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Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively. 62 of 155 evaluable patients (40%) showed concurrent systemic progression/ relapse. 82% of all CNS events occurred within two years after study inclusion or randomization. 87% of patients showed extranodal involvement outside the CNS. Patients generally had poor outcomes with a median overall survival (OS) of 3.4 months (95% CI 2.9–4.2) and a 2-year OS of 15% (10–22%). Outcomes did not differ depending on the site or time point of CNS events. Patients with isolated CNS events demonstrated significantly better OS (p= 0.023). Twenty-five patients were consolidated with autologous or allogeneic stem cell transplantation and achieved a 3-year OS of 36% (20–66%). This large study including more than 5000 DLBCL patients highlights the unmet medical need to improve the outcome of DLBCL patients suffering from CNS relapse.

•In young low-risk patients with DLBCL (aaIPI 0-1), CNS relapse remains a rare event regardless of frontline therapy and prophylaxis.•In young high-risk patients with DLBCL (aaIPI 2-3), intensified therapy including agents crossing the BBB leads to low rates of CNS relapse.

Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma.

The addition of rituximab to chemotherapy has substantially improved outcomes for patients with B-cell malignancies. The mechanisms of action of rituximab include activation of natural killer cells. Killer-cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with HLA. We evaluated the clinical impact of KIR–HLA genotypes on rituximab-containing therapy.

R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial.

PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61–80 in an open-label, randomized phase 3 trial. Alemtuzumab was given on day 1, to a total of 360?mg in 21 patients, or 120?mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade =3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% [15%–39%], 28% [15%–40%], and 37% ([23%–50%] for A-CHOP, and 24% [12%–35%], 29% [17%–41%], and 56% [44%–69%] for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HREFS: 0.7 ([95% CI: 0.5–1.1]; p?=?0.094), HRPFS: 0.8 ([95% CI: 0.5–1.2]; p?=?0.271), HROS: 1.4 ([95% CI: 0.9–2.4]; p?=?0.154). The IPI score was validated, and male sex (HREFS2.5) and bulky disease (HREFS2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.

Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2–2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2–2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3–2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYCrearrangements and double expresser status (DE). LAMIShighand simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.

Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.

Introduction:Patients (pts) with relapsed or refractory ( R/ R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo consolidative high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Rituximab, gemcitabine and oxaliplatin (R-GemOx) is a common immuno-chemotherapy regimen used in this setting. The objective of the open-label, phase 3, NIVEAU study (NCT03366272) was to evaluate the efficacy and safety of Nivolumab added to R-GemOx in pts with R/ RLBCL after 1 prior line of therapy not eligible for HDCT/HSCT owing to age and/or comorbidities.

Background

Introduction:The original IPI remains valid to identify prognostic groups of DLBCL patients (pts) treated with R-CHOP (Ruppert et al. Blood 2020) and has been used to define eligibility for more than 20 studies randomizing pts between R-CHOP and R-CHOP + X, none of which except the Polarix study met its endpoint. One reason why some studies failed was the inclusion of IPI 2/3 pts equalizing the difference between standard and experimental arm although significant survival differences in pts with higher IPI were detected. Following the WHO-HAEM5 classification, determination of BCL2and MYCrearrangements is mandatory to diagnose DLBCL, NOS and HGBL- MYC/ BCL2. As surrogate markers, we included immunohistochemistry (IHC) for MYC and BCL2 into the IPI model hoping for a wider spread of survival curves and better selection of pts suitable for future clinical trials.

