High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary diffuse large B-cell CNS lymphoma (MARTA): a single-arm, phase 2 trial.

BACKGROUND: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL. METHODS: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m2 (day 1), intravenous cytarabine 2 g/m2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete. FINDINGS: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications. INTERPRETATION: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials. FUNDING: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg.

Intrathecal IgM synthesis as a diagnostic marker in patients with suspected CNS lymphoma.

For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the diagnostic potential of intrathecal IgM synthesis in primary and secondary CNSL (PCNSL and SCNSL). In this retrospective study, patients with a biopsy-proven diagnosis of PCNSL or SCNSL were compared with patients with other neurological diseases in whom CNSL was initially the primary radiological differential diagnosis based on MRI. Sensitivity and specificity of intrathecal IgM synthesis were calculated using receiver operating characteristic curves. Seventy patients with CNSL were included (49 PCNSL and 21 SCNSL) and compared to 70 control patients. The sensitivity and specificity for the diagnosis of CNSL were 49% and 87%, respectively, for the entire patient population and 66% and 91% after selection for cases with tumor access to the CSF system and isolated intrathecal IgM synthesis. In cases with MRI-based radiological suspicion of CNSL, intrathecal IgM synthesis has good specificity but limited sensitivity. Because of its low-threshold availability, analysis of intrathecal IgM synthesis has the potential to lead to higher diagnostic accuracy, especially in resource-limited settings, and deserves further study.

Anti-CD20-atezolizumab-polatuzumab vedotin in relapsed/refractory follicular and diffuse large B-cell lymphoma.

PURPOSE: New therapies are needed for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase 1b, open-label trial evaluated two anti-CD20-based triplet combinations. METHODS: Patients with R/R follicular lymphoma (FL; n = 13) were treated with obinutuzumab, atezolizumab, and polatuzumab vedotin (G-atezo-pola; 1.4 mg/kg/1.8 mg/kg) and patients with R/R diffuse large B-cell lymphoma (DLBCL; n = 23) received rituximab (R)-atezo-pola. The primary efficacy endpoint was complete response (CR) at end of induction (EOI) by PET-CT (investigator assessed; modified Lugano 2014 criteria). Safety endpoints were also assessed. RESULTS: 13 FL patients were treated and evaluable for safety; 2/23 DLBCL patients did not receive treatment and were not included in the safety population. Median observation time was 23.3 and 5.7 months in the FL and DLBCL cohorts, respectively. At EOI, CR rates in FL patients treated with G-atezo-pola at pola doses of 1.4 mg/kg (N = 3) and 1.8 mg/kg (N = 7) were 33% and 14%, respectively. In DLBCL patients receiving R-atezo-pola, the CR rate at EOI was 13%. In the FL cohort, 62% of patients experienced a grade 3-5 adverse event (AE; including two deaths) and 31% developed a serious AE (SAE). In DLBCL patients, R-atezo-pola was associated with a lower incidence of grade 3-5 AEs (24%; one death) and SAEs (10%). In both cohorts, the most common grade 3-5 AEs were hematologic toxicities. CONCLUSION: Based on these safety issues, considered as related specifically to G-atezo-pola, and limited efficacy, no further development of either combination is planned. TRIAL REGISTRATION: NCT02729896; Date of registration: April 6, 2016.

Landscape of 4D Cell Interaction in Hodgkin and Non-Hodgkin Lymphomas.

Profound knowledge exists about the clinical, morphologic, genomic, and transcriptomic characteristics of most lymphoma entities. However, information is currently lacking on the dynamic behavior of malignant lymphomas. This pilot study aimed to gain insight into the motility of malignant lymphomas and bystander cells in 20 human lymph nodes. Generally, B cells were faster under reactive conditions compared with B cells in malignant lymphomas. In contrast, PD1-positive T cells did not show systematic differences in velocity between reactive and neoplastic conditions in general. However, lymphomas could be divided into two groups: one with fast PD1-positive T cells (e.g., Hodgkin lymphoma and mantle cell lymphoma; means 8.4 and 7.8 µm/min) and another with slower PD1-positive T cells (e.g., mediastinal grey zone lymphoma; mean 3.5 µm/min). Although the number of contacts between lymphoma cells and PD1-positive T cells was similar in different lymphoma types, important differences were observed in the duration of these contacts. Among the lymphomas with fast PD1-positive T cells, contacts were particularly short in mantle cell lymphoma (mean 54 s), whereas nodular lymphocyte-predominant Hodgkin lymphoma presented prolonged contact times (mean 6.1 min). Short contact times in mantle cell lymphoma were associated with the largest spatial displacement of PD1-positive cells (mean 12.3 µm). Although PD1-positive T cells in nodular lymphocyte-predominant Hodgkin lymphoma were fast, they remained in close contact with the lymphoma cells, in line with a dynamic immunological synapse. This pilot study shows for the first time systematic differences in the dynamic behavior of lymphoma and bystander cells between different lymphoma types.

