Search

Correction: Journal of Cancer Research and Clinical Oncology (2022) 148:1171-1181, https://doi.org/10.1007/s00432-021-03702-7

Purpose High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels. Methods Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17–32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography–mass spectrometry (LC–MS). Toxicities were assessed according to National Cancer Institute—Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80–455%) and showed toxic MTX plasma concentrations (range 3.1–182.4 µmol/L) before glucarpidase injection. The drug was administered 42–70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02–2.03 µmol/L. MTX rebound was detected in plasma 42–73 h after glucarpidase initiation, but concentrations remained consistent at Conclusion Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue.

The evaluation of bone marrow morphology by experienced hematopathologists is essential in the diagnosis of acute myeloid leukemia (AML); however, it suffers from a lack of standardization and inter-observer variability. Deep learning (DL) can process medical image data and provides data-driven class predictions. Here, we apply a multi-step DL approach to automatically segment cells from bone marrow images, distinguish between AML samples and healthy controls with an area under the receiver operating characteristic (AUROC) of 0.9699, and predict the mutation status of Nucleophosmin 1 (NPM1)—one of the most common mutations in AML—with an AUROC of 0.92 using only image data from bone marrow smears. Utilizing occlusion sensitivity maps, we observed so far unreported morphologic cell features such as a pattern of condensed chromatin and perinuclear lightening zones in myeloblasts of NPM1-mutated AML and prominent nucleoli in wild-type NPM1 AML enabling the DL model to provide accurate class predictions.

The aim of this study was to prospectively compare the MIFAP protocol, which had been shown to be effective in patients with relapsed and refractory Hodgkin’s lymphoma (HL) or aggressive non-Hodgkin’s lymphoma (NHL), to an established regimen like Dexa-BEAM. Seventy-three adult patients with HL (N = 25) or aggressive NHL (N = 48) suffering from relapse or refractory disease were randomly allocated to receive two cycles of Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, melphalan; N = 37) or MIFAP (mitoxantrone, fludarabine, cytarabine, cisplatin; N = 36) prior to a consolidating high-dose therapy and hematopoietic cell transplantation (HCT). Primary endpoint was the overall response rate (ORR) [complete response (CR) and partial response (PR)] after two courses of salvage chemotherapy. The ORR was 51% (CR 38%) and 53% (CR 36%) in the Dexa-BEAM arm and in the MIFAP arm (both not significant), respectively. There was a significantly higher grade 3–4 toxicity after MIFAP compared to Dexa-BEAM. Thirty-five patients were consolidated by autologous (N = 29), allogeneic (N = 1) or sequential autologous/allogeneic (N = 5) HCT. No significant differences were found in progression-free survival (PFS) and overall survival (OS) between the Dexa-BEAM and the MIFAP arms. Compared to Dexa-BEAM, MIFAP is associated with a higher toxicity and does not improve the outcome of patients with recurrent HL or aggressive NHL. For those patients, innovative treatment concepts like recently developed immunotherapies are necessary. EudraCT number 2021-001937-38. 7 April 2021, retrospectively registered.

Summary Background 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. Methods In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18–60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT00129090 . Findings Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1–11·1), 10-year event-free survival was 51% (95% CI 42–61) in the R-MegaCHOEP group and 57% (47–67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9–1·8], p=0·23). 10-year progression-free survival was 59% (50–68) in the R-MegaCHOEP group and 60% (51–70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7–1·7], p=0·64). 10-year overall survival was 66% (57–76) in the R-MegaCHOEP group and 72% (63–81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8–2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11–22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group. Interpretation Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted. Funding Deutsche Krebshilfe (German Cancer Aid).

We conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to standard-dose granulocyte colony-stimulating factor (G-CSF), defined by 6 CD34 + cells/kg recipient body-weight (CD34+/kg RBW) after 1st apheresis. A single dose of 240 µg/kg P was injected subcutaneously at 10 p.m. on the day of the 1st apheresis. Thirty-seven allogeneic PBSC donors underwent study treatment. The median CD34+ count in peripheral blood was 15/µl on Day 1 after G-CSF alone, versus 44/µl on Day 2 after G-CSF plus P (p 8 on Day 1 and 2.8 × 108 on Day 2. In contrast to a median yield of only 1.31 × 106 CD CD34+/kg RBW on Day 1, triggering study inclusion, a median of 3.74 × 106 CD CD34+/kg RBW were collected with G-CSF plus P on Day 2. Of 37 donors, 21 reached the target cell count of >4.5 × 106 CD34+/kg RBW (57%, 95%CI 40–73%). No donor experienced a severe adverse event requiring treatment. In conclusion, P might be considered on a case-by-case basis for healthy allogeneic donors with very poor stem cell mobilization success after G-CSF.