Salvage chemotherapy induces disease remissions in patients with relapsed or refractory (r/r) T-cell lymphomas, but fails to provide lasting tumor control. We analyzed the outcome after peripheral blood stem and bone marrow transplantation (PBSCT, n= 80; BMT, n= 4) from matched related (MRD, n= 22) or matched and unmatched unrelated donors (MUD and MMD, n= 53 and n= 9, respectively) following conditioning with fludarabine, busulfan, and cyclophosphamide (FBC) for 84 consecutive patients with r/r T-cell malignancies. At start of conditioning LDH was elevated in 50% of cases, and residual tumor (PD, SD, PR) was detectable in 84% of patients. In total, 38% (95% CI 33–44) of the patients were alive and disease-free after a median observation time of 14.5 (range 1.8 to 114) months. Univariate and multivariate analyses identified low ECOG status, as well as occurrence of acute GvHD as favorable factors for outcome. Lymphoma-directed conditioning with fludarabin, busulfan and cyclophosphamid (FBC-12), and allogeneic stem cell transplantation resulted in long-term survival for a proportion of patients with r/r peripheral T-cell lymphoma, including those with PR and SD only after salvage therapy.

Patients with acute myeloid leukemia (AML) and a FLT3internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P< .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.govas #NCT01477606.

Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.

Background

In order to better understand the water vapor (WV) intrusion into the tropical stratosphere, a mesoscale simulation of the tropical tropopause layer using the BRAMS (Brazilian version of Regional Atmospheric Modeling System (RAMS)) model is evaluated for a wet season. This simulation with a horizontal grid point resolution of 20 km × 20 km cannot resolve the stratospheric overshooting convection (SOC). Its ability to reproduce other key parameters playing a role in the stratospheric WV abundance is investigated using the balloon-borne TRO-Pico campaign measurements, the upper-air soundings over Brazil, and the satellite observations by Aura Microwave Limb Sounder, Microwave Humidity Sounder, and Geostationary Operational Environmental Satellite 12. The BRAMS exhibits a good ability in simulating temperature, cold-point, WV variability around the tropopause. However, the simulation is typically observed to be warmer by ~2.0°C and wetter by ~0.4 ppmv at the hygropause, which can be partly affiliated with the grid boundary nudging of the model by European Centre for Medium-Range Weather Forecasts operational analyses. The modeled cloud tops show a good correlation (maximum cross-correlation of ~0.7) with Geostationary Operational Environmental Satellite 12. Furthermore, the overshooting cells detected by Microwave Humidity Sounder are observed at the locations, where 75% of the modeled cloud tops are higher than 11 km. Finally, the modeled inertia-gravity wave periodicity and wavelength are comparable with those deduced from the radio sounding measurements during TRO-Pico campaign. The good behavior of BRAMS confirms the SOC contribution in the WV abundance, and variability is of lesser importance than the large-scale processes. This simulation can be used as a reference run for upscaling the impact of SOC at a continental scale for future studies. The model depicts the typical variability of temperature and water vapor in the tropical tropopause layer, and the gravity wave propertiesHigh modeled cloud tops are observed at the overshooting locations detected by MHS, showing similar variability as GOES-12 measurementsImpact of stratospheric sudden warming occurring in the Arctic is detected in the tropical tropopause layer over South America

The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD–positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio ≥ 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242.

To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study.

To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFIoccurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P= .842) and overall survival (86% vs 88%; P= .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFIpatients compared with 2586 non-ECFIpatients (4.2% vs 2.8%; P= .038), whereas this was not observed with rituximab (1.6% in 83 ECFIvs 3.4% in 1252 non-ECFIpatients; P= .682). In 88 ECFIpatients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P= .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFIpatients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study.

The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.

The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P= .14) as a result of a higher early death rate (26% vs 14%; P= .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P= .95 and P= .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P= .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.govas #NCT00151255.

To determine the effect of gender on outcome, the male hazard ratio for progression-free survival (HRPFS-male) was determined in patients with diffuse large B-cell lymphoma (DLBCL). In young patients (MapThera International Trial study), HRPFS-male was 1.3 (P = .092) without and 1.1 (P = .660) with rituximab. In elderly patients (RICOVER-60 study), HRPFS-male was 1.1 (P = .348) with CHOP but increased to 1.6 (P = .004) with R-CHOP. The similar improvements of outcome in young patients were associated with similar rituximab clearances in young males and females (9.89 vs 10.38 mL/h; P = .238), whereas the greater benefit for elderly females was associated with a slower rituximab clearance (8.47 vs 10.59 mL/h; P = .005) and hence higher serum levels and longer exposure times, attributable to an age-dependent (P = .004) decrease of rituximab clearance in females but not males. Compared with elderly females, all other subgroups had significantly faster rituximab clearances and hence appear to be suboptimally dosed when rituximab is given at 375 mg/m2. Although early results of pharmacokinetic-based prospective trials designed to exploit the full therapeutic potential of rituximab suggest that increased doses and/or prolonged exposure times can improve the outcome of elderly males with DLBCL, further studies are warranted that address the optimization of rituximab dose and schedule in all subgroups of DLBCL patients.

