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Introduction: In epidemiological studies, chronic inflammation or previous major infection have revealed to be associated with an increased risk of developing Hodgkin lymphoma (HL). The association of chronic inflammation with the disease outcome is poorly defined. In this retrospective study based on 92 consecutive HL patients, we explored the incidence of previous inflammatory processes or previous major infection in newly diagnosed HL patients and their association with treatment outcome. Methods: Medical history before lymphoma diagnosis including previous infection; dental inflammation; cutaneous problems; and inflammatory respiratory, gastrointestinal, or musculoskeletal diseases was collected from the patient records. Also clinical HL presentation, given treatments, and the disease outcome were recorded. Results: Forty-six percent of HL patients had some of the studied inflammatory factor at the time of diagnosis. Chronic dermatological diseases were present in 16.3% of patients, and they were associated with an improved relapse-free survival (p = 0.028). Dermatological issues were also associated with early-stage disease and the absence of B-symptoms. Other studied inflammatory factors were not associated with any clinical variables or treatment outcome. Conclusion: Our results demonstrated that among patients with HL, preexisting cutaneous symptoms are associated with a limited-stage disease, the absence of B-symptoms, and favorable prognosis.

Although treatment for diffuse large B-cell lymphoma (DLBCL) has taken some notable steps in the 2000s, there are still subgroups of patients suffering from high mortality and relapse rates. To further improve treatment outcomes, it is essential to discover new mechanisms of chemotherapy resistance and create new treatment approaches to overcome them. In the present study, we analyzed the expression of chemokines and their ligands in systemic and testicular DLBCL. From our biopsy sample set of 21 testicular and 28 systemic lymphomas, we were able to demonstrate chemokine profile differences and identify associations with clinical risk factors. High cytoplasmic CXCL13 expression had correlations with better treatment response, lower disease-related mortality, and limited stage. This study suggests that active CXCR5/CXCL13 signaling could overtake the CXCR4/CXCL12 axis, resulting in a better prognosis.

The purpose of this RNA sequencing study was to investigate the biological mechanism underlying how the transcription factors (TFs) Twist1 and Zeb1 influence the prognosis of mycosis fungoides (MF). We used laser-captured microdissection to dissect malignant T-cells obtained from 40 skin biopsies from 40 MF patients with stage I–IV disease. Immunohistochemistry (IHC) was used to determinate the protein expression levels of Twist1 and Zeb1. Based on RNA sequencing, principal component analysis (PCA), differential expression (DE) analysis, ingenuity pathway analysis (IPA), and hub gene analysis were performed between the high and low Twist1 IHC expression cases. The DNA from 28 samples was used to analyze the TWIST1 promoter methylation level. In the PCA, Twist1 IHC expression seemed to classify cases into different groups. The DE analysis yielded 321 significant genes. In the IPA, 228 significant upstream regulators and 177 significant master regulators/causal networks were identified. In the hub gene analysis, 28 hub genes were found. The methylation level of TWIST1 promoter regions did not correlate with Twist1 protein expression. Zeb1 protein expression did not show any major correlation with global RNA expression in the PCA. Many of the observed genes and pathways associated with high Twist1 expression are known to be involved in immunoregulation, lymphocyte differentiation, and aggressive tumor biology. In conclusion, Twist1 might be an important regulator in the disease progression of MF.

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.

Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREG

BackgroundVenous thromboembolic events (VTEs) remain a major cause of mortality and morbidity among lymphoma patients. Accurate risk-prediction models are lacking, however, especially in the high VTE risk subgroup of diffuse large B-cell lymphoma (DLBCL). The relationship between patient-, disease- and treatment-related factors and the VTE risk is yet incompletely defined in this disease entity. MethodsIn this retrospective study, we analyzed the risk factors for VTEs in DLBCL patients treated with first-line (1L) chemoimmunotherapy in Kuopio and Oulu University Hospitals (2010-2019). Univariate and multivariate analysis (Cox regression) of VTE risk factors was performed. Two novel VTE risk scores were developed and compared by ROC (receiver operating characteristic) analysis.ResultsVTE occurred in 17.2% (n=59) in the whole population, of which seven cases occurred during anticoagulant therapy. Statistically significant risk factors for VTE included age >65 years, ECOG (Eastern Cooperative Oncology Group) >1, thrombophilia, bulky disease, LDH > ULN (lactate dehydrogenase; upper limit of normal) and IPI (International Prognostic Index) 4-5. In a multivariate Cox regression model, previous history of thrombophilia and bulky disease were independent risk factors for VTE (p=0.000 and p=0.032, respectively). VTE at 1L had no significant effect on survival (overall survival, progression-free survival or disease-specific survival) at 2 or 5 years of follow-up. Two different VTE risk scores were tested in DLBCL patients treated in 1L. ROC analysis was used to assess the ability of the score to classify VTE risk. A risk score 2 (age >65/LDH > ULN/ ECOG>1/thrombophilia = 1 p., bulky disease 2 p.) received a higher ROC value (0.680) than risk score 1. In the “high risk” group (5 p., according to risk score 2), VTE risk was increased, at 35.3%. ConclusionsThrombophilia and bulky disease were independent risk factors for VTE in 1L-treated DLBCL patients. A novel VTE risk score was developed, to be further qualified.