ObjectiveTo determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.MethodsSixty-five patients (median age 62 years, range 27–75; median Karnofsky performance score 70, range 20–90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.ResultsMedian follow-up for surviving patients was 19.6 years (17.5–23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9–5.9); for patients ≤60 years, 11.0 years (95% CI 4.8–17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.ConclusionAt a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.Classification of evidenceThis work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.

Despite the increasing role of molecular markers, differential counts and morphology of hematopoietic cells in the bone marrow (BM) remain essential diagnostic criteria in hematological diseases. However, the respective reference values for BM myelogram commonly used came from small series with limited numbers of healthy individuals. We evaluated the myelograms of 236 healthy individuals who underwent unrelated bone marrow donation. Health check-ups were performed 4 weeks prior to harvest. Samples for this study, taken from the first aspiration, were stained according to the standard Pappenheim method. Three experienced investigators assessed cellularity, megakaryopoiesis, and differential counts independently. The median donor age was 31 (range 18–51) years. Predonation tests did not reveal any relevant morbidity. Thirty-seven out of 42 hypocellular marrow samples were from younger donors up to 39 years. Content of megakaryocytes was normal in 210 specimens (89%). Gender and body mass index had significant impact on hematopoiesis, whereas age had not. The number of erythroblasts was higher (about 32%) and the proportion granulopoiesis slightly lower (about 50%) compared with previous studies. Differential counts showed also some differences with respect to individual maturation stages in these lines. Interrater comparisons showed greater reliability for the assignment of cells to the different hematopoietic cell lines than for single-cell diagnoses. This study largely confirms the results for cell counts in normal human bone marrow available from previous reports and provides some insights into factors that affect individual cell populations. It also reveals substantial variability among even experienced investigators in cytological diagnoses.

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P

Allogeneic hematopoietic cell transplantation (HCT) during chemotherapy-induced aplasia may offer long-term survival in acute myeloid leukemia (AML) with otherwise poor prognosis including ELN adverse risk, relapsed or refractory disease. However, the value of residual morphologic disease prior HCT in this context has not been conclusively settled until yet. Therefore, we aimed to investigate variables predicting outcome in this unique setting of sequential conditioning therapy, with a focus on pretreatment morphologic blast count. In contrast to the most popular FLAMSA-RIC protocol, we used a melphalan-based conditioning regimen during aplasia.We retrospectively analyzed data from 173 AML patients who underwent a sequential melphalan-based conditioning therapy between 2003 and 2015 at our centre. All patients participated either in the prospective Phase 2 BRIDGE trial (NCT01295307), the Phase 3 AML2003 study (NCT00180102) or were treated according to this protocol and underwent allogeneic HCT after melphalan-based conditioning in treatment-induced aplasia.Median bone marrow blast count prior to conditioning was 10% (range, 0-96%). Four year probabilities of EFS and OS were 34% (95% CI, 28-43%) and 43% (95% CI, 36-52%), respectively. In multivariate analysis, blast count20% was associated with worse EFS (HR = 1.93;Allogeneic HCT in aplasia with a melphalan-based conditioning regimen has the potential to cure a subset of adverse risk AML patients, even with persistent morphological disease prior HCT. However, a high pre-transplant blast count still indicates patients with a dismal prognosis, especially in the relapsed patient group, for whom post-transplant strategies should be considered to further optimize post HCT outcome.

Inflammation plays an important role in chimeric antigen receptor (CAR) T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR T-cell treatment is widely unknown. We evaluated the prevalence of CHIP, using a targeted deep sequencing approach, in a cohort of patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma before and after CAR T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia, and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34%) before CAR T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR T-cell treatment but had an improved overall survival (not reached vs 265 days, P = .003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic use of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (with the exception of ferritin), or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR T-cell therapy and is not associated with an inferior outcome.