Fluid overload is associated with increased 90-day mortality in AML patients undergoing induction chemotherapy.

Treatment-related complications contribute substantially to morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Although AML patients are susceptible to fluid overload (FO) (e.g., in the context of chemotherapy protocols, during sepsis treatment or to prevent tumor lysis syndrome), little attention has been paid to its role in AML patients undergoing induction chemotherapy. AML patients receiving induction chemotherapy between 2014 and 2019 were included in this study. FO was defined as ≥5% weight gain on day 7 of induction chemotherapy compared to baseline weight determined on the day of admission. We found FO in 23 (12%) of 187 AML patients undergoing induction chemotherapy. Application of >100 ml crystalloid fluids/kg body weight until day 7 of induction chemotherapy was identified as an independent risk factor for FO. AML patients with FO suffered from a significantly increased 90-day mortality rate and FO was demonstrated as an independent risk factor for 90-day mortality. Our data suggests an individualized, weight-adjusted calculation of crystalloid fluids in order to prevent FO-related morbidity and mortality in AML patients during induction chemotherapy. Prospective trials are required to determine the adequate fluid management in this patient population.

Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas.

The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.

Acute kidney injury adversely affects the clinical course of acute myeloid leukemia patients undergoing induction chemotherapy.

Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5, p = 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%, p < 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI.

Use of carbapenems and glycopeptides increases risk for Clostridioides difficile infections in acute myeloid leukemia patients undergoing intensive induction chemotherapy.

Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.

Impact of Clostridioides difficile infection on the outcome of patients receiving a hematopoietic stem cell transplantation.

OBJECTIVES: Clostridioides difficile infections (CDI) are common in autologous (auto-HSCT) or allogenic hematopoietic stem cell transplant (allo-HSCT) recipients. However, the impact of CDI on patient outcomes is controversial. We conducted this study to examine the impact of CDI on patient outcomes. METHODS: We performed a retrospective single-center study, including 191 lymphoma patients receiving an auto-HSCT and 276 acute myeloid leukemia (AML) patients receiving an allo-HSCT. The primary endpoint was overall survival (OS). Secondary endpoints were causes of death and, for the allo-HSCT cohort, GvHD- and relapse-free survival (GRFS). RESULTS: The prevalence of CDI was 17.6% in the AML allo-HSCT and 7.3% in the lymphoma auto-HSCT cohort. A higher prevalence of bloodstream infections, but no differences concerning OS or cause of death were found for patients with CDI in the auto-HSCT cohort. [AU] In the allo-HSCT cohort, OS and GRFS were similar between CDI and non-CDI patients. However, the leading cause of death was relapse among non-CDI patients, but it was infectious diseases in the CDI group with fewer deaths due to relapse. CONCLUSIONS: CDI was not associated with worse survival in patients receiving a hematopoietic stem cell transplantation, and there were even fewer relapse-related deaths in the AML allo-HSCT cohort.

Obesity is associated with an impaired survival in lymphoma patients undergoing autologous stem cell transplantation.

Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a potentially curative treatment option for relapsed and refractory lymphomas. Obesity displays an emerging epidemic risk factor for global mortality and is associated with an increased mortality in cancer patients. To date, the impact of obesity on the outcome of lymphoma patients undergoing auto-HSCT is understudied. We conducted a retrospective single-center study assessing 119 lymphoma patients who underwent auto-HSCT. Overall survival (OS) served as the primary endpoint whereas progression free survival (PFS), cumulative incidence of non-relapse related mortality (NRM) and cumulative incidence of relapse were analyzed as secondary endpoints. Obese patients (Body mass index, BMI≥30) had significantly lower OS (45.3% vs. 77.9%; p = 0.005) and PFS (29.8% vs. 67.2%; p<0.001) compared to non-obese patients at 48 months post-transplantation. The cumulative incidence of NRM displayed no significant differences while the cumulative incidence of relapse was significantly increased in patients with BMI≥30 (66.2% vs. 21.5%; p<0.001). Patients with a BMI<25 and overweight patients (BMI 25-30; 76.1% vs. 80.9%; p = 0.585), showed no significant difference in OS, whereas patients with BMI≥30 exhibited significant lower OS when compared to either of both groups (76.1% vs. 45.3%; p = .0.021 and 80.9% vs. 45.3%; p = 0.010). Furthermore, in a multivariate analysis, obesity was identified as an independent risk factor for death (Hazard ratio 2.231; 95% CI 1.024 to 4.860; p = 0.043). Further studies are needed to evaluate the reasons for the higher relapse rate causing higher mortality in obese patients.

miRNA-26b downregulation in peripheral blood mononuclear cells of patients with hepatitis C associated lymphomas is restored by successful interferon-free antiviral therapy.

BACKGROUND: Patients with chronic HCV infection are at increased risk of developing B-cell non-Hodgkin lymphoma (B-NHL). Regression of HCV-associated B-NHL (HCV-NHL) can be achieved through HCV eradication using interferon (IFN). However, only about two-thirds of patients with sustained virological response (SVR) also had a consecutive lymphoma response. miRNA-26b is associated with HCV-NHL response to antiviral therapy. Recent data suggest that IFN-free direct-acting antiviral (DAA) regimens also have anti-lymphoma activity in this patient population. METHODS: We report four patients with HCV-NHL who were treated with different IFN-free DAA regimens as oncological monotherapy in our centre between 2015 and 2016. We analysed the virological and lymphoproliferative disease response. Moreover, we analysed miRNA-26b expression in peripheral blood mononuclear cells at different time points during antiviral therapy for all included patients as well as for a total of 10 controls with (n=5) and without (n=5) chronic HCV infection. RESULTS: All patients had marginal zone lymphoma subtype and received different DAA regimens for 12-24 weeks. All four patients achieved SVR, but only three patients also had lymphoma response (one complete response, two partial responses). One patient showed progression to a high-grade lymphoma subtype after SVR. miRNA-26b expression was generally decreased in patients with HCV-NHL. Moreover, miRNA-26b expression was restored in those HCV-NHL patients with lymphoma response after 6 months (P=0.009). CONCLUSIONS: We have demonstrated that IFN-free DAA treatment of HCV can improve or even cure NHL. miRNA-26b-levels could be a potentially useful biomarker to predict lymphoma response in HCV-NHL patients.

The Impact of Early Corticosteroid Pretreatment Before Initiation of Chemotherapy in Patients With Primary Central Nervous System Lymphoma.

BACKGROUND: The optimal timing of corticosteroid (CS) treatment in patients with primary central nervous system (CNS) lymphoma (PCNSL) remains controversial. While poor clinical presentation may justify early treatment with CS, this may ultimately result in reduced concentrations of chemotherapeutic agents via perturbations in the permeability of the blood-brain barrier. OBJECTIVE: To investigate whether early CS exposure is associated with beneficial outcomes and/or reduced occurrence of adverse events as opposed to delayed/concomitant administration. METHODS: Herein we performed a retrospective observational analysis using patients that were prospectively entered into a database. All patients whom were admitted to the University Hospital between 2009 and 2015 with newly diagnosed PCNSL were included within our study. RESULTS: Our cohort included 50 consecutive patients diagnosed with PCNSL; of these, in 30 patients CS administration was initiated prior to chemotherapy (early), whilst in the remaining 20 patients CS administration was initiated concomitantly with their chemotherapeutic regimen (concomitant). Within the early vs concomitant CS administration groups, no significant differences were observed with regard to progression-free survival (PFS) (P = .81), overall survival (OS) (P = .75), or remission (P = .68; odds ratio 0.76 and confidence interval [95%] 0.22-2.71). Critically, the timing of CS initiation was not associated with either PFS (P = .81) or PFS (P = .75). CONCLUSION: Early CS administration was not associated with a deterioration in response to chemotherapy, PFS, or OS. As such, administration of CS prior to initiation of chemotherapy is both reasonable and safe for patients with newly diagnosed PCNSL.

