9 results on '"Junghanss, Christian"'
Search Results
2. Combined BCL-2 and PI3K/AKT Pathway Inhibition in KMT2A -Rearranged Acute B-Lymphoblastic Leukemia Cells.
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Holz, Clemens, Lange, Sandra, Sekora, Anett, Knuebel, Gudrun, Krohn, Saskia, Murua Escobar, Hugo, Junghanss, Christian, and Richter, Anna
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PI3K/AKT pathway ,ACUTE leukemia ,HEMATOLOGIC malignancies ,CHRONIC lymphocytic leukemia ,ACUTE myeloid leukemia - Abstract
Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with KMT2A rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene BBC3 as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Allogeneic hematopoietic stem cell transplantation improves long-term outcome for relapsed AML patients across all ages: results from two East German Study Group Hematology and Oncology (OSHO) trials.
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Heinicke, Thomas, Krahl, Rainer, Kahl, Christoph, Cross, Michael, Scholl, Sebastian, Wolf, Hans-Heinrich, Hähling, Detlev, Hegenbart, Ute, Peter, Norma, Schulze, Antje, Florschütz, Axel, Volker, Schmidt, Reifenrath, Kolja, Zojer, Niklas, Junghanss, Christian, Sayer, Herbert G., Maschmeyer, Georg, Christian, Späth, Hochhaus, Andreas, and Fischer, Thomas
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HEMATOPOIETIC stem cell transplantation ,OLDER patients ,OVERALL survival ,ACUTE myeloid leukemia ,HEMATOLOGY - Abstract
Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem. [ABSTRACT FROM AUTHOR]
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- 2021
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4. Correction to: Allogeneic hematopoietic stem cell transplantation improves long‑term outcome for relapsed AML patients across all ages: results from two East German Study Group Hematology and Oncology (OSHO) trials.
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Heinicke, Thomas, Krahl, Rainer, Kahl, Christoph, Cross, Michael, Scholl, Sebastian, Wolf, Hans‑Heinrich, Hähling, Detlev, Hegenbart, Ute, Peter, Norma, Schulze, Antje, Florschütz, Axel, Schmidt, Volker, Reifenrath, Kolja, Zojer, Niklas, Junghanss, Christian, Sayer, Herbert G., Maschmeyer, Georg, Späth, Christian, Hochhaus, Andreas, and Fischer, Thomas
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HEMATOPOIETIC stem cell transplantation ,ACUTE myeloid leukemia ,HEMATOLOGY ,ONCOLOGY ,OVERALL survival - Abstract
Correction to: Allogeneic hematopoietic stem cell transplantation improves long-term outcome for relapsed AML patients across all ages: results from two East German Study Group Hematology and Oncology (OSHO) trials A Overall survival (OS) of patients with AML after frst relapse according to age. C Overall survival (OS) of patients with AML after frst relapse according to favorable, intermediate, and unfavorable cytogenetics. [Extracted from the article]
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- 2021
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5. Pretreatment long interspersed element (LINE)-1 methylation levels, not early hypomethylation under treatment, predict hematological response to azacitidine in elderly patients with acute myeloid leukemia.
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Cross, Michael, Bach, Enrica, Tran, Thao, Krahl, Rainer, Jaekel, Nadja, Niederwieser, Dietger, Junghanss, Christian, Maschmeyer, Georg, and Al-Ali, Haifa Kathrin
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METHYLATION ,EPIGENETICS ,CYTOSINE ,AZACITIDINE ,MYELOID leukemia ,CANCER chemotherapy - Abstract
Background: Epigenetic modulations, including changes in DNA cytosine methylation, are implicated in the pathogenesis and progression of acute myeloid leukemia (AML). Azacitidine is a hypomethylating agent that is incorporated into RNA as well as DNA. Thus, there is a rationale to its use in patients with AML. We determined whether baseline and/or early changes in the methylation of long interspersed element (LINE)-1 or CDH13 correlate with bone marrow blast clearance, hematological response, or survival in patients with AML treated with azacitidine. Methods: An open label, phase I/II trial was performed in 40 AML patients (median bone marrow blast count was 42%) unfit for intensive chemotherapy treated with azacitidine 75 mg/m2/day subcutaneously for 5 days every 4 weeks. Bone marrow mononuclear cell samples were taken on day 0 (pretreatment) and day 15 during the first treatment cycle; LINE-1 and CDH13 methylation levels were quantified by methylation-specific, semiquantitative, real-time polymerase chain reaction. Results: Treatment with azacitidine significantly reduced LINE-1 but not CDH13 methylation levels over the first cycle (P , 0.0001). Absolute LINE-1 methylation levels tended to be lower on day 0 (P = 0.06) and day 15 of cycle 1 (P = 0.03) in patients who went on to achieve subsequent complete remission, partial remission or hematological improvement versus patients with stable disease. However, the decrease in LINE-1 methylation over the first treatment cycle did not correlate with subsequent response (P = 0.31). Baseline methylation levels of LINE-1 or CDH13 did not correlate with disease-related prognostic factors, including cytogenetic risk, relapsed/refractory AML, or presence of NPM1 or FLT3 mutations. No correlation was observed between LINE-1 or CDH13 methylation levels and overall survival. Conclusion: Analysis of baseline LINE-1 methylation levels may help identify elderly AML patients who are most likely to respond to azacitidine therapy. [ABSTRACT FROM AUTHOR]
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- 2013
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6. Survey and analysis of the efficacy and prescription pattern of sorafenib in patients with acute myeloid leukemia.