To determine the effect of gender on outcome, the male hazard ratio for progression-free survival (HRPFS-male) was determined in patients with diffuse large B-cell lymphoma (DLBCL). In young patients (MapThera International Trial study), HRPFS-malewas 1.3 (P= .092) without and 1.1 (P= .660) with rituximab. In elderly patients (RICOVER-60 study), HRPFS-malewas 1.1 (P= .348) with CHOP but increased to 1.6 (P= .004) with R-CHOP. The similar improvements of outcome in young patients were associated with similar rituximab clearances in young males and females (9.89 vs 10.38 mL/h; P= .238), whereas the greater benefit for elderly females was associated with a slower rituximab clearance (8.47 vs 10.59 mL/h; P= .005) and hence higher serum levels and longer exposure times, attributable to an age-dependent (P= .004) decrease of rituximab clearance in females but not males. Compared with elderly females, all other subgroups had significantly faster rituximab clearances and hence appear to be suboptimally dosed when rituximab is given at 375 mg/m2. Although early results of pharmacokinetic-based prospective trials designed to exploit the full therapeutic potential of rituximab suggest that increased doses and/or prolonged exposure times can improve the outcome of elderly males with DLBCL, further studies are warranted that address the optimization of rituximab dose and schedule in all subgroups of DLBCL patients.

Introduction:Considering the increasing numbers of lymphoma patients (pts) surviving long-term, late effects of current treatment strategies such as secondary (sec) malignancies gain increasing importance. Many treatment regimens used in pts with lymphoma (R-CHOEP, DA-EPOCH-R, BEACOPP) include etoposide, a cytotoxic agent reported to increase sec leukemias. In order to further investigate the role of etoposide in inducing sec malignancies in pts with aggressive lymphoma we analyzed the R-MegaCHOEP trial (Schmitz et al., Lancet Oncology 2012) where young, high-risk pts with aggressive B-cell lymphomas had received R-CHOEP or R-MegaCHOEP, a regimen containing very high doses of etoposide (4g/m2). We compared rates of secondary tumors to incidences found in young patients treated with R-CHOP only.

Haenel: Amgen, Novartis, Roche, Celgene, Takeda, Bayer:Honoraria.Truemper:Janssen:Consultancy;Mundipharma:Research Funding;Nordic Nanovector:Consultancy;Roche:Research Funding;Seattle Genetics:Research Funding;Takeda Europe:Consultancy, Research Funding.Held:MSD:Consultancy;Acrotech, Spectrum:Research Funding;Amgen:Research Funding;BMS:Consultancy, Other: Travel Grants, Research Funding;Roche:Consultancy, Other: travel grants, Research Funding.Borchmann:Bristol Myers Squibb:Research Funding;Takeda:Research Funding.Dreyling:Celgene:Consultancy, Research Funding, Speakers Bureau;Roche:Consultancy, Research Funding, Speakers Bureau;Beigene:Consultancy;Janssen:Consultancy, Research Funding, Speakers Bureau;Novartis:Consultancy;Abbvie:Research Funding;Astra Zeneca:Consultancy;Bayer:Consultancy, Speakers Bureau;Gilead:Consultancy, Research Funding, Speakers Bureau.Viardot:Roche:Honoraria, Other: advisory board;Kite/Gilead:Honoraria, Other: advisory board;Novartis:Honoraria, Other: advisory board;Amgen:Honoraria, Other: advisory board.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;Gilead:Consultancy;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding.Ott:NIH:Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America..Lenz:Bayer:Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen:Consultancy, Honoraria, Research Funding, Speakers Bureau;Novartis:Consultancy;Gilead:Consultancy, Honoraria, Research Funding, Speakers Bureau;AQUINOX:Research Funding;AstraZeneca:Consultancy, Honoraria, Research Funding;Celgene:Consultancy, Honoraria, Speakers Bureau;Verastem:Research Funding;Morphosys:Consultancy, Honoraria, Research Funding;Roche:Consultancy, Honoraria, Research Funding, Speakers Bureau;Agios:Research Funding;BMS:Consultancy.Schmitz:Riemser:Honoraria;Takeda:Honoraria;Janssen:Research Funding;Bristol-Myers Squibb:Current equity holder in publicly-traded company.

