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The manageable toxicity profile of obinutuzumab (GA101; G) alone or with chemotherapy in first-line (1L; fit and non-fit) and relapsed/refractory (R/R) patients with chronic lymphocytic leukaemia (CLL) was established in the primary analysis of the Phase IIIb GREEN trial (Clinicaltrials.gov: NCT01905943). The final analysis (cut-off, 31 January 2019) is reported here. Patients received G (1000 mg) alone (G-mono; fit and non-fit patients) or with chemotherapy [fludarabine and cyclophosphamide (FC; fit patients); chlorambucil (non-fit patients); bendamustine (any patient)]. Study endpoints were safety (primary) and efficacy (secondary). Subgroup analyses were performed on prognostic biomarkers in 1L CLL. Overall, 630 patients received 1L and 341 received R/R CLL treatment. At the final analysis, no new safety signals were observed [Grade ≥ 3 adverse events (AEs): 1L 82·7%, R/R 84·5%; serious AEs: 1L 58·1%, R/R 62·5%]. Neutropenia (1L 50·5%, R/R 53·4%) and thrombocytopenia (1L 14·6%, R/R 19·1%) were the most common Grade 3-5 AEs. G-mono-, G-bendamustine and G-FC-treated patients with unmutated immunoglobulin heavy chain trended towards shorter progression-free survival. Achievement of minimal residual disease negativity was greatest in 1L patients treated with G-FC. In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses supported efficacy in the specific subgroups., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Clinical research has resulted in an improvement of treatment options for patients with immune thrombocytopenia (ITP) over the last years. However, only few data exist on the real-life management of patients with ITP. To expand the knowledge, a multicenter, national survey was undertaken in 26 hematology practices distributed all over Germany. All patients with a diagnosis of ITP were documented using questionnaires, irrespective of the diagnosis date over a period of 2 years. Overall, data of 1023 patients were evaluated with 56% of patients being older than 60 years. Seventy-nine percent of the patients had chronic (> 12 months), 16% persistent (> 3-12 months), and 5% newly diagnosed (0-3 months) ITP. In 61% of cases, the disease lasted 3 or more years before survey documentation started. Main strategies applied as first-line therapy consisted of steroids in 45% and a "watch and wait" approach in 41% of patients. During second- and third-line strategies, treatment with steroids decreased (36% and 28%, respectively), while treatment modalities such as TPO-RAs increased (19% and 26%, respectively). As expected, patients with a low platelet count and thus a higher risk for bleeding and mortality received treatment (esp. steroids) more frequently during first line than those with a higher platelet count. Up to a third of patients were treated with steroids for more than a year. Overall, our study provides a cross-section overview about the current therapeutic treatment landscape in German ITP patients. The results will help to improve therapeutic management of ITP patients.

Background: Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016., Methods: We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting., Results: In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population., Conclusion: The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals.

The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator's choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2-6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade ≥3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade ≥3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade ≥3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. ( clinicaltrials.gov identifier: 01905943 )., (Copyright© 2018 Ferrata Storti Foundation.)

Unlabelled: Circulating endothelial progenitor cells (EPCs) actively supply cells that may participate in tumor angiogenesis. The differing effects of low-dose metronomic trofosfamide as opposed to conventional dose-dense chemotherapy on plasma levels of vascular endothelial growth factor (VEGF) and the numbers of circulating EPC are reported., Patients and Methods: Blood samples were obtained from cancer patients, 18 receiving oral metronomic chemotherapy of trofosfamide with or without celecoxib, and 24 receiving conventional dose-dense chemotherapy, eight of them in adjuvant intention. Mononuclear cells were analyzed by flow cytometry for CD34, CD45 and vascular endothelial growth factor-receptor 2 (VEGF-R2) coexpression, defining EPCs, and for plasma levels of VEGF by ELISA at day 0, 10 and 21 of therapy., Results: After conventional dose-dense chemotherapy, the numbers of circulating EPCs and the VEGF plasma concentrations increased sharply, doubling pretherapeutic levels at day 21. In contrast, under low-dose metronomic chemotherapy, the numbers of circulating EPCs decreased significantly and VEGF plasma concentrations remained unchanged., Conclusion: These observations provide evidence that conventional dose-dense chemotherapy leads to rebound EPC mobilization even when given with adjuvant intention, while low-dose metronomic scheduling of cytotoxic substances such as trofosfamide may sharply reduce EPC release into the circulation.

