Publications by authors named "Wolfgang E Berdel"

351 Publications

Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML.

Blood Adv 2021 Sep 24. Epub 2021 Sep 24.

University Children's Hospital Münster, Muenster, Germany.

We have recently identified the G protein-coupled neuropeptide receptor Calcitonin receptor-like (CALCRL) as an independent prognostic biomarker and a therapeutic target in more than 1500 adult patients with acute myeloid leukemia (AML). Here, we confirmed CALCRL expression as a prognostic factor in a cohort of 284 pediatric patients with AML. High CALCRL expression was independently associated with event free survival (EFS) (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.36-2.57; P=0.0001), overall survival (OS) (HR, 1.55; 95% [CI], 1.06-2.27; P=0.025) and cumulative incidence of relapse (CIR) (HR, 2.10; 95% CI, 1.49-1.96; P<0.0001) when adjusting for age, white blood cell count and genetic risk. Despite its association with leukemia stem cell (LSC) signatures, CALCRL expression remained associated with all endpoints when compared to the LSC17 score. The strong association of CALCRL expression with the risk of relapse also in the pediatric population supports its role as novel age-independent master regulator of relapse-initiating drug-tolerant AML cells in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021005236DOI Listing
September 2021

A Clinically Applicable Gene Expression based Score predicts Resistance to Induction Treatment in Acute Myeloid Leukemia.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), Germany.

Prediction of resistant disease at initial diagnosis of acute myeloid leukemia (AML) can be achieved with high accuracy by using cytogenetic data and 29 gene expression markers (PS29MRC). Our aim was to establish PS29MRC as a clinically usable assay by using the widely implemented NanoString platform and further validate the classifier in a more recently treated patient cohort. 351 patients with newly diagnosed AML intensively treated within the AMLCG registry were analyzed. As a continuous variable, PS29MRC performed best in predicting induction failure in comparison to previously published risk models (OR=2.37; p=1.20·10-9). The classifier was strongly associated with overall survival (HR=1.38; p=2.62·10-6). We were able to establish a previously defined cut-off that allows a classifier dichotomization (PS29MRCdic). PS29MRCdic significantly identified induction failure with 59% sensitivity, 77% specificity and 72% overall accuracy (OR=4.81; p=4.15·10-10). PS29MRCdic was able to improve the ELN-2017 risk classification within every category (favorable: OR=5.44; p=0.017; intermediate: OR=4.43; p=0.011; adverse: OR=2.52; p=0.034). Median patients' overall survival with high PS29MRCdic was 1.8 years compared to 4.3 years of low-risk patients. In multivariate analysis including ELN-2017, clinical and genetic markers, only age and PS29MRCdic were independent predictors of refractory disease. In patients aged 60 or older, only PS29MRCdic was left as significant variable. In summary, we confirmed PS29MRC as a valuable classifier that can be calculated and reproduced on a widely available platform to identify high-risk patients in AML. Risk classification can still be refined beyond ELN-2017 and predictive classifiers might facilitate clinical trials focusing on these high-risk AML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004814DOI Listing
September 2021

The role of autologous stem cell transplantation (ASCT) in aggressive B-cell lymphomas: real-world data from a retrospective single-center analysis.

Ann Hematol 2021 Nov 3;100(11):2733-2744. Epub 2021 Sep 3.

Department of Medicine A, Hematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0-163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34 cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (< 12 months) after first-line therapy showed a trend towards an inferior PFS and OS. Deaths after ASCT were predominantly caused by lymphoma relapse and/or progression (64%) or due to infections (23%). In conclusion, high-dose chemotherapy followed by ASCT in the era of novel targeted agents remains a feasible and effective approach for patients with high-risk or relapsed aggressive B-cell lymphomas. Remission status and age at ASCT, and the number of infused stem cells were of prognostic relevance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04650-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510902PMC
November 2021

Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia.

Blood Adv 2021 09;5(17):3279-3289

Masaryk University and University Hospital, Department of Internal Medicine, Hematology and Oncology, Brno, Czech Republic.