Information regarding the curative role of allogeneic stem cell transplantation (allo-HCT) in systemic anaplastic large cell lymphoma (sALCL) is scarce. We analyzed the results of allo-HCT in patients with relapsed/refractory sALCL with special emphasis on the role of brentuximab vedotin (BV) as a bridge to allo-HCT. Forty-four patients (24 females, median age 38 years) with sALCL were included. Twenty-three patients (52%) received BV before allo-HCT; BV-treated patients were more heavily pretreated (≥3 lines of therapy in 74% vs. 38%, p = 0.04). Twenty-three patients (52%) were in complete remission (CR) at allo-HCT. Three-year nonrelapse mortality and incidence of relapse (IR) after allo-HCT were 7% and 40%, respectively. With a median follow-up of 39 (12-69) months for survivors, 3-year progression-free survival (PFS) and overall survival were 53% and 74%, respectively. Univariate analysis showed that heavily pretreated patients and those not in CR had a higher IR and a lower PFS. The use of BV before transplant did not impact on any of the outcomes. Allo-HCT is a curative therapeutic strategy in a significant proportion of patients with relapsed/refractory sALCL; BV does not seem to modify transplant-related outcomes but might be able to render more patients candidates for this curative treatment.

In den vergangenen Jahren nahm die Anzahl von Krebspatienten durch die demographische Entwicklung der Bevolkerung, zunehmende Komorbiditaten und eine insgesamt steigende Lebenserwartung von Krebspatienten auf deutschen Intensivstationen kontinuierlich zu. Trotz dieser Entwicklung ist die Pravalenz und Versorgungsstruktur von Patienten mit hamatologisch-onkologischen(HO)-Erkrankungen auf deutschen Intensivstationen kaum bekannt. Ziel dieser Arbeit war die Erhebung der Pravalenz und Versorgung dieses Patientenkollektivs an 2 Stichtagen. An 2 Stichtagen wurde die Pravalenz von Krebspatienten (Punktpravalenz) auf deutschen Intensivstationen anhand eines Onlinefragebogens prospektiv erhoben. Angaben zur Struktur der jeweiligen Klinik und Intensivstation und demographische Daten der am Erhebungstag stationaren Krebspatienten wurden von den teilnehmenden Zentren anonymisiert in ein eCRF eingegeben. Deutschlandweit haben 4 % der angeschriebenen Intensivstationen an der Studie teilgenommen. Annahernd jeder 4. Patient auf der ICU/IMC-Station wies eine Krebserkrankung auf (n = 316/1319; 24 %; HO-Patienten). Die haufigsten Aufnahmegrunde auf die ICU/IMC-Station waren postoperative Uberwachung (n = 83/221; 38 %), respiratorische Instabilitat (n = 79/221; 36 %), kardial bedingte Kreislaufinstabilitat (n = 52/221; 24 %) und Sepsis (n = 47/221; 21 %). 67 % (n = 147/221) der Patienten hatten einen soliden Tumor und 22 % (n = 48/221) eine hamatologische Grunderkrankung. 78 % (n = 173/221) der dokumentierten Krebspatienten erhielten ein „Full-Code“-Intensivmanagement. 43 % (n = 94/221) der HO-Patienten wurden beatmet und 41 % (n = 90/221) erhielten Katecholamine. Der mediane SAPS-II-Score (Simplified Acute Physiology Score) war 35 (interquartile range [IQR] = 24–48) und der mediane TISS-Score (Therapeutic Intervention Scoring System) betrug 10 (IQR = 10–15). Analyse und Auswertung der zentrumsubergreifend erhobenen Daten erlauben erstmalig fur Deutschland die Bestimmung der Pravalenz und Versorgungssituation von hamatologischen und onkologischen Patienten auf ICU/IMC-Stationen. Jeder 4. Patient in der vorliegenden Studie wies als Haupt- oder Nebendiagnose eine maligne Grunderkrankung auf (n = 316/1319 = 24 %). Das Versorgungsmanagement bei dieser Patientengruppe ist komplex und bedarf einer engen interdisziplinaren Zusammenarbeit.

Standard first-line therapy for younger patients with peripheral T-cell lymphoma consists of six courses of CHOP or CHOEP consolidated by high-dose therapy and autologous stem cell transplantation (AutoSCT). We hypothesized that consolidative allogeneic transplantation (AlloSCT) could improve outcome. 104 patients with nodal peripheral T-cell lymphoma except ALK+ ALCL, 18 to 60 years of age, all stages and IPI scores except stage 1 and aaIPI 0, were randomized to receive 4 x CHOEP and 1 x DHAP followed by high-dose therapy and AutoSCT or myeloablative conditioning and AlloSCT. The primary endpoint was event-free survival (EFS) at three years. After a median follow-up of 42 months, 3-year EFS of patients undergoing AlloSCT was 43% (95% confidence interval [CI]: 29%; 57%) as compared to 38% (95% CI: 25%; 52%) after AutoSCT. Overall survival at 3 years was 57% (95% CI: 43%; 71%) versus 70% (95% CI: 57%; 82%) after AlloSCT or AutoSCT, without significant differences between treatment arms. None of 21 responding patients proceeding to AlloSCT as opposed to 13 of 36 patients (36%) proceeding to AutoSCT relapsed. Eight of 26 patients (31%) and none of 41 patients died due to transplant-related toxicity after allogeneic and autologous transplantation, respectively. In younger patients with T-cell lymphoma standard chemotherapy consolidated by autologous or allogeneic transplantation results in comparable survival. The strong graft-versus-lymphoma effect after AlloSCT was counterbalanced by transplant-related mortality. CHO(E)P followed by AutoSCT remains the preferred treatment option for transplant-eligible patients. AlloSCT is the treatment of choice for relapsing patients also after AutoSCT.