Background: The ifosfamide metabolite chloroacetaldehyde had been made responsible for side effects only. We found in previous studies a strong cytotoxicity on human MX-1 tumor cells and xenografts in nude mice. Chloroacetaldehyde is supposed to act via alkylation or by inhibition of mitochondrial oxidative phosphorylation with decrease of ATP. The aim of this study was to further elucidate chloroacetaldehyde's mode of action., Methods: MX-1 breast carcinoma cells were measured for ATP-content after exposure to chloroacetaldehyde. Further, the effect of chloroacetaldehyde on DNA-synthesis and its potency of causing strand-breaks or cross-links were investigated by bromodeoxyuridine-incorporation, comet-assay and a DNA interstrand cross-linking-assay., Results: Chloroacetaldehyde in high concentrations induces a reduction of ATP-levels when anaerobic glycolysis is blocked by oxamate and reduces the bromodeoxyuridine-incorporation to 46.3% after 4 h when used in IC(50) concentrations (7.49 mumol/l). In addition we observed DNA single strand-breaks in MX-1 cells treated with chloroacetaldehyde visible in the Comet assay, but no DNA-cross-linking by comet assay and cross-linking assay., Conclusion: In summary, our results show that chloroacetaldehyde influences the oxidative phosphorylation in mitochondria, however, this is observed only in high concentrations and is not of clinical relevance because the tumor cells regenerate ATP by anaerobic glycolysis. Nevertheless, chloroacetaldehyde causes DNA-strand-breaks and strong inhibition of DNA-synthesis.

Background: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course., Patients and Methods: Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT., Results: Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively., Conclusions: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

Patients with primary progressive or refractory Hodgkin's disease (HD) or aggressive non-Hodgkin's lymphoma (NHL) have a particularly poor prognosis. Here we report the results of autologous tandem transplantation in these patients. Patients aged 18-55 years with primary progressive or refractory relapsed HD and aggressive NHL were included. Patients received high-dose etoposide (2000 mg/m(2)) followed by peripheral blood stem cell harvest (PBSC). The first high-dose chemotherapy (TMC) consisted of thiotepa (750 mg/m(2)), mitoxantrone (40 mg/m(2)), and carboplatin (990 mg/m(2)). Patients with no change (NC), partial remission (PR), or complete remission (CR) after TMC then received BEAM with carmustine (300 mg/m(2)), etoposide (1200 mg/m(2)), cytarabine (1600 mg/m(2)), and melphalan (140 mg/m(2)). Patients with bulky disease (>5 cm) or residual lymphoma received involved field radiotherapy. Twenty-five patients were included (HD=10, NHL=15, median age 34 years). Two patients with HD achieved a CR and five patients a PR [response rate (RR) 70%]. Three patients (30%) experienced treatment failure including two deaths due to peritransplant complications. Five patients with aggressive NHL were in CR and two patients in PR (RR 46%). Of the eight patients (56%) with treatment failure, three had progressive disease and five died from peritransplant complications. Freedom from treatment failure (FFTF) and overall survival (OS) for all patients after 12 months was 28% and 40%, respectively. Tandem HDCT followed by autologous stem cell transplantation (ASCT) offers a chance of cure in these poor prognostic patients, but is associated with risks.

Background: We designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD)., Patients and Methods: Eligibility criteria included age 18-65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, high-dose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT)., Results: A total of 102 patients (median age 34 years, range 18-64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3-61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P <0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P <0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were significant for OS., Conclusion: Based on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol).

Catheter-related infections cause considerable morbidity in hospitalised patients. The incidence does not seem to be higher in neutropenic patients than in non- neutropenic patients. Gram-positive bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the most frequently cultured pathogens, followed by Candida species. In contrast, Gram-negative bacteria play only a minor role in catheter-related infections. Positive blood cultures are the cornerstone in the diagnosis of catheter-related infections, while local signs of infection are only rarely present. However, a definite diagnosis generally requires the removal of the catheter and its microbiological examination. The role plate method with semiquantitative cultures (Maki) has been established as standard in most laboratories. Other standard procedures use quantitative techniques (Sherertz, Brun-Buisson) and are more sensitive. For therapy of catheter-related infections, antibiotics are administered according to the susceptibility of the cultured organism. Routine administration of gylcopepticed antibiotics is not indicated. Removal of the catheter has to be considered in any case of suspected catheter-related infection and is obligatory in Staphylococcus aureus and Candida infections. Tunnel or pocket infection of long-term catheters is always an indication for removal. In the future, the rate of catheter-related infections in neutropenic patients may be reduced by the use of catheters coated with antimicrobial agents.