Introduction

Houot: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Kite: Honoraria; Gilead: Honoraria; MSD: Honoraria; Bristol-Myers Squibb: Honoraria. Poeschel:Roche: Other: Travel, Accommodations, Expenses; Amgen: Other: Travel, Accommodations, Expenses; Abbvie: Other: Travel, Accommodations, Expenses. André:Abbvie: Consultancy; Celgene: Other, Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Seattle Genetics: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Johnson & Johnson: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Dreyling:Beigene: Consultancy; Bayer: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Tilly:BMS: Honoraria. Casasnovas:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Kerkhoff:BMS: Honoraria. De Leval:Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Lunaphore Technologies SA: Consultancy, Honoraria; Abbvie: Honoraria; Roche Diagnostics: Honoraria. Gaulard:takeda: Honoraria, Research Funding; innate pharma: Research Funding. Held:Roche: Consultancy, Other: travel grants, Research Funding; MSD: Consultancy; Acrotech, Spectrum: Research Funding; Amgen: Research Funding; BMS: Consultancy, Other: Travel Grants, Research Funding.Nivolumab in peripheral T-cell lymphoma

The clinical value of allogeneic hematopoietic stem cell transplantation (alloHSCT) and autologous hematopoietic stem cell transplantation (autoHSCT) in the subtype of acute myeloid leukemia (AML) with double mutant CEBPA (CEBPAdm) has remained unsettled. Among 2983 patients analyzed for CEBPA mutational status (age 18-60 years) treated on 4 published Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group (HOVON/SAKK) and 3 German-Austrian AML Study Group (AMLSG) protocols (2 published, 1 registered, clinicaltrials.gov NCT00151255), 124 had AML with CEBPAdm and achieved first complete remission (CR1). Evaluation of the clinical impact of alloHSCT and autoHSCT vs chemotherapy was performed by addressing time dependency in the statistical analyses. Thirty-two patients proceeded to alloHSCT from a matched related (MRD, n = 29) or a matched unrelated donor (MUD, n = 3), 20 to autoHSCT in CR1 and 72 received chemotherapy. Relapse-free survival was significantly superior in patients receiving an alloHSCT or autoHSCT in CR1 as compared with chemotherapy (P < .001), whereas overall survival was not different (P < .12). Forty-five patients relapsed. Of 42 patients treated with reinduction therapy, 35 achieved a second CR (83%) and most patients (n = 33) received an alloHSCT MRD, n = 11; MUD, n = 19; haplo-identical donor, n = 3). Survival of relapsed patients measured from date of relapse was 46% after 3 years. Adult AML patients with CEBPAdm benefit from alloHSCT and autoHSCT; relapsed patients still have a favorable outcome after reinduction followed by alloHSCT.