Blood cancer journal 11(5), 95 (2021). doi:10.1038/s41408-021-00485-5, Published by Nature Publishing Group, London [u.a.]

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study. ispartof: FRONTIERS IN IMMUNOLOGY vol:11 ispartof: location:Switzerland status: published

Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL. Electronic supplementary material The online version of this article (10.1007/s10637-020-00916-3) contains supplementary material, which is available to authorized users.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4. For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4, and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4. At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.

The diagnosis of myelodysplastic syndromes (MDS) is often challenging, time- and resource-consuming. A thorough analysis of complete blood count (CBC) parameters could, however, help to screen for MDS among other causes of cytopenia. To test this hypothesis, 109 newly-diagnosed MDS patients and 399 cytopenic patients older than 50 years with confirmed absence of MDS were enrolled in a prospective study. Multiparametric analysis highlighted three CBC parameters that were significantly different between the two cohorts: mean corpuscular volume, absolute neutrophil count and median neutrophil complexity and width of dispersion of the events measured (Ne-WX), which were used to define an MDS-CBC score. This score enables the prediction of MDS with 86% sensitivity and 88% specificity. The MDS-CBC score excluded MDS in 89% of cytopenic controls. Moreover, high score values at MDS diagnosis significantly correlated with decreased event-free (P = 0·02) and overall survival (P = 0·01). The power of this score was confirmed in an independent validation cohort (MDS n = 34, cytopenic controls n = 28). The MDS-CBC score is an easy and fast tool to exclude or suspect MDS in unselected patients with cytopenia of unknown reasons at the time of analysis, by prompting blood smear examination. It may thus improve allocation of further MDS-specific work-up in patients with cytopenia at the time of CBC assessment.

To predict the need of intensive care unit admission with organ support during the transplantation hospital stay in 101 consecutives allogeneic hematopoietic cell transplantation (allo-HCT) recipients the added predictive utility of three times per week Copeptin, MR-proADM, MR-proANP, NT-proBNP, IL-6, Procalcitonin, d-dimer and three times per week bed-sided pulmonary function test was determined in comparison with an index model. The index model was calculated by multivariate regression analysis out of the patients’ routine laboratory parameters. To calculate the added predictive utility of the investigated markers the Δ-AUC and the continuous net reclassification improvement (cNRI + 2 to − 2), splitted for events and non-events were calculated for each marker in comparison with the index model. According to the Δ-AUC, none of the parameters improved risk prediction. In contrast, the cNRI was significantly improved for events and non-events by Copeptin (event 0.75, p value 0.0013; non-event 0.4, p value 0.000079) and for events by NT-proBNP (0.6, p value 0.018). d-dimer and PCT significantly predicted the non-event. Of the spirometry parameters, the FEF50% improved prediction of event and non-event according to the cNRI model. Our data support the additional serial analysis of Copeptin and NT-proBNP in allo-HCT recipients during the transplantation hospital stay.