Objective: This study focuses on the pharmacokinetics of trofosfamide (TRO) and metabolites after oral administration of TRO., Methods: Twelve patients with solid tumors and non-Hodgkin lymphomas were treated with 450 mg TRO orally for 7 days. TRO and the stable metabolites ifosfamide (IFO), cyclophosphamide (CYC), 2- and 3-dechloroethylifosfamide (2-DCE, 3-DCE) were determined by GC and the sum of the 4-OH-metabolites was measured by HPLC., Results: A fast metabolism of TRO with a half-life of about 1 h was observed. IFO was the main stable metabolite, whereas CYC was only detected in minor quantities. The peak levels and the AUC of the 4-OH-metabolites were 9.5 and 4.3 times higher than observed after an equimolar IFO dose. Only 6% of the administered dose was recovered in urine within 24 hours as stable metabolites. TRO was under limit of detection., Conclusions: Our results confirm that dechloroethylation of TRO to IFO is a major metabolic pathway. Additionally, we found considerable 4-hydroxylation not shown previously. With respect to the low levels of IFO and CYC observed, the sum of 4-OH-metabolites cannot be explained by hydroxylation of these metabolites only. Hence, we assume a direct 4-hydroxylation of TRO occurring to a high extent. Bioavailability of TRO could not be calculated directly, because TRO is only available as an oral formulation. The bioavailability of oral IFO, however, is reported to be almost 100%. Therefore, after normalization of the dose, a bioavailability of 32% for IFO after oral TRO could be calculated. Thus, in contrast to previous reports, direct 4-hydroxylation of TRO seems to be the main metabolic pathway.

Metabolic activation of ifosfamide (IFO) leads to the active 4-hydroxy-metabolite and to a substantial liberation of chloroacetaldehyde (CAA). CAA has been presumed responsible for side effects of IFO. We recently have shown cytotoxic effects of CAA against human tumor cells in vitro. The aim of this study was to demonstrate antitumor effects of CAA in vivo, and to compare its potency to 4-OH-IFO. Pharmacokinetics of IFO and metabolites were evaluated after infusion of 250 mg/kg IFO in mice. The area under the curve (AUC) for 4-hydroxyifosfamide (4-OH-IFO) and CAA were 138. 5 and 102.4 micromol. h/liter, respectively. To compare pharmacokinetics and antitumor effects, the mice received isolated infusion of 4-OH-IFO or CAA in equimolar doses to IFO. Administration of 4-OH-IFO yielded AUC values comparable with those obtained after administration of the parent drug. In contrast, infusion of isolated CAA via tail vein gave a low AUC value of 51.5 micromol. h/liter due to slow flow in the tail vein and rapid degradation. Administration of the parent drug gave highly cytotoxic intratumoral peak concentrations of 25 and 12 micromol/kg tumor weight for 4-OH-IFO and CAA in MX1 xenotransplanted nude mice. Both IFO and isolated 4-OH-IFO led to complete remissions. Administration of isolated CAA (75 mg/kg) delayed tumor growth significantly. The equitoxic dose of isolated 4-OH-IFO was 40 mg/kg. On a molar basis CAA was seven times less potent as 4-OH-IFO. However, on the basis of achieved AUC values, CAA seems to exhibit a similar antitumor activity to 4-OH-IFO.

Background and Objectives: Optimal mobilization and harvest of hematopoietic progenitors are essential for peripheral blood stem cell transplantation after myeloablative high-dose chemotherapy. Conflicting data have been published concerning the most useful, cost-effective collection strategy which is also convenient for patients., Materials and Methods: A total of 66 leukaphereses in 20 patients were retrospectively evaluated. We assessed the predictive value of the number of white blood cells, mononuclear cells (MNCs) and CD34+ cells in peripheral blood for the yield of CD34+ cells in leukapheresis products. The concentrations of MNCs and CD34+ cells were quantified simultaneously by a flow cytometric procedure using fluorescent microparticles. Their collection efficiencies were calculated based on a newly developed formula., Results: The collected hematopoietic progenitor concentration could be predicted only by the number of peripheral blood CD34+ cells prior to apheresis (r = 0.902; p<0.01). Furthermore, the mobilization of at least 30 CD34+ cells/microl peripheral blood was a good predictor that a single leukapheresis would yield a minimum of 2.0x10(6) CD34+ cells/kg body weight. The collection efficiencies calculated by the new formula were 55.2+/-10.7% and 57.7+/-11.2% for MNCs and CD34+ cells, respectively., Conclusion: The precise quantification of MNCs and CD34+ cells by a direct flow cytometric assay, as well as the new formula to determine the collection efficiencies, has an impact on optimizing high-quality stem cell products.