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Röllig, Christoph, Brandts, Christian, Shaid, Shabnam, Hentrich, Marcus, Krämer, Alwin, Junghanß, Christian, Schleyer, Eberhard, Müller-Tidow, Carsten, Berdel, Wolfgang E., Ritter, Barbara, Pflüger, Karl-Heinz, Kramer, Michael, Haibach, Martina, Ehninger, Gerhard, Serve, Hubert, and Krause, Stefan W.
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DRUG efficacy ,DRUG prescribing ,ACUTE myeloid leukemia ,CARCINOGENESIS ,GRAM-negative bacteria ,PATIENTS - Abstract
Sorafenib is a multi-kinase inhibitor with activity against several intracellular kinases which may play a role in the pathogenesis of acute myeloid leukemia (AML). In vitro data and results from early clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. However, clinical data are still sparse, and there are only a few reported cases of monotherapy. The aim of the present research was to collect clinical data on efficacy and safety in a systematic way by conducting a survey on clinical experience with sorafenib. Thirty institutions were asked to document all patients treated with sorafenib diagnosed with AML. Of all 29 evaluable patients, six (21%) responded to sorafenib containing treatment by achieving a complete remission (CR, n = 2) or complete remission with incomplete platelet recovery (CRi, n = 4). In 23 patients receiving sorafenib as monotherapy, the CRi rate amounted to 13% and no CRs were documented. Of the 18 FLT-ITD positive patients with sorafenib monotherapy, two patients achieved a CRi (11%). In five FLT3-ITD negative cases, one CRi was documented (20%). Our results suggest the potential ability of the drug to induce remissions in refractory or relapsed AML even when given as monotherapy. [ABSTRACT FROM AUTHOR]
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- 2012
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7. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
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Al-Ali, Haifa K., Jaekel, Nadja, Junghanss, Christian, Maschmeyer, Georg, Krahl, Rainer, Cross, Michael, Hoppe, Gisa, and Niederwieser, Dietger
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AZACITIDINE ,ACUTE myeloid leukemia ,OLDER patients ,DRUG therapy ,CYTOGENETICS ,PATIENTS ,MEDICAL care - Abstract
The safety and efficacy of azacitidine (5-day schedule) were assessed in a multicenter study in 40 patients (median age 72 years) with acute myeloid leukemia (AML) medically unfit for ( n == 20) or resistant to chemotherapy ( n == 20) from April to October 2008. Median marrow blasts were 42%. After a median follow-up of 13 months, response (complete remission [CR]/partial remission [PR]/hematologic improvement [HI]) was 50% and 10% in newly diagnosed and relapsed/refractory patients, respectively ( p == 0.008). Median time-to-response was 2.5 months with a median duration of 5.9 months. Median survival was not reached for responders versus 3.8 months for 15 (38%) patients with stable disease ( p < 0.045). High-risk cytogenetics was associated with inferior survival ( p == 0.05). Lower marrow blasts on day 15 of cycle 1, irrespective of pretreatment count, predicted subsequent response ( p == 0.01). Azacitidine is active and well tolerated in elderly patients with newly diagnosed AML. [ABSTRACT FROM AUTHOR]
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- 2012
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8. Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study.