Achievement of complete remission (CR) signifies a crucial milestone in the therapy of acute myeloid leukemia (AML) while refractory disease is associated with dismal outcomes. Hence, accurately identifying patients at risk is essential to tailor treatment concepts individually to disease biology. Machine Learning (ML) is a branch of computer science that can process large data sets for a plethora of purposes. The underlying mechanism does not necessarily begin with a manually drafted hypothesis model. Rather the ML algorithms can detect patterns in pre-processed data and derive abstract information. We used ML to predict CR and 2-year overall survival (OS) in a large multi-center cohort of 1383 AML patients who received intensive induction therapy using clinical, laboratory, cytogenetic and molecular genetic data. To enable a customizable and reusable technological approach and achieve optimal results, we designed a data-driven platform with an embedded, automated ML pipeline integrating state-of-the-art software technology for data management and ML models. The platform consists of five scalable modules for data import and modelling, data transformation, model refinement, machine learning algorithms, feature support and performance feedback that are executed in an iterative manner to approach step-wisely the optimal configuration. To reduce dimensionality and the the risk of overfitting, dynamic feature selection was used, i.e. features were selected according to their support by feature selection algorithms. To be included in an ML model, a feature had to pass a pre-determined threshold of overall predictive power determined by summing the normalized scores of the feature selection algorithms. Features below the threshold were automatically excluded from the ML models for the respective iteration. In that way, features of high redundancy or low entropy were automatically filtered out. Our classification algorithms were completely agnostic of pre-existing risk classifications and autonomously selected predictive features both including established markers of favorable or adverse risk as well as identifying markers of so-far controversial relevance. De novo AML, extramedullary AML, double-mutated (dm) CEBPA, mutations of CEBPA-bZIP, NPM1, FLT3-ITD, ASXL1, RUNX1, SF3B1, IKZF1, TP53, U2AF1, t(8;21), inv(16)/t(16;16), del5/del5q, del17, normal or complex karyotypes, age and hemoglobin at initial diagnosis were statistically significant markers predictive of CR while t(8;21), del5/del5q, inv(16)/t(16;16), del17, dm CEBPA, CEBPA-bZIP, NPM1, FLT3-ITD , DNMT3A, SF3B1, U2AF1, TP53, age, white blood cell count, peripheral blast count, serum LDH and Hb at initial diagnosis as well as extramedullary manifestations were predictive for 2-year OS. For prediction of CR and 2-year OS, AUROCs ranged between 0.77 - 0.86 and 0.63 - 0.74, respectively. We provide a method to automatically select predictive features from different data types, cope with gaps and redundancies, apply and optimize different ML models, and evaluate optimal configurations in a scalable and reusable ML platform. In a proof-of-concept manner, our algorithms utilize both established markers of favorable or adverse risk and also provide further evidence for the roles of U2AF1, IKZF1, SF3B1, DNMT3A and bZIP mutations of CEBPA in AML risk prediction. Our study serves as a fundament for prospective validation and data-driven ML-guided risk assessment in AML at initial diagnosis for the individual patient. Image caption: Patient features were automatically selected by machine learning to predict complete remission (CR) and 2-year overall survival (OS) after intensive induction therapy. Based on a continuous feature support metric with a predefined cut-off of 0.5 (determined by optimal classification performance), 27 and 25 features were automatically selected for prediction of CR (A) and 2-year OS (C), respectively. For each of these features predicted by machine learning, odds ratios and 95% confidence intervals (CI) were calculated for CR (B) and 2 year OS (D). BMB: bone marrow blast count; FLT3h/low: FLT3-ITD ratio, h=high>0.5; Hb: hemoglobin; karyotype, c: complex aberrant karyotype (≥ 3 aberrations); karyotype, n: normal karyotype (no aberrations); LDH: lactate dehydrogenase; PBB: peripheral blood blast count; PLT: platelet count; WBC: white blood cell count. Figure 1 Figure 1. Disclosures Schetelig: Roche: Honoraria, Other: lecture fees; Novartis: Honoraria, Other: lecture fees; BMS: Honoraria, Other: lecture fees; Abbvie: Honoraria, Other: lecture fees; AstraZeneca: Honoraria, Other: lecture fees; Gilead: Honoraria, Other: lecture fees; Janssen: Honoraria, Other: lecture fees . Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Baldus: Celgene/BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. 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. Middeke: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Jazz: Consultancy; Astellas: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Novartis: Consultancy; Gilead: Consultancy; Glycostem: Consultancy; UCB: Honoraria.