New MR perfusion features in primary central nervous system lymphomas: pattern and prognostic impact.

PURPOSE: Some MR perfusion features predict overall survival (OS) and progression-free survival (PFS) in glioblastomas. Prognostic value of MR perfusion in primary CNS lymphomas (PCNSL) remains unexplored being the aim of this investigation. METHODS: We retrospectively analyzed 3Tesla dynamic susceptibility contrast MR perfusion in 37 pre-surgical PCNSL for normalized regional cerebral blood volume rCBVmean and rCBVmax and for a PCNSL-typical shoulder-like increase of the time-signal intensity curve ("TSIC-shoulder"), indicating moderate vessel permeability. These MR perfusion features, tumor and edema size, number of lesions and patient characteristics were correlated with OS and PFS. RESULTS: Only patient's age was prognostic for OS (p = 0.0037) and PFS (p = 0.0088). 23 PCNSL had the TSIC-shoulder, a middle-sized diameter (39.5 ± 10.8 mm), volume (15.7 ± 11.3 ml), peritumoral edema (23 ± 8.7 mm) and moderately increased rCBVmean and rCBVmax (1.7 ± 0.5; 3.9 ± 1.2). Seven PCSNL with the TSIC-shoulder presented a sun-like pattern ("rCBV-sun") with a rim of marginally high rCBV. These unifocal PCNSL were larger (43 ± 11.2 mm; 25.62 ± 19.2 ml), with more peritumoral edema (32.8 ± 7.6 mm) and lower CBVmean (0.8 ± 0.3) and rCBVmax (2.2 ± 0.7), compared to the remaining six multifocal PCNSL without the TSIC-shoulder (26.3 ± 8.3 mm; 4.7 ± 4 ml; 16.3 ± 6.4 mm; 2.4 ± 1.6; 4.4 ± 2.3). CONCLUSIONS: Only patient age was predictive for OS and PFS of PCNSL; MR perfusion parameters and features were not. Most PCNSL revealed the TSIC-shoulder, moderate size, peritumoral edema and rCBV increase. However, larger, solitary PCNSL additionally had a rCBV-sun pattern and more edema, maybe due to a centrifugal vessel proliferation, whereas smaller, multifocal PCNSL contain apparently more concentrated and less permeable blood vessels represented by higher rCBV, no TSIC-shoulder and less edema.

Clinical Impact of Colonization with Multidrug-Resistant Organisms on Outcome after Autologous Stem Cell Transplantation: A Retrospective Single-Center Study.

A significant increase in infections caused by multidrug-resistant organisms (MDRO) has been observed in recent years, resulting in an increase of mortality in all fields of health care. Hematological patients are particularly affected by MDRO infections because of disease- and therapy-related immunosuppression. To determine the impact of colonization with MDRO on overall survival, we retrospectively analyzed data from patients undergoing autologous hematopoietic stem cell transplantation at our institution. In total, 184 patients were identified, mainly patients with lymphomas (n = 98, 53.3%), multiple myelomas (n = 80, 43.5%), germ cell cancers (n = 5, 2.7%), or acute myeloid leukemia (n = 1, .5%). Forty patients (21.7%) tested positive for MDRO colonization. At a median follow-up time of 21.5 months, the main causes of death were infection in colonized and disease progression in noncolonized patients. Nonrelapse mortality (NRM) was higher in patients who tested positive for MDRO than in the noncolonized group (25.4% versus 3%, P < .001). Interestingly, NRM in neutropenia after autologous transplantation did not differ between colonized and noncolonized patients. Colonized patients, however, had inferior overall survival after autologous transplantation in univariate (61.7% versus 73.3%, P = .005) as well as in multivariate analysis (hazard ratio, 2.463; 95% confidence interval, 1.311 to 4.626; P = .005). We conclude that the period after discharge from hospital after autologous transplantation seems critical and patients with MDRO colonization should be observed closely for infections in the post-transplantation period in outpatient care.

HIV-Associated Malignant Lymphoma.