The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11 mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11 mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11 mutations were associated with concomitant mutations in NPM1 (63%), DNMT3A (37%), and NRAS (21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P < .001) and higher white blood cell counts (P = .007) compared with PTPN11 wild-type patients. In a multivariable analysis, PTPN11 mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P < .001), relapse-free survival (HR: 1.52; P = .013), and a lower rate of complete remission (odds ratio: 0.46; P = .008). Importantly, the deleterious effect of PTPN11 mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11 mutations (HR: 2.28; P < .001) but not found with dominant PTPN11 mutations (HR: 1.07; P = .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11 mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525221PMC
September 2021

CEBPA Mutations in 4708 Patients with Acute Myeloid Leukemia - Differential Impact of bZIP and TAD Mutations on Outcome.

Blood 2021 Jul 28. Epub 2021 Jul 28.

Medizinische Fakultät Carl Gustav Carus, TU Dresden, Dresden, Germany.

Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis, however the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adult AML patients recruited into Study Alliance Leukemia trials to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%), 131 CEBPAbi and 109 CEBPAsm (60 affecting the amino-terminal transactivation domains (CEBPAsmTAD) and 49 the carboxy-terminal DNA-binding or basic leucine zipper region (CEBPAsmbZIP)). Interestingly, CEBPAbi and CEBPAsmbZIP patients shared several clinical factors, i.e. were significantly younger (median 46 years and 50 years) and had higher WBC counts at diagnosis (median 23.7 and 35.7 109/l) compared to CEBPAsmTAD patients (median age 63 yrs., median WBC 13.1 109/l; p<.001). Co-mutations were also similar in both groups, e.g. GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs. 6.7% CEBPAsmTAD; p<.001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs. 38.3% CEBPAsmTAD; p<.001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (median OS: 103 and 63 vs. 13 months) and event-free survival (median EFS: 20.7 and 17.1 vs. 5.7 months), in univariate and multivariable analyses. More detailed analysis revealed that the clinical and molecular features as well as the favorable survival were confined to patients showing in-frame mutations in bZIP (CEBPAbZIP-inf). When grouping patients into CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and other non-CEBPAbZIP-inf patients), only CEBPAbZIP-inf patients showed superior CR rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009680DOI Listing
July 2021

Targeting Tissue Factor to Tumor Vasculature to Induce Tumor Infarction.

Cancers (Basel) 2021 Jun 7;13(11). Epub 2021 Jun 7.

Department of Medicine A (Hematology, Hemostaseology, Oncology, Pneumology), University Hospital Muenster, D-48149 Muenster, Germany.

Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13112841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201357PMC
June 2021

Loss-of-Function Mutations of Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia.

Cancers (Basel) 2021 Apr 26;13(9). Epub 2021 Apr 26.

Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital, 60177 Brno, Czech Republic.

Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The corepressor and its homolog, the , have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. and mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were , and . Mutated and loss-of-function mutations of were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005-2.134), = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163-3.117), = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990-2.258), = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of regarding risk stratification in AML, which may influence treatment allocation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13092095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123716PMC
April 2021

Dose escalation and expansion phase I studies with the tumour-targeting antibody-tumour necrosis factor fusion protein L19TNF plus doxorubicin in patients with advanced tumours, including sarcomas.

Eur J Cancer 2021 06 23;150:143-154. Epub 2021 Apr 23.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, Albert Schweitzer Campus 1, 48149 Muenster, Germany. Electronic address:

Background: L19TNF is a recombinant fusion protein composed of a human antibody fragment and human tumour necrosis factor. L19TNF targets the EDB domain of oncofetal fibronectin highly expressed in tumour vasculature and induces tumour remission in mouse tumours. We summarise two phase I trials testing a combination of L19TNF with doxorubicin in patients with solid tumours, particularly soft tissue sarcomas (STS).

Patients And Methods: The first study, an open-label, dose-escalation and expansion phase I study of L19TNF plus doxorubicin, enrolled 27 patients. Three cohorts (10.4-17 μg/kg L19TNF) of patients received L19TNF intravenously at days 1, 3, and 5 and doxorubicin (75 mg/m, then 60 mg/m) on day 1 every 3 weeks. The expansion cohort enrolled patients with STS. The second study tried to re-escalate the doxorubicin dose to 75 mg/m with 13 μg/kg L19TNF. Among primary objectives was the establishment of a recommended dose (RD).

Results: The combination was safely applicable. Dose-limiting toxicity occurred either at 17 μg/kg L19TNF or at 75 mg/m doxorubicin. RD is 13 μg/kg L19TNF plus 60 mg/m doxorubicin. In 15 STS patients of the extension cohort evaluable for efficacy, antitumour activity was observed with complete remission in 1, partial remission in 1 and minor tumour shrinkage in 7 patients. The median overall survival for this heavily pretreated cohort was 14.9 months.