Background Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common indolent and aggressive B-cell lymphomas, respectively. Although the combination of anti-CD20 therapies rituximab (R) or obinutuzumab (G) with chemotherapy has led to improved patient (pt) outcomes, R/R disease remains a challenge, with a high unmet need. The potent and selective MDM2 antagonist idasanutlin (idasa) activates the p53 pathway, leading to anti-tumor activity. The BCL-2 inhibitor venetoclax (ven) has shown clinical activity in hematologic diseases including R/R NHL. In a Phase Ib/II study (NCT02624986), idasa could be safely combined in a doublet treatment (tx) regimen with R or G in R/R FL or DLBCL pts. Here we report the tolerability, safety and preliminary efficacy of the triplet tx regimen of idasa plus ven and G in R/R NHL pts. Methods BH39147 (NCT03135262) was an open-label, multicenter, non-randomized, Phase Ib/II study with a dose-escalation phase followed by an expansion phase. The dose-escalation phase evaluated idasa and ven combined with G in all pts (FL and DLBCL) until the maximum tolerated dose (MTD) was reached. Idasa and ven dose escalations started at 100 and 200 mg PO QD, respectively, on days 1-5 of each 28-day cycle (safety cohort); in subsequent cohorts, ven was given on days 1-10 of each cycle. G was given at a fixed dose of 1000 mg IV on days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles. Pts received 6 cycles of induction tx. The primary objective of the dose-escalation phase was to determine recommended Phase II doses for idasa and ven in combination with G. Efficacy objectives included evaluating the complete response (CR) rate at the end of induction (EOI) per investigator based on PET-CT. The trial was stopped prior to initiation of the expansion phase; results are presented for the dose-escalation cohorts evaluating idasa plus ven and G. Results Of the 29 pts enrolled, 14 each had a diagnosis of FL or DLBCL at study entry, and 1 had an unknown diagnosis at study entry that was later confirmed as FL. The median age was 70 y (range, 25-82), 58.6% of pts were male, and 67.9% had an ECOG PS of 1 or 2. The majority of pts had advanced-stage disease at enrollment, with 58.6% having received ≥ 3 lines of prior anti-lymphoma therapy; 17.2% and 24.1% of pts had received 1 and 2 prior lines of tx, respectively. Median (range) tx durations during induction were 1.3 mo (0-6) for idasa, 1.5 mo (0-7) for ven and 1.5 mo (0-6) for G; post-induction median (range) tx durations (n = 4) were 3.8 mo (0-4), 3.8 mo (0-4) and 8.4 mo (0-11), respectively. The safety-evaluable population was composed of 29 pts. Grade 3/4 adverse events (AEs) occurred in 86.2% of pts, with neutropenia (79.3%), thrombocytopenia (62.1%), leukopenia (27.6%) and anemia (20.7%) as the most common. No Grade 5 AEs were reported. Serious AEs occurred in 48.3% of pts and were most commonly neutropenia (10.3%). AEs led to treatment discontinuation in 41.4% of pts, with thrombocytopenia (17.2%) and neutropenia (13.8%) being the most common. AEs related to idasa, ven and G were reported in 86.2%, 89.7% and 79.3% of pts, respectively. Dose-limiting toxicities were reported in 4 pts (13.8%): neutropenia (n = 3; 10.3%), hyperbilirubinemia (n = 1; 3.4%) and transaminitis (n = 1; 3.4%). The MTD for idasa was determined to be 150 mg in combination with 200-mg ven and G and 100 mg in combination with 400-mg ven and G. Preliminary efficacy data are shown in the table. Among all pts, 20.7% (FL, n = 5; DLBCL, n = 1) had a CR at EOI per investigator (PET-CT) based on modified Lugano 2014 criteria. Per investigator based on Lugano 2014 criteria, the CR rate at EOI (CT) was 13.8% (FL, n = 3; DLBCL, n = 1), and the complete metabolic response rate at EOI (PET-CT) was 24.1% (FL, n = 6; DLBCL, n = 1). Conclusions This study successfully showed the combinability of idasa and ven with an anti-CD20 agent. MTDs were determined for idasa and ven in combination with G in FL and DLBCL pts. No new safety signals related to any of the study drugs were identified, and the observed safety profiles were consistent with those of each individual study drug. While the combination is feasible and promising, other agents and approaches in the field make this combination less likely to proceed further. As a consequence, this trial has been discontinued following the dose-escalation/proof-of-concept phase to focus on new tx combinations. Figure Disclosures Kamdar: Roche:Research Funding.Augustson:Roche:Other: Support of parent study and funding of editorial support.Edwards:Roche:Other: Support of parent study and funding of editorial support.Hertzberg:Roche:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support;Gilead:Membership on an entity's Board of Directors or advisory committees;MSD:Membership on an entity's Board of Directors or advisory committees;Abbvie:Honoraria;BMS:Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees.Johnston:Roche:Other: Support of parent study and funding of editorial support.Kim:Alexion Pharmaceuticals Inc.:Honoraria, Research Funding.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding;Gilead:Consultancy.Smith:TG Therapeutics:Consultancy, Research Funding;Genentech/Roche:Consultancy, Other: Support of parent study and funding of editorial support, Research Funding;BMS:Consultancy;Karyopharm:Consultancy, Research Funding;FortySeven:Research Funding;Pharmacyclics:Research Funding;Acerta:Research Funding;Janssen:Consultancy;Celgene:Consultancy, Research Funding.Stevens:Amgen, MorphoSys:Consultancy.Monnet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Zhao:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Nouet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Marinova:Roche:Current Employment, Other: Support of parent study and funding of editorial support.