The clinical value of allogeneic hematopoietic stem cell transplantation (alloHSCT) and autologous hematopoietic stem cell transplantation (autoHSCT) in the subtype of acute myeloid leukemia (AML) with double mutant CEBPA(CEBPAdm) has remained unsettled. Among 2983 patients analyzed for CEBPAmutational status (age 18-60 years) treated on 4 published Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group (HOVON/SAKK) and 3 German-Austrian AML Study Group (AMLSG) protocols (2 published, 1 registered, clinicaltrials.govNCT00151255), 124 had AML with CEBPAdm and achieved first complete remission (CR1). Evaluation of the clinical impact of alloHSCT and autoHSCT vs chemotherapy was performed by addressing time dependency in the statistical analyses. Thirty-two patients proceeded to alloHSCT from a matched related (MRD, n = 29) or a matched unrelated donor (MUD, n = 3), 20 to autoHSCT in CR1 and 72 received chemotherapy. Relapse-free survival was significantly superior in patients receiving an alloHSCT or autoHSCT in CR1 as compared with chemotherapy (P< .001), whereas overall survival was not different (P< .12). Forty-five patients relapsed. Of 42 patients treated with reinduction therapy, 35 achieved a second CR (83%) and most patients (n = 33) received an alloHSCT MRD, n = 11; MUD, n = 19; haplo-identical donor, n = 3). Survival of relapsed patients measured from date of relapse was 46% after 3 years. Adult AML patients with CEBPAdm benefit from alloHSCT and autoHSCT; relapsed patients still have a favorable outcome after reinduction followed by alloHSCT.

In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RAS being affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT (37%) and FLT3 (17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation (hazard ratio [HR] = 1.67; P = .04], log10(WBC) (HR = 1.33; P = .02), and trisomy 22 (HR = 0.54; P = .08) were relevant factors for relapse-free survival; for overall survival, FLT3 mutation (HR = 2.56; P = .006), trisomy 22 (HR = 0.45; P = .07), trisomy 8 (HR = 2.26; P = .02), age (difference of 10 years, HR = 1.46; P = .01), and therapy-related AML (HR = 2.13; P = .14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).

In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2(V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RASbeing affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT(37%) and FLT3(17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KITmutation (hazard ratio [HR] = 1.67; P= .04], log10(WBC) (HR = 1.33; P= .02), and trisomy 22 (HR = 0.54; P= .08) were relevant factors for relapse-free survival; for overall survival, FLT3mutation (HR = 2.56; P= .006), trisomy 22 (HR = 0.45; P= .07), trisomy 8 (HR = 2.26; P= .02), age (difference of 10 years, HR = 1.46; P= .01), and therapy-related AML (HR = 2.13; P= .14) revealed as prognostic factors. The adverse effects of KITand FLT3mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).

Pharmacokinetics of 8 doses of rituximab (375 mg/m2) given in combination with 2-week cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone (CHOP-14) was determined by ELISA in 20 elderly patients with diffuse large B-cell lymphoma (DLBCL) 10 minutes before and after each infusion and 1 week and 1, 2, 3, 6, and 9 months after the last infusion. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Concentration-time data were fitted into an open 2-compartment model and total clearance, central compartment volume, intercompartment clearance, and volume of distribution at steady-state (Vdss) were investigated. Total clearance was 9.43 mL/h and Vdsswas 9.61 l. Rituximab clearance was reduced (8.21 mL/h vs 12.68 mL/h; P= .003) and elimination half-life was prolonged in women compared with men (t1/2β= 30.7 vs 24.7 days; P= .003). Body weight also affected Vdss(0.1 l increase of Vdssper kilogram above median of 75 kg). A sex-dependent effect and the higher weight of males contribute to their faster rituximab clearance, which might explain why elderly males benefit less from the addition of rituximab to CHOP than females. This trial was registered on www.clinicaltrials.govas numbers NCT00052936, EU-20243 (RICOVER-60 Trial), EU-20534, and NCT00726700 (Pegfilgrastim Trial).