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.

Bulky and residual tumor are considered to increase the risk of relapse in diffuse large B‐cell lymphoma (DLBCL) patients. Radiotherapy is conventionally used to reduce the risk, but the evidence is controversial. We performed a retrospective analysis to evaluate the significance of bulky and residual tumor treated with or without radiotherapy in DLBCL patients. We analyzed 312 DLBCL patients treated from 2010‐2017 in Oulu University Hospital. A bulky tumor was detected in 123 patients and 55 of these patients (44.3%) received consolidative radiation therapy (RT) to the bulky tumor. Residual tumor meeting the required criteria was found in 138 (39.3%) patients, and 65 (45.5%) of these patients received consolidative RT to the site of residual tumor. iPET‐CT scans were performed in 102 patients. In multivariate analyses, bulky was an independent risk factor in limited stage patients in progression free survival (HR 6.43 [95%CI 1.609‐25.710]; P = .008) not related to International prognostic index (HR 1.35 [95% CI 0.256‐7.124]; P = .724) or age (HR 1.62 [95% CI 0.468‐5.638]; P = .445). This was not seen in advanced stage patients or in patients with residual tumor. Radiotherapy to the bulky or residual tumor was not able to improve the long‐term PFS of patients. In this study, it appears that performing iPET is the most convincing method in improving evaluation and in finding patients with increased risk of relapse. Evidently, patients with negative iPET will not benefit from including RT in the treatment after metabolic complete response (CR), and patients with primary refractory disease are most likely in the group of positive iPET., Among patients with limited stage DLBCL, we found a statistically significant effect of bulky tumor to the outcome, but this was not seen in advanced stage disease or in patients with residual tumor. Radiotherapy to the bulky or residual tumor was not able to improve the long‐term PFS and evidently patients with negative iPET won't benefit from including RT in treatment after metabolic complete response. Patients with primary refractory disease are most likely in the group of positive iPET.

Peripheral T-cell lymphomas (PTCLs) constitute a heterogenous disease entity. Standard first line treatment is not validated due to rarity of these diseases. Upfront autologous stem cell transplant...

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.

Background Data are limited on the long-acting granulocyte-colony stimulating factors (G-CSFs) pegfilgrastim (PEG) and lipegfilgrastim (LIPEG) compared with filgrastim (FIL) regarding the mobilization efficiency of CD34+ cells, graft cellular composition, and engraftment. Study design and methods In this prospective nonrandomized study, 36 patients with non-Hodgkin lymphoma received FIL, 67 received PEG, and 16 patients received LIPEG as a cytokine after chemotherapy. We analyzed the mobilization and collection of CD34+ cells, cellular composition of blood grafts, and hematologic recovery after auto-SCT according to the type of G-CSF used. Results Patients in the LIPEG group had fewer apheresis sessions (1 vs. 2, p = 0.021 for FIL and p = 0.111 for PEG) as well as higher median blood CD34+ cell counts at the start of the first apheresis (LIPEG 74 × 106 /L vs. FIL 31 × 106 /L, p = 0.084 or PEG 27 × 106 /L, p = 0.021) and CD34+ yields of the first apheresis (FIL 5.1 × 106 /kg vs. FIL 2.3 × 106 /kg, p = 0.105 or PEG 1.8 × 106 /kg, p = 0.012). Also, the costs associated with G-CSF mobilization and apheresis were lower in the LIPEG group. The graft composition was comparable except for the higher infused CD34+ cell counts in the LIPEG group. The engraftment kinetics were significantly slower in the FIL group. Conclusion LIPEG appears to be more efficient compared with PEG after chemotherapy to mobilize CD34+ cells for auto-SCT demonstrated as fewer sessions of aphereses needed as well as 2.8-fold CD34+ cell yields on the first apheresis day. Early hematologic recovery was more rapid in the LIPEG group. Thus further studies on LIPEG in the mobilization setting are warranted.