Acquired immune deficiency syndrome (AIDS)-related lymphomas (ARL) still represent a relevant field of clinical research. For most histological subtypes of ARL, no optimal initial therapy has been clearly defined so far. Rituximab plus chemotherapy is feasible and effective and should be offered to all patients with CD20-positive ARL regardless of their CD4 cell count. Combination antiretroviral therapy (cART) should be given concomitantly with chemotherapy, bearing in mind potential drug-drug interactions. Appropriate treatment of ARL is determined by a number of factors such as lymphoma stage, performance status, comorbidities, histological subtype, and immunosuppression. Treatment should principally be the same as in human immunodeficiency virus (HIV)-negative lymphoma patients. In HIV-related Hodgkin's lymphoma, high cure rates have been achieved with stage-adapted treatment approaches, albeit with worse outcomes compared to immunocompetent patients.

A strong host response and lack of MYC expression are characteristic for diffuse large B cell lymphoma transformed from nodular lymphocyte predominant Hodgkin lymphoma.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.

Diffuse large B cell lymphoma derived from nodular lymphocyte predominant Hodgkin lymphoma presents with variable histopathology.

BACKGROUND: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) usually presents in middle aged men and shows an indolent clinical behavior. However, up to 30% of the patients present a secondary transformation into aggressive diffuse large B cell lymphoma (DLBCL). The aim of the present study was to characterize morphology and immunophenotype of this kind of DLBCL in detail and compare it with conventional DLBCL. METHODS: Morphology and immunophenotype of 33 cases of NLPHL with simultaneous or sequential transformation into DLBCL were investigated. These cases were compared with 41 de novo DLBCL in Finnish men. RESULTS: The majority of cases exhibited different immunophenotypes in the NLPHL and the DLBCL components. The immunophenotype of the DLBCL secondary to NLPHL was heterogeneous. However, BCL6, EMA, CD75 and J-chain were usually expressed in both components (≥73% positive). Overall, the NLPHL component was more frequently positive for EMA, CD75 and J-chain than the DLBCL component. In contrast, B cell markers, CD10 and BCL2, were more frequently expressed and were expressed at higher levels in the DLBCL component than in the NLPHL component. In the independent series of de novo DLBCL 4 cases could be identified with a growth pattern and immunophenotype that suggested that they had arisen secondarily from NLPHL. CONCLUSIONS: The morphology and immunophenotype of DLBCL arisen from NLPHL is heterogeneous. Further characterization of the particular molecular features of this subgroup is warranted to be able to better identify these cases among conventional DLBCL.

Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial.

PURPOSE: The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. PATIENTS AND METHODS: All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives. RESULTS: Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity. CONCLUSION: In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.

DNA methylation of tumor suppressor genes in clinical remission predicts the relapse risk in acute myeloid leukemia.

Epigenetic changes play an important role in leukemia pathogenesis. DNA methylation is among the most common alterations in leukemia. The potential role of DNA methylation as a biomarker in leukemia is unknown. In addition, the lack of molecular markers precludes minimal residual disease (MRD) estimation for most patients with hematologic malignancies. We analyzed the potential of aberrant DNA promoter methylation as a biomarker for MRD in acute leukemias. Quantitative real-time PCR methods with bisulfite-modified DNA were established to quantify MRD based on estrogen receptor alpha (ERalpha) and/or p15(INK4B) methylation. Methylation analyses were done in >370 DNA specimens from 180 acute leukemia patients and controls. Methylation of ERalpha and/or p15(INK4B) occurred frequently and specifically in acute leukemia but not in healthy controls or in nonmalignant hematologic diseases. Aberrant DNA methylation was detectable in >20% of leukemia patients during clinical remission. In pediatric acute lymphoblastic leukemia, methylation levels during clinical remission correlated closely with T-cell receptor/immunoglobulin MRD levels (r = +0.7, P < 0.01) and were associated with subsequent relapse. In acute myelogenous leukemia patients in clinical remission, increased methylation levels were associated with a high relapse risk and significantly reduced relapse-free survival (P = 0.003). Many patients with acute leukemia in clinical remission harbor increased levels of aberrant DNA methylation. Analysis of methylation MRD might be used as a novel biomarker for leukemia patients' relapse risk.