Pharmacokinetics of 8 doses of rituximab (375 mg/m2) given in combination with 2-week cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone (CHOP-14) was determined by ELISA in 20 elderly patients with diffuse large B-cell lymphoma (DLBCL) 10 minutes before and after each infusion and 1 week and 1, 2, 3, 6, and 9 months after the last infusion. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Concentration-time data were fitted into an open 2-compartment model and total clearance, central compartment volume, intercompartment clearance, and volume of distribution at steady-state (Vdss) were investigated. Total clearance was 9.43 mL/h and Vdss was 9.61 l. Rituximab clearance was reduced (8.21 mL/h vs 12.68 mL/h; P = .003) and elimination half-life was prolonged in women compared with men (t1/2β = 30.7 vs 24.7 days; P = .003). Body weight also affected Vdss (0.1 l increase of Vdss per kilogram above median of 75 kg). A sex-dependent effect and the higher weight of males contribute to their faster rituximab clearance, which might explain why elderly males benefit less from the addition of rituximab to CHOP than females. This trial was registered on www.clinicaltrials.gov as numbers NCT00052936, EU-20243 (RICOVER-60 Trial), EU-20534, and NCT00726700 (Pegfilgrastim Trial).

To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as −5/5q−, −7/7q−, −16/16q−, −18/18q−, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.

To assess the frequency of TP53alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53mutations were found in 141 of 234 (60%) and TP53losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P< .0001) and by a higher frequency of specific copy number alterations, such as −5/5q−, −7/7q−, −16/16q−, −18/18q−, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53is the most frequently known altered gene in CK-AML. TP53alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK+. MK+ patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of −5/5q−, −7, 7q−, abnl(12p), abnl(17p), −18/18q−, −20/20q−, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)–related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and tyrosine kinase domain mutations (P = .02) were less frequent in MK+. Response to induction therapy and overall survival in MK+ patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK+. MK+patients were significantly older (P= .0001), had lower white blood counts (P= .0006), and lower percentages of BM blasts (P= .0004); MK was associated with the presence of −5/5q−, −7, 7q−, abnl(12p), abnl(17p), −18/18q−, −20/20q−, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)–related cytogenetic abnormalities (P< .0001, each); and NPM1mutations (P< .0001), FLT3internal tandem duplications (P< .0001), and tyrosine kinase domain mutations (P= .02) were less frequent in MK+. Response to induction therapy and overall survival in MK+patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.

Optical remote sensing techniques have obvious advantages for monitoring gas and aerosol emissions, since they enable the operation over large distances, far from hostile environments, and fast processing of the measured signal. In this study two remote sensing devices, namely a Lidar (Light Detection and Ranging) for monitoring the vertical profile of backscattered light intensity, and a Sodar (Acoustic Radar, Sound Detection and Ranging) for monitoring the vertical profile of the wind vector were operated during specific periods. The acquired data were processed and compared with data of air quality obtained from ground level monitoring stations, in order to verify the possibility of using the remote sensing techniques to monitor industrial emissions. The campaigns were carried out in the area of the Environmental Research Center (Cepema) of the University of Sao Paulo, in the city of Cubatao, Brazil, a large industrial site, where numerous different industries are located, including an oil refinery, a steel plant, as well as fertilizer, cement and chemical/petrochemical plants. The local environmental problems caused by the industrial activities are aggravated by the climate and topography of the site, unfavorable to pollutant dispersion. Results of a campaign are presented for a 24- hour period, showing data of a Lidar, an air quality monitoring station and a Sodar.

Paratarg-7, a frequent autoantigenic target, and all other autoantigenic targets of human paraproteins molecularly defined to date are hyperphosphorylated in the respective patients compared with healthy controls, suggesting that hyperphosphorylation of autoantigenic paraprotein targets is a general mechanism underlying the pathogenesis of these paraproteins. We now show that hyperphosphorylation of paratarg-7 occurs because of an additional phosphorylation of Ser17, which is located within the paraprotein-binding epitope. Coimmunoprecipitation identified phosphokinase C ζ (PKCζ) as the kinase responsible for the phosphorylation of most, and phosphatase 2A (PP2A) as the phosphatase responsible for the dephosphorylation of all hyperphosphorylated autoantigenic targets of paraproteins. Single-nucleotide polymorphisms (SNPs) or mutations of PKCζ and PP2A were excluded. However, PP2A was inactivated by phosphorylation of its catalytic subunit at Y307. Stimulation of T cells from healthy carriers of wild-type paratarg-7 induced a partial and transient hyperphosphorylation between days 4 and 18, which was maintained by incubation with inhibitors of PP2A, again indicating that an inactivation of PP2A is responsible for the hyperphosphorylation of autoantigenic paraprotein targets. We conclude that the genetic defect underlying the dominantly inherited hyperphosphorylation of autoantigenic paraprotein targets is not in the PP2A itself, but in genes or proteins controlling PP2A activity by phosphorylation of its catalytic subunit.