Background: Autologous stem cell transplantation (auto-SCT) is a treatment option for patients with primary central nervous system lymphoma (PCNSL). Methods: In this prospective multicenter study, the effects of blood graft cellular content on hematologic recovery and outcome were analyzed in 17 PCNSL patients receiving auto-SCT upfront. Results: The infused viable CD34⁺ cell count > 1.7 × 10⁶/kg correlated with more rapid platelet engraftment (10 vs. 31 days, P = 0.027) and with early neutrophil recovery (day + 15) (5.4 vs. 1.6 × 10⁹/L, P = 0.047). A higher number of total collected CD34⁺ cells > 3.3 × 106/kg infused predicted worse 5-year progression-free survival (PFS) (33% vs. 100%, P = 0.028). In addition, CD3⁺CD8⁺ T cells > 78 × 10⁶/kg in the infused graft impacted negatively on the 5-year PFS (0% vs. 88%, P = 0.016). Conclusions: The cellular composition of infused graft seems to impact on the hematologic recovery and PFS post-transplant. Further studies are needed to verify the optimal autograft cellular content in PCNSL.

DLBCL is the most common type of non-Hodgkin lymphoma with a substantial group of patients suffering a poor prognosis. Therefore more specific markers are required for better understanding of disease biology and treatment. This study demonstrates that testis-specific antioxidant enzymes TXNDC2, TXNDC3, and TXNDC6 alongside oxidative stress marker 8-OHdG are expressed in both testicular and systemic DLBCL, and their presence or absence has correlations with clinical risk factors such as the number of extranodal effusion, the appearance of B-symptoms, and treatment response. Biopsy samples were collected from 28 systemic and 21 testicular male DLBCL patients. The samples were histostained with TXNDC2, TXNDC3, TXNDC6, and 8-OHdG, then graded by a hematopathologist blinded to clinical data. Immunoelectron microscopy was used as a second method to confirm the reliability of the acquired immunohistochemistry data. The absence of nuclear TXNDC2 expression in testicular DLBCL cells correlated with worse primary treatment response, cytoplasmic TXNDC3 expression in testicular and systemic DLBCL associated with lower frequency of B-symptoms, and TXNDC6 expression in cytoplasm in systemic DLBCL had a clinical significance with higher LD levels suggesting a role in the biological nature of these lymphomas. Overall, TXNDC3 cytoplasmic expression is correlated with a more positive outcome in both testicular and systemic DLBCL, while TXNDC6 cytoplasmic expression is associated with a negative outcome in systemic DLBCL.

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

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...

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 >30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 >30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

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.

Background: Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0–3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m2) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1–21. The primary endpoint was overall response assessed in the intention-to-treat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials.gov, number NCT02460276. Findings: Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17·8 months (IQR 14·7–20·9), 38 (76%, 95% CI 63–86) patients had an overall response, including 28 (56%, 42–69) patients who had a complete response and ten (20%, 11–33) who had a partial response. The most common grade 3–4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Interpretation: Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial. Funding: Janssen and Celgene.

Clinical practice points Testicular cancer with brain metastases is related to poor prognosis because the penetration of chemotherapeutic agents is decreased by the blood–brain barrier. The standard treatment of brain metastases—whole brain radiation therapy combined with chemotherapy—is related to a limited increase in survival and considerable deleterious cognitive effects. The blood–brain barrier can be transiently disrupted using hyperosmolar intra-arterial mannitol injection. When combined with intra-arterial chemotherapy, therapeutic intratumoral concentrations can be attained. In experienced centers, blood–brain barrier disruption therapy is relatively safe with a low incidence of catheter-related complications. Blood–brain barrier disruption therapy is a promising treatment modality for brain metastases as an alternative to whole brain radiation therapy.