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. Methods:We analyzed 1536 pts aged 18-60 years with aggressive B-cell lymphoma treated in the prospective phase 3 trials FLYER (NCT00278421; n=588, median observation time (OT)=66 months), UNFOLDER (NCT00278408; n=695, median OT=72 months) and MegaCHOEP (NCT00129090; n=253, median OT=112 months) to compare the cumulative incidences of sec neoplasms. We performed a competing risk analysis for time from randomization to occurrence of sec malignancy (myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or other) according to first-line therapy with R-CHOP (n=1283) vs. R-CHOEP (n=127) vs. R-MegaCHOEP (n=126). We used a cause-specific hazard model adjusted for gender, age (>50 vs. Results:Adjusting for competing events, we found sec MDS/AML in 0.3% of pts treated with R-CHOP, in 1% of pts treated with R-CHOEP and in 2% of pts following treatment with R-MegaCHOEP. Cause-specific hazard ratios showed a trend for increased risk for sec AML following R-MegaCHOEP in comparison to R-CHOP (HR 5.2, 95%CI (1.0; 27.5), p=0.052) while R-CHOEP did not significantly increase the incidence of sec AML (HR 1.4, 95%CI (0.1; 14.0), p=0.777). Male gender and age >50 years showed a trend for increasing sec AML. We found very similar incidences of sec solid tumors (not MDS/AML) affecting 4% of pts treated with R-CHOP or R-MegaCHOEP and 6% of pts following R-CHOEP regimen. The only factor significantly increasing the risk of sec solid tumors was age >50 years (HR 2.6, 95%CI (1.5; 4.3), p Conclusions:This analysis shows that sec malignancies represent rare events in younger patients with aggressive B-cell lymphoma, even after extreme dose-escalation of etoposide. Compared to standard R-CHOP, 8 cycles of R-CHOEP were not associated with increased risk of sec AML or solid tumors thus remaining an attractive first-line treatment for young high-risk pts with DLBCL. Disclosures 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.

The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is an established salvage regimen for lymphoma patients. We hypothesized that a modified administration schedule for cisplatin and cytarabine results in lower toxicity and improved efficacy. We retrospectively analysed 119 patients with relapsed or refractory, aggressive, or indolent B-cell lymphomas, mantle-cell lymphomas, peripheral T-cell lymphomas, or Hodgkin’s lymphomas who were treated with the modified DHAP (mDHAP) regimen (dexamethasone 40 mg 15 min-i.v. infusion, days 1–4; cytarabine 2 × 0.5 g/m2 1 h-i.v. infusion, days 1–4; cisplatin 25 mg/m2 24 h-i.v. infusion, days 1–4). Responding and eligible patients underwent stem-cell transplantation. In total, 185 treatment cycles were evaluable. Severe myelosuppression was the main toxicity occurring in 90% of the cycles. Febrile neutropenia or documented infection was found in less than 40%. Two patients died related to treatment (TRM, 1.7%). Nephrotoxicity did not exceed CTC grade 3, which occurred in four cycles only (2.2%). Complete (CR) or partial (PR) responses after mDHAP were documented in 16% and 39% (overall response rate 55%). Harvest of autologous stem cells was successful in 94 (79%) patients and 85 patients (71%) proceeded to stem-cell transplantation. The median overall and progression-free survival was 50.8 and 25.8 months. An improvement in efficacy could not be observed after modified DHAP regimen; however, manageable toxicity and reduced renal complications suggest further investigation. The study, however, also underlines the need for new concepts in the management of advanced and high-risk lymphomas.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

This study was conducted to characterize and compare peripheral blood stem cell grafts from healthy donors who underwent granulocyte colony-stimulating factor (G-CSF) mobilization and subsequently received 1 dose of plerixafor after insufficient stem cell yields were achieved at the first apheresis. Aliquots from 35 donors were collected from the first apheresis after mobilization with G-CSF alone and from the second apheresis after additional plerixafor administration. Samples were freshly analyzed for cellular subsets by 8-color flow cytometry. Leukapheresis samples mobilized with additional plerixafor showed a significant increase of total nucleated cells, including B cells, CD4+ and CD8+ T cells, and CD34+ hematopoietic stem and progenitor cells. Absolute numbers of plasmacytoid dendritic cells were also significantly increased, whereas no changes were detected for myeloid dendritic cells. Furthermore, absolute numbers of regulatory T cells increased, with naive CD45RA+ regulatory T cells showing the highest rise. Finally, strikingly higher numbers of myeloid-derived suppressor cells were detected in the plerixafor and G-CSF–mobilized graft. The mobilization of peripheral stem cells in healthy donors with G-CSF and plerixafor led to a significant difference in cellular graft composition compared with G-CSF alone. The clinical impact of the different cell composition for the graft recipient warrants further clinical investigation.