Paratarg-7, a frequent autoantigenic target, and all other autoantigenic targets of human paraproteins molecularly defined to date are hyperphosphorylated in the respective patients compared with healthy controls, suggesting that hyperphosphorylation of autoantigenic paraprotein targets is a general mechanism underlying the pathogenesis of these paraproteins. We now show that hyperphosphorylation of paratarg-7 occurs because of an additional phosphorylation of Ser17, which is located within the paraprotein-binding epitope. Coimmunoprecipitation identified phosphokinase C ζ (PKCζ) as the kinase responsible for the phosphorylation of most, and phosphatase 2A (PP2A) as the phosphatase responsible for the dephosphorylation of all hyperphosphorylated autoantigenic targets of paraproteins. Single-nucleotide polymorphisms (SNPs) or mutations of PKCζ and PP2A were excluded. However, PP2A was inactivated by phosphorylation of its catalytic subunit at Y307. Stimulation of T cells from healthy carriers of wild-type paratarg-7 induced a partial and transient hyperphosphorylation between days 4 and 18, which was maintained by incubation with inhibitors of PP2A, again indicating that an inactivation of PP2A is responsible for the hyperphosphorylation of autoantigenic paraprotein targets. We conclude that the genetic defect underlying the dominantly inherited hyperphosphorylation of autoantigenic paraprotein targets is not in the PP2A itself, but in genes or proteins controlling PP2A activity by phosphorylation of its catalytic subunit.

To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P< .0001) and they had lower white blood counts (P= .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P< .0001); t-AML patients had NPM1mutations (P< .0001) and FLT3internal tandem duplications (P= .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P< .0001 and P= .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P= .02 and P= .22, respectively) and overall survival in younger intensively treated patients (P= .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

Acute myeloid leukemia (AML) is a hematologic malignancy that is treated in medically fit patients with intensive induction chemotherapy (IT) and postremission therapy to achieve a complete and long-term remission. The incidence of obesity in the general population is steadily increasing and has been identified as a major risk factor for all-cause mortality. Despite previous studies assessing the role of obesity in AML patients undergoing IT, there is an ongoing debate on the impact of obesity on patient outcome as well as the optimal dosing strategy in obese AML patients.

Schliemann: Boehringer-Ingelheim: Research Funding; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fransecky: Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Medac: Honoraria; Takeda: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Platzbecker: Celgene/BMS: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Baldus: Jazz: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria.

Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

The introduction of the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen 30 years ago was the great breakthrough in the treatment of advanced-stage aggressive lymphomas. About 50% of all patients treated with CHOP achieved complete remission, and about one third experienced long-term disease-free survival and cure. Attempts to improve results by modifications of CHOP using escalated doses, additional drugs, or the alternative use of putatively non–cross-resistant chemotherapy regimens were not confirmed in randomized trials. With the availability of granulocyte colony-stimulating factor (G-CSF) and the tool of autologous stem cell support in the 1990s, dose escalation, dose densification (by interval reduction), or combinations thereof were pursued to increase dose intensity. While dose-escalation strategies, including high-dose approaches necessitating stem cell support, have not been demonstrated unequivocally yet to be superior to a baseline CHOP-21, dose-dense (biweekly) modifications improved the outcome of young and elderly patients with aggressive lymphomas compared to baseline CHOP-21. The challenges in the era of the monoclonal antibody rituximab are the identification of the ideal chemotherapy partner for rituximab both with respect to potential synergistic effects and to the lack of interference with its effector mechanisms. Finally, the issue of intensifying rituximab within such approaches must be addressed by appropriately designed randomized trials.