Introduction Follicular lymphoma (FL) is the most common indolent lymphoma. Majority of the patients with FL have a good respond to first-line treatment. Relapses are common and many patients need to be re-treated (Izutsu K. J Clin Exp Hematop 2014). Treatment results of indolent non-Hodgkin lymphomas have improved vastly in last decades. This is resulting from the use of therapeutic antibodies such as rituximab (Friedberg JW. Haematologica 2008). With improved survival the risk of secondary malignancies may be higher. Some of the regimens used in the treatment of FL, especially alkylating agents, have been associated with the risk of secondary hematological malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Incidence of secondary MDS/AML peaks 4-6 years after the initial treatment. Secondary MDS/AML have poor prognosis. The incidence of secondary hematological malignancies and the impact of various treatment regimens among different lymphomas is still largely unknown (Friedberg JW. Haematologica 2008). Data of 1045 patients with FL was collected to find out the incidence of secondary hematological malignancies. We also wanted to know if the incidence is related to certain types of treatment or chemotherapy regimens. Methods This is a retrospective registry study. Clinical data was collected from six hospitals in Finland and two hospitals in Spain. We analyzed clinical data from hospital records of all patients with FL diagnosed between 1997 and 2016. Information such as age, stage, details of treatment, possible relapses, current status and details about secondary hematological malignancy were investigated. Results Median follow-up time was 5.6 years. Baseline characteristics and treatment-related data are presented in Table 1. Altogether 984 of all patients received treatment for lymphoma and from all patients 80.1% received rituximab during treatment. In all patients the 1-year PFS was 92.1% and the 5-year PFS 59.8%. The 5-year DSS was 91.6% and the 5-year OS was 84.1%. The incidence of secondary hematological malignancies is presented in Figure 1a. From all patients 15 (1.4%) developed secondary hematological malignancy. There were 5 cases of MDS, 4 AML, 1 acute promyelosytic leukemia, 1 acute lymphoblastic leukemia, 1 chronic lymphosytic leukemia, 1 chronic myelosytic leukemia, 1 large granular lymphosytic leukemia and 1 myeloma. The 5-year risk for secondary hematological malignancy was 1.3% and the approximated 10-year risk was 3.0%. The risk of secondary hematological malignancy was associated with the number of treatment lines (p=0.039), Figure 1b. There was no statistically significant difference between different first-line chemotherapy regimens. However, there was a trend presenting higher risk, when using alkylating regimens in the first line. With CHOP-like treatment the 5-year risk was 1.1% and the approximated 10-year risk was 3.6%. Conclusions This is a retrospective study from rituximab era. The prognosis of follicular lymphoma is good with the current treatment methods and the risk of secondary hematological malignancy seems to be low. Due to low incidence, it seems, that it is not necessary to avoid chemotherapy in the fear of secondary hematological malignancies. However, multiple lines of treatment are associated with higher risk for secondary hematological malignancies. Therefore, the use of regimens with long remission, like rituximab maintenance, would probably reduce the risk of secondary hematological malignancies. Disclosures No relevant conflicts of interest to declare.

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.

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.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.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.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.

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL) over the last 10-15 years, this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, with an overall response rate (ORR) of 68% as a single agent in the relapse situation. In vitro, ibrutinib has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. A phase I trial with this combination has been performed in 22 patients with untreated follicular lymphoma (Alliance 051103). In this trial, rash was the most common adverse event (AE), occuring in 73% of pts, with grade 3 rash in 32%. Methods: Eligibility criteria were: patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing was performed on frozen tumor cells from bone marrow at time of relapse, including the following genes: ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment. Given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in 12 months, June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. In total, 17/50 pts have discontinued treatment (n=9 due to PD, n=4 due to AE, n=2 withdrew consent, n=1 proceeded to alloSCT and n=1 due to other cause). Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). One event of laboratory tumor lysis syndrome was reported, and two events of atrial fibrillation, without reduction or discontinuation of ibrutinib. With a median follow up time of 7 months, 29 patients were evaluable for efficacy as of July 14, 2016. The ORR to date is 83% with 12 patients achieving CR (41%) and 12 PR (41%). Median duration of response and PFS has not been reached. One of three evaluable patients with progression on single agent ibrutinib responded with a PR, with ongoing response at 9 months. Of the 13 patients evaluable for MRD at 6 months, 7/12 patients have achieved molecular remission in blood and 7/13 in bone marrow. Conclusions: So far, the combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in patients with R/R MCL, associated with molecular remission. Cutaneous toxicity was manageable, in contrast to what has been reported with a similar combination in untreated patients with follicular lymphoma. Up-dated results will be presented at the annual meeting, including data on mutational profile as biomarker for efficacy. This trial was registered at http://clinicaltrials.gov as NCT02460276. Disclosures Jerkeman: Gilead: Research Funding; Mundipharma: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Niemann:Abbvie: Research Funding; Roche: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.

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.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.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 neutrophils0.5 × 10(9) /L and 14 days for platelets20 × 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).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.

