMA levels are probably associated with organ dysfunction, which is rare in this group of patients, of whom about 95% can be successfully managed at the hematology ward.

Lenalidomide is an immunomodulatory drug that is also currently used in transplant-eligible patients with multiple myeloma. Previous studies have suggested a negative impact of lenalidomide on the mobilization of CD34In a multicenter, prospective study, we analyzed the mobilization of CD34Patients in the lenalidomide arm had lower median peak CD34Lenalidomide-based induction seems to have an impact on the number of aphereses performed, but not on the total yields of the CD34

Objective. Elevated levels of a cell surface glycoprotein, soluble cluster of differentiation 14 (sCD14), have been observed in patients with sepsis. Only scarce data are available on sCD14 in hematological patients with chemotherapy-induced febrile neutropenia. The study aim was to investigate sCD14 as an early biomarker in febrile neutropenia after intensive chemotherapy to detect a rapidly deteriorating clinical course early enough to avoid serious infectious complications. Patients and Methods. This prospective study included 87 adult hematological patients at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The study endpoints were septic shock, severe sepsis, and positive blood culture findings. sCD14 was analyzed from day 0 to day 2, and its prognostic capacity was compared to that of C-reactive protein and procalcitonin. Results. Plasma level of sCD14 predicted the development of septic shock on day 1 () and day 2 but not the development of severe sepsis or blood culture positivity in hematological patients with chemotherapy-induced febrile neutropenia. Conclusions. Soluble CD14 did not predict an overall complicated course at the early stages of febrile neutropenia. However, it was helpful in predicting the progression of the clinical course of neutropenic fever to septic shock., published version, peerReviewed

Objectives The cell cycle is under strict regulation by the retinoblastoma, p53 and p27 pathways, and the disruption of these pathways is an important characteristic of diffuse large B-cell lymphoma (DLBCL). In this study, we wanted to assess the function and prognostic significance of these pathways in DLBCL patients. Methods Tissue samples from 120 DLBCL patients treated by means of R-CHOP-type chemotherapy were stained for the cell cycle–regulating proteins p16, p21, p27 and p53, and the germinal centre (GC) phenotype was determined according to Hans' algorithm. Based on the number of impaired cell cycle–regulating pathways a predictive score was obtained, covering three different prognostic groups: a ‘favourable’ group with damage in 0–1 of the studied pathways, a ‘poor’ group with damage in all three pathways and an ‘intermediate’ group comprising the rest of the patients. Results The prognosis of non-GC DLBCL patients was significantly poorer vs. GC phenotype patients (P = 0.015). The prognostic score proved especially useful among non-GC phenotype patients, with 3-yrs relapse-free survival of 100% vs. 62.6% vs. 24.3% in the ‘favourable-’, ‘intermediate-’ and ‘poor prognosis’ groups, respectively (P = 0.003). Conclusion The prognosis of non-GC DLBCL patients is progressively impaired with the accumulation of damage in different cell cycle–regulating pathways.

Early diagnosis of complicated course in febrile neutropenia is cumbersome due to the non-specificity of clinical and laboratory signs of severe infection. This prospective study included 100 adult hematological patients with febrile neutropenia after intensive chemotherapy at the onset of fever (d0) and for 3 days (d1-d3) thereafter. The study aim was to find early predictors for complicated course of febrile neutropenia, defined as bacteremia or septic shock. Interleukin 6 (IL-6), interleukin 10 (IL-10), procalcitonin (PCT) and C-reactive protein (CRP) all predicted complicated course of febrile neutropenia on d0, but only PCT was predictive throughout the study period. For IL-10 on d0-1 with cut-off 37 ng/L, sensitivity was 0.71, specificity 0.82, positive predictive value 0.52 and negative predictive value 0.92. For PCT on d0-1 with cut-off 0.13 μg/L, the respective measures were 0.95, 0.53, 0.36, and 0.98. For the combination of IL-10 and PCT on d0-1 with the same cut-offs, specificity improved to 0.85 and positive predictive value to 0.56. In conclusion, the present study confirms the high negative predictive value of PCT and provides new evidence for IL-10 as an early predictor for complicated course of febrile neutropenia in hematological patients. Combining IL-10 with PCT improves the early prediction for complicated course of febrile neutropenia.

Lymphoma risk is increased in middle-aged patients in association with chronic active sarcoidosis. The sarcoidosis- lymphoma syndrome poses a challenge for differential diagnosis particularly in the era of fluoro-deoxy-glucose positron emission tomography-computed tomography (FDG-PET-TT). Upon detection of enlargement of lymph nodes, the diagnosis should be confirmed with a histological sample.

The most common means of mobilizing autologous stem cells is G-CSF alone or combined with cyclophosphamide (CY) to obtain sufficient CD34(+) cells for one to two transplants. There are few prospective, randomized studies investigating mobilization regimens in multiple myeloma (MM), especially after lenalidomide-based induction. We designed this prospective, randomized study to compare low-dose CY 2 g/m(2)+G-CSF (arm A) and G-CSF alone (arm B) after lenalidomide-based up-front induction in MM. Of the 80 initially randomized patients, 69 patients were evaluable, 34 and 35 patients in arms A and B, respectively. The primary end point was the proportion of patients achieving a yield of >= 3x10(6)/kg CD34(+) cells with 1 - 2 aphereses, which was achieved in 94% and 77% in arms A and B, respectively (P = 0.084). The median number of aphereses needed to reach the yield of >= 3x10(6)/kg was lower in arm A than in arm B (1 vs 2, P = 0.035). Two patients needed plerixafor in arm A and five patients in arm B (P = 0.428). Although CY-based mobilization was more effective, G-CSF alone was successful in a great majority of patients to reach the defined collection target after three cycles of lenalidomide-based induction.