More than 60% of patients with non-Hodgkin lymphoma (NHL) are age60 years at presentation. The purpose of this study was to compare the potential risks and benefits of allogeneic hematopoietic cell transplantation (alloHCT) in elderly patients with NHL with younger patients in a large sample, also taking into account comorbidity information. All patients age ≥18 years who had undergone alloHCT from a matched sibling or unrelated donor for NHL between 2003 and 2013 and were registered with the European Society for Blood and Marrow Transplantation were eligible for the study. The primary study endpoint was 1-year nonrelapse mortality (NRM). A total of 3919 patients were eligible and were categorized by age: young (Y), 18 to 50 y (n = 1772); middle age (MA), 51 to 65 y (n = 1967); or old (O), 66 to 77 y (n = 180). Follicular lymphoma was present in 37% of the patients; diffuse large B cell lymphoma, in 30%; mantle cell lymphoma, in 21%, and peripheral T cell lymphoma, in 11%. At the time of alloHCT, 85% of the patients were chemosensitive and 15% were chemorefractory. With a median follow-up of 4.5 years in survivors, NRM at 1 year was 13% for the Y group. 20% for the MA group, and 33% for the O group (P.001), whereas relapse incidence and overall survival (OS) at 3 years in the 3 groups were 30%, 31%, and 28% (P = .355) and 60%, 54%, and 38% (P.001), respectively. Multivariable adjustment for confounders, including sex, NHL subset, time from diagnosis, chemosensitivity, donor, and conditioning, confirmed older age as a significant predictor for NRM and OS, but not for relapse risk. Although comorbidity was a significant predictor of NRM in a subset analysis restricted to the 979 patients with comorbidity information available, age retained its significant impact on NRM. In conclusion, our data show that alloHCT in patients age65 y provides similar NHL control as seen in younger patients but is associated with a higher NRM that is not fully explained by comorbidity. Thus, although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group.

IF 5.128; International audience; The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non‐transformed nodal, extra‐nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1–8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy‐based high‐dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub‐group and more transplants performed in recent years in the other sub‐groups. After a median follow‐up of 5 years, 5‐year cumulative incidence of relapse/progression and non‐relapse mortality were 38% and 9%, respectively. Five‐year event‐free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five‐year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt’s lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

Despite the rapid development of molecular markers during the last years, the morphology of blood and bone marrow cells still keeps the crucial role for diagnosis and subclassification of the different subtypes of myelodysplastic syndromes (MDS), as recently confirmed by the new 2016 WHO classification [1]. Nevertheless, morphologic diagnosis is not always self-evident. While increased blast cells are often in-line with advanced MDS subtypes, early forms with mild morphological changes can represent a diagnostic challenge. Especially in these cases, morphologic experience is crucial but should be embedded into further information on disease history, exclusion of other underlying diseases, as well as additional cytogenetic, molecular, and immunophenotypic data to confirm diagnosis of MDS.

BACKGROUND The collection of hematopoietic stem cells from the peripheral blood of healthy donors has been established as a highly efficient method. Nevertheless, some donors have a moderate or poor chance of harvest success with standard mobilization regimens. STUDY DESIGN AND METHODS We retrospectively reviewed data from 7216 unrelated healthy donors, who underwent granulocyte–colony-stimulating factor mobilization and consecutive leukapheresis for allogeneic stem cell transplantation. We tested different donor variables of potential influence and established a statistical model for prediction of upfront mobilization capacity and harvest success. In addition, we calculated the likelihood of a successful harvest dependent on predicted preapheresis CD34+ count and recipient weight. RESULTS Female sex, older age, smoking, elevated lactate dehydrogenase, higher relative lymphocyte count, and higher large unstained cell count at baseline were negatively correlated with the CD34+ cell count on Day +5 (p

Background For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. Patients and Methods A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m2 over 1 h, every 12 h, days 1–5), or continuous infusion (CI) (150 mg/m2 over 24 h, days 1–5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG. Results The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). Conclusion A 5-day course of Ara-C 2 × 1000 mg/m2 administered as bolus versus Ara-C 150 mg/m2 administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML. Clinical trial number LN_NN_2004_39/EudraCT number 2014-000083-18.

This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients. Electronic supplementary material The online version of this article (10.1007/s00277-018-3312-y) contains supplementary material, which is available to authorized users.

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.