The efficacy of mafosfamide purging depends on factors like incubation time, drug and erythrocyte concentration. To determine the influence of protein-bound SH groups in the incubation medium, the cytotoxicity of mafosfamide on G-CSF mobilized CD34+/- cells was evaluated by short-term culture assays and drug concentration measurements. 100 micromol/ml mafosfamide was incubated for 30 min in five buffers (PBS, PBS with 1%, 5% and 10% BSA and plasma). The mean calculated areas under the concentration-time curves (AUC) were 2489 +/- 198, 1561 +/- 286, 976 +/- 201, 585 +/- 62 and 605 +/- 196 micromol/l/min. The mean reductions of CFU-GM growth were 79.4%, 73.0%, 62.5%, 30.3%, 6.2% respectively. Similar results were obtained for BFU-E. Regression analysis showed a good correlation between cytotoxicity and AUCs (CFU-GM: r = 0.8195; BFU-E: r = 0.8207). This effect is well explained by the different concentrations of SH moieties in the incubation medium resulting in a higher drug binding capacity. The profound difference between AUCs and CFU-GMs in plasma and 10% BSA cannot be explained by the quantity of SH-groups. It is probably due to an additional enzymatic drug degeneration by the 3'-5'exonuclease subsite of plasma DNA polymerase. In conclusion, the concentration of albumin-associated SH groups strongly influences the cytotoxicity of mafosfamide. It has to be considered as a new and important aspect in ex vivo bone marrow purging.

The initial metabolism of ifosfamide (IFO) consists of two different pathways, which lead to the alkylating metabolite 4-hydroxy-IFO and to chloroacetaldehyde (CAA). CAA has been reported to cause side effects, such as neuro- and nephrotoxicity, whereas no direct antitumor effect has been described thus far. Therefore, two human tumor cell lines (MXI and S117) and a renal tubular cell line (Landa Leiden) were exposed to 4-hydroxy-IFO, CAA, and a combination of both. The concentrations used were in the same range as measured in the blood of 10 patients treated with 5 g/m2 IFO. The cell survival was measured using the MTT assay. Similar dose-response curves were found for both metabolites. For the MX1 tumor, the IC50s of 4-hydroxy-IFO and CAA were 10.8 and 8.6 microM, respectively. For the reduction of S117 cell survival, higher concentrations of the metabolites were needed (25.0 microM 4-hydroxy-IFO and 15.3 microM CAA). Combination treatment of the cells resulted in an approximately additive effect. Both metabolites exhibited similar toxicity against Landa Leiden cells. Our results indicate that CAA has its own cytotoxic profile against tumor cells. Hence, we conclude that the molecular mechanism of action of IFO seems to be only in part an alkylating effect and that CAA may play an important role in the therapeutic efficacy of IFO.

The low bone marrow toxicity of high dose alkylating agents when given in combination with whole body hyperthermia (WBH) may be explained in part by the parallel induction of the granulocyte colony stimulating factor. Since transforming growth factor beta (TGF beta) is known to act synergistically with colony stimulating factors, we performed studies of TGF beta expression under WBH in 12 patients with histologically confirmed metastatic sarcoma. Each patient was given ifosfamide, carboplatin, and etoposide combined with WBH (41.8 degrees C, 1 h). Plasma specimens far determination of TGF beta levels were taken prior to WBH and at different time points after start of WBH. Immunoreactive TGF beta 1 and TGF beta 2 were measured by ELISA. Follow-up revealed a significant increase in TGF beta 1 and TGF beta 2 in 9 of 12 patients, starting 2 h after begin of WBH and peaking 10 h later. The mean value for TGF beta 1 prior to therapy was 3.3 ng/ml (range: 0.9-7.3 ng/ml), rising after 12 h to 5.3 ng/ml (range: 2.8-11,5 ng/ml) (p<0.05). The values for TGF beta 2 were 3.1 ng/ml (range: 1.9-4.1 ng/ml) and 3.9 ng/ml (range: 3.2-4.5 ng/ml) (p<0.05), respectively, Both TGF beta 1 and TGF beta 2 had to be activated in vitro by acidification, Initial TGF beta 1 and TGF beta 2 levels did not differ from those in healthy controls. Collectively, our data indicate enhanced TGF beta 1 and TGF beta 2 expression under WBH and support the thesis that TGF beta is a myeoloprotective factor because it stimulates granulopoiesis. The transient growth arrest of very early stem cells by TGF beta may be an additional factor contributing to the low myelotoxicity of alkylating agents when given under WBH.