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Wandt, Hannes, Schaefer-Eckart, Kerstin, Wendelin, Knut, Pilz, Bettina, Wilhelm, Martin, Thalheimer, Markus, Mahiknecht, Ulrich, Ho, Anthony, Schaich, Markus, Kramer, Michael, Kaufmann, Martin, Leimer, Lothar, Schwerdtfeger, Rainer, Conradi, Roland, Dölken, Gottfried, Kienner, Anne, Hänel, Mathias, Herbst, Regina, Junghanss, Christian, and Ehninger, Gerhard
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BLOOD platelet transfusion , *HEMATOLOGIC malignancies , *CLINICAL trials , *DRUG therapy , *ACUTE myeloid leukemia - Abstract
The article presents information on a study on the comparison of therapeutic platelet transfusion and routine prophylactic transfusion in patients with haematological malignancies. A multicentre and randomised parallel-group trial was done at eight haematology centres in Germany. The patients who passed through chemotherapy for acute myeloid leukaemia or autologous stem-cell transplantation for haematological cancer received routine platelet transfusion. INSET: Panel: Research in context.
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- 2012
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9. Final Evaluation of a Clinical Phase III Trial Comparing Treosulfan to Busulfan-Based Conditioning Therapy Prior to Allogeneic Hematopoietic Stem Cell Transplantation of Adult Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients Ineligible to Standard Myeloablative Regimens
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Beelen, Dietrich, Markiewicz, Miroslaw, Stelljes, Matthias, Remenyi, Peter, Wagner-Drouet, Eva-Maria, Dreger, Peter, Bethge, Wolfgang, Ciceri, Fabio, Stölzel, Friedrich, Junghanß, Christian, Michallet, Mauricette, Schaefer-Eckart, Kerstin, Grigoleit, Goetz, Scheid, Christof, Patriarca, Francesca, Mico, Maria Caterina, Niederwieser, Dietger, Hilgendorf, Inken, Russo, Domenico, and Socié, Gerard
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CLINICAL trials , *BUSULFAN , *HEMATOPOIETIC stem cell transplantation , *GRAFT versus host disease , *MYELODYSPLASTIC syndromes , *ACUTE myeloid leukemia - Abstract
Background Allogeneic hematopoietic stem cell transplantation (HCT) remains a challenge in elderly and comorbid AML and MDS patients. This patient population is at increased risk for non-relapse mortality (NRM) when treated with standard myeloablative conditioning and was selected to compare a newly developed treosulfan-based with a well-established reduced intensity busulfan-based preparative regimen in a prospective randomized clinical phase III trial. Methods Adult patients with AML in remission or MDS scheduled for HCT from matched related or unrelated donors, aged ≥50 years or with a comorbidity index (HCT-CI) of >2 were enrolled by a central stratified randomization procedure. Treatment arms consisted of intravenous (IV) treosulfan (10 g/m²/day [d-4 to d-2]) or IV busulfan (3.2 mg/kg/day [d-4 to d-3]), both combined with IV fludarabine (30 mg/m²/day [d-6 to d-2]). The primary objective was to compare event-free survival (EFS) at two years with relapse/progression of disease, graft failure, or death reported as events. Secondary endpoints were safety evaluation (according to CTCAE v4.03), engraftment, chimerism, overall survival (OS), relapse/progression incidence (RI), NRM and acute or chronic GvHD. After a previously conducted confirmatory interim analysis (based on 476 patients), which resulted in early termination of patient accrual due to significant non-inferiority of treosulfan treatment with improved EFS, NRM and OS (Beelen et al., ASH 2017), results of the final analysis of all 570 randomized patients including post surveillance data are provided here. Results Median age of the 551 patients (352 AML; 199 MDS) included in the full analysis set (268 treosulfan; 283 busulfan) was 60 years (range: 31, 70). Frequencies of early adverse events (d-6 to d+28) and incidences of acute and chronic GvHD were largely comparable between the two regimens, while extensive chronic GvHD was numerically in favor of treosulfan (19.7% vs. 26.7%; p=0.0750). Primary neutrophil recovery at day +28 was comparable, while the rate of complete donor-type chimerism (day +28) was higher after treosulfan (93.2% vs. 83.3%; p<0.0001). After a median follow-up of 29 months (range: 3.0, 54.3) the 2-year EFS was significantly higher in the treosulfan arm (65.7% vs. 51.2%; hazard ratio [HR] 0.64; p=0.0012) as was OS (72.7% vs. 60.2%; HR 0.64; p=0.0037) and NRM (12.0% vs. 20.4%; HR 0.63; p=0.0343). RI was comparable between both regimens (22.0% vs. 25.2%; HR 0.82; p=0.2631). Results were consistent within all pre-defined major prognostic subgroups of patients. Conclusions Final evaluation of this phase III trial substantiates the previous confirmatory analysis resulting in significantly improved survival after treosulfan-based conditioning. Due to the reduction of NRM a major clinical benefit of the new treosulfan conditioning regimen was demonstrated in the selected AML/MDS patient population. [ABSTRACT FROM AUTHOR]
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- 2019
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