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.

Neutropenic sepsis is a common clinical problem in hematological patients receiving intensive chemotherapy. Complications will develop in a minority of these patients. Biomarkers can be used for the recognition of infection as well as to estimate its severity and risk of complications and also to assess treatment response. Experience gained from other patient groups or sepsis patients treated in intensive care units cannot be directly extrapolated to hematological patients. Numerous biomarkers of infections have been investigated in hematological patients, but no optimal marker has been found. C-reactive protein is still the most commonly used biomarker in hematological patients, but procalcitonin may be a real challenger, although more studies are still needed.

Copeptin, the surrogate marker of arginine vasopressin (AVP), has been suggested to be a useful biomarker in monitoring sepsis reflecting hemodynamic imbalance and stress state. This prospective study conducted at a hematology ward in a Finnish University Hospital aimed to investigate whether plasma copeptin predicts the development of complicated course of neutropenic fever (bacteremia or need for treatment at intensive care unit) in 100 hematological patients experiencing their first neutropenic fever episode after intensive chemotherapy for hematological malignancy. Contrary to study presumptions, not elevated copeptin but the lack of a proper initial increase of plasma copeptin (0.02 ng/mL from day 0 to day 1) predicted blood culture positive sepsis (p=0.023) and gram-negative bacteremia (p=0.045). No correlation was observed with plasma sodium, blood pressure or evaluated osmolality. Plasma copeptin correlated inversely with the same day pentraxin 3 on day 0-day 2 (all p-values0.001) and with C-reactive protein on day 1 (p=0.015). In conclusion, copeptin did not correlate with disease severity, but the lack of a proper initial increase was associated with bacteremic complications of febrile neutropenia in hematological patients. The findings suggest the possibility of central dysregulation of AVP release and do not support the use of copeptin as a biomarker of septic complications in this patient group.

Background CXCR4 receptor antagonist plerixafor is used to mobilize hematopoietic stem cells. No detailed data regarding the effects of plerixafor on other blood cell components have been published but may be of importance in regard to graft composition collected after plerixafor injection. Patients and methods The study included thirty-nine patients with non-Hodgkin lymphoma (NHL) mobilized with chemotherapy plus G-CSF. Plerixafor was given pre-emptively in twenty patients due to poor mobilization or low collection yield. Nineteen NHL patients served as controls. We evaluated CD34 + counts and WBC counts and differential from the morning of the first plerixafor injection and 8h after the plerixafor injection. From the control patients the corresponding values were evaluated on the morning of the first apheresis and 24h before it. Results The first plerixafor dose increased CD34 + counts and number of leukocytes, neutrophils, lymphocytes, eosinophils and monocytes. Leukocyte, neutrophil, lymphocyte, monocyte and eosinophil counts were higher after plerixafor injection compared to the control group at the time of the first apheresis. Minimal graft (⩾2×10 6 /kg CD34 + cells) was collected in 85% of plerixafor treated patients, with a single apheresis in 45% of the patients. Discussion Plerixafor significantly increases B-CD34 + cell counts on the next morning making effective blood stem cell collection possible in the majority of the patients mobilizing poorly. It also influences other blood cell components but impact of this observation in regard to graft content and post-transplant course needs to be assessed in further studies.

There is no consensus on treatment strategies for elderly patients with mantle cell lymphoma (MCL). In this prospective phase II study we investigated whether the poor outcome could be improved, with reasonable toxicity, by prolonging the immunochemotherapy. Ten cycles of alternating cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)/cytarabine (AraC) with eight doses of rituximab (R) were given as induction. The potential synergism of intermediate-dose AraC and fludarabine was tested in cycles 6-8. Induction was followed by bimonthly rituximab maintenance for 2 years. The median age of the 60 included patients was 74 years, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) was intermediate or high risk in 98% of the patients. The overall response rate was 95% (complete response/complete response unconfirmed 87%). The response of 11 patients improved with cycles 6-8 (R-fludarabine-AraC). Progression-free survival was 70% and overall survival 72% at 4 years, respectively. Treatment related mortality was 2%. Severe infections were rare, with only one grade 4 infection. More dose reductions were needed during fludarabine-containing courses as compared to R-AraC. In 20 patients a transient grade 4 neutropenia without severe infections was recorded during maintenance. In conclusion, elderly patients with MCL can be treated relatively intensively with acceptable toxicity.

Mobilization and collection of stem cells is difficult in a proportion of patients intended for autologous stem cell transplantation (ASCT). We have evaluated mobilization kinetics of blood CD34(+) cells (B-CD34(+)) to form basis for algorithm to facilitate rational pre-emptive plerixafor use. Altogether 390 chemomobilized patients were included.Forty-three patients (11%) did not reach BCD34+count ≥10×10(6)/l. Mobilization kinetics differed according to the mobilization capacity observed. Among those who were very poor or inadequate mobilizers (peak BCD34(+)count ≤5×10(6)/l and 6–10×10(6)/l, respectively), BCD34+counts rarely rose after white blood cells (WBC) >5–10×10(9)/l, whereas in many standard mobilizers a later rise in CD34(+) counts could be observed. Four algorithms based on WBC and CD34(+) counts were constructed. According to this patient series, algorithm II (WBC >5×109/l and BCD34+≤10×10(6)/l) and algorithm IV (WBC >10×10(9)/l andB-CD34(+) ≤10×10(9)/l) were the most applicable. For algorithm II the sensitivity was 0.97 and specificity 1.00, respectively, to identify patients for plerixafor use provided that all patients with B-CD34+ maximum ≤10×10(6)/l would have needed plerixafor.This simple model needs a prospective validation.