Introduction Early immune recovery after autologous transplantation has in various studies been reported to be of clinical significance in non-Hodgkin lymphoma (NHL) patients. Especially the recovering of lymphocytes 15 days post-transplant (ALC-15) has previously been reported to predict outcome and disease-free survival. However, these results have not been detected in all studies. There is currently limited data available on the factors affecting the course and speed of the early immune recovery. Further, most of these results are somewhat controversial and usually from retrospective studies. Patients and methods Seventy-two patients with NHL were included into this prospective study. There were 35 males and 37 females with a median age of 62 years. The most common histology was diffuse large B-cell lymphoma (DLBCL) (44%) and 79% of the patients were in first complete or partial remission at the time of the auto-SCT. Patients with either the histology of DLBCL, T cell lymphoma or one patient with Burkitts (transformation from follicular lymphoma) were considered having aggressive lymphoma histology. All patients were mobilized with chemotherapy plus G-CSF. In addition, plerixafor was given for 24 poorly mobilizing patients. Cryopreserved graft samples from each collection were analyzed with flow cytometry for CD34+ cells, T and B lymphocytes and NK cells. Complete blood counts were evaluated at +15 days and 1 month post-transplant and a flow cytometry of lymphocyte subsets (T, NK, B) was performed one month after the graft infusion. Associations of various factors (age, gender, histology, disease status, use of plerixafor or rituximab, graft CD34+ counts and lymphocyte subsets) to various cut-off levels of ALC15, ALC30 and lymphocyte subsets at 1 month post-transplant were evaluated. Uni- and multivariate as well as survival analysis was performed. Results In multivariate analysis, ALC-15³ 0.5 x 109/L was found to associate with the higher number of CD34+ (p = 0.015) and primitive CD34+ CD133- CD38- cells (p = 0.005) in the infused grafts as well as the use of plerixafor (p = 0.004). Diagnosis of mantle cell or follicular lymphoma was associated with decreased probability of ALC-15³ 0.5 x 109/L. In the whole patient cohort the mean PFS of patients with of ALC-15³ 0.5 x 109/L was 897 days compared to. 606 days in patients with ALC-15 < 0.5 x 109/L (p = 0.252) and the mean OS was 957 days vs. 618 days (p = 0.021), respectively. In patients with aggressive histology, the mean PFS was 915 days in patients with ALC-15 ³ 0.5 x 109/L vs. 404 days in patients with ALC-15 < 0.5 x 109/L (p = 0.030), the mean OS was 987 days vs. 427 days (p = 0.002), respectively Conclusions Our prospective results verify the importance of early immune recovery in respect to outcome in transplanted NHL patients. Therefore the evaluation of the early immune recovery seems to be of clinical significance and also an easy and affordable method for individual disease-related risk analysis. Patients with aggressive histology and slow immune recovery may need additional post-transplant treatment to prevent relapse or disease progression. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Valtola: Sanofi: Honoraria. Varmavuo:Roche: Consultancy; Celgene: Consultancy. Keskinen:TEVA: Consultancy. Jantunen:Sanofi: Honoraria; Genzyme: Honoraria; Genzyme: Consultancy.

Although oxidative stress plays an important role in the biology of solid malignant tumors, little is known about oxidative stress in hematological malignancies. In this study, we evaluated the immunohistochemical expression and clinical correlations of oxidative stress markers and several essential antioxidant enzymes in B-cell lymphomas. Paraffin-embedded diagnostic tissue samples from 18 diffuse large B-cell lymphomas (DLBCL), 18 follicular lymphomas (FL), 19 Hodgkin lymphomas (HL), 7 chronic lymphocytic leukemias (CLL), 7 mantle cell lymphomas (MCL) and 7 mucosa-associated lymphoid tissue (MALT) lymphomas, together with samples from 6 reactive lymph nodes were stained for oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and antioxidant enzymes manganese superoxide dismutase (MnSOD), thioredoxin (Trx) and γ-glutamyl cysteine synthetase (γ-GCS). There was increased 8-OHdG reactivity in DLBCL compared to more indolent lymphomas and reactive lymph nodes. Positivity for Trx was most intense in HL. In DLBCL, positivity for 8-OHdG and nitrotyrosine associated with shorter survival (p = 0.032 and p = 0.026, respectively). This study showed increasing expression of oxidative stress markers and antioxidant enzymes in a series of lymph node samples evolving from reactive lymph nodes to indolent and aggressive lymphomas. These markers seem to have strong prognostic value, but this has to be verified in larger studies.