Conclusion: L19TNF can be safely applied in combination with doxorubicin and induces encouraging tumour remissions in patients with soft tissue sarcomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.03.038DOI Listing
June 2021

Unintended Regulatory Caused Early Death-A Difficult Endpoint in Cancer Patient Care and Treatment.

Cancers (Basel) 2021 Mar 22;13(6). Epub 2021 Mar 22.

Department of Medicine A (Hematology, Hemostaseology, Oncology, Pneumology), University Hospital of Muenster, D-48149 Muenster, Germany.

The pharmacological armory against cancer has been growing, with many new drugs approved. The Good Clinical Practice (GCP)-based Clinical Trials Directive was adopted in the EU in 2001, with the important objectives of achieving better patient safety and improved quality of clinical trial conduct. However, clinical experience with the implementation of the regulation raises the question as to whether aspects of this regulatory framework can cause harm to some patients. This question also arises in daily clinical cancer patient care when the time between the publication of pivotal study results and their approval, and details of post-approval regulations, are scrutinized. Clinical observations, provocatively summarized as "unintended regulatory caused early death", are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13061457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005202PMC
March 2021

Allogeneic hematopoietic stem cell transplantation for therapy-related myeloid neoplasms following treatment of a lymphoid malignancy.

Leuk Lymphoma 2021 08 29;62(8):1930-1939. Epub 2021 Mar 29.

Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany.

Advances in lymphoma treatment lead to increasing numbers of long-term survivors. Thus, secondary therapy-related myeloid neoplasms (t-MN) gain clinical relevance. We analyzed 38 t-MN patients receiving an allogeneic stem cell transplantation (SCT) after successful cytotoxic treatment of Hodgkin lymphoma ( = 9), non-Hodgkin lymphoma ( = 24), and multiple myeloma ( = 5), who had developed t-AML ( = 20) or t-MDS ( = 18). Overall survival (OS) and relapse-free survival at 3 years after allogeneic SCT were 43% and 39%. The cumulative incidences of relapse and non-relapse mortality (NRM) at 3 years were 19% and 42%. More than one therapy line for the lymphoid malignancy resulted in a significantly higher NRM rate and inferior 3-year-OS. Our data indicate that allogeneic SCT for patients with t-MN after treatment of a lymphoid malignancy leads to OS rates comparable to patients transplanted for MN. Multiple lines of lymphoma therapy increase NRM and lead to inferior survival after allogeneic SCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2021.1894645DOI Listing
August 2021

Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.

Leukemia 2021 09 18;35(9):2517-2525. Epub 2021 Feb 18.

Klinik für Hämatologie und Onkologie - Stammzelltransplantation, Agaplesion Diakonieklinikum Rotenburg, Rotenburg, Germany.

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01148-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410595PMC
September 2021

Decitabine treatment in 311 patients with acute myeloid leukemia: outcome and impact of mutations - a registry based analysis.

Leuk Lymphoma 2021 06 5;62(6):1432-1440. Epub 2021 Jan 5.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany.

We performed a registry-based analysis of 311 AML patients treated with decitabine in a standard of care setting to assess response and survival data with a distinct focus on the impact of the mutation status. Median age was 73 years. 172 patients received decitabine first-line and 139 in r/r disease. The ORR (whole cohort) was 30% with a median overall survival of 4.7 months. First-line patients achieved better responses than r/r-patients (ORR: 38% vs. 21%) resulting in a median OS of 5.8 months vs. 3.9 months. NGS based mutation analysis was performed in 180 patients. 20 patients (11%) harbored a mutation. Response rates and survival did not differ significantly between mutated patients and wild-type patients. This analysis of a large cohort of AML patients provides response rates and OS data after decitabine treatment. Interestingly, outcome was not negatively influenced by a mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1864354DOI Listing
June 2021

Long-Term Follow-Up on Systemic Bevacizumab Treatment in Recurrent Respiratory Papillomatosis.

Laryngoscope 2021 06 31;131(6):E1926-E1933. Epub 2020 Dec 31.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a primarily benign disease affecting the entire respiratory tract. Treatment is challenging and usually involves surgical interventions and adjuvant medications. Previously, promising results on systemic administration of bevacizumab have been reported. However, experience on long-term systemic use in patients with RRP is not yet available. Here, we present our long-term follow-up on RRP patients undergoing systemic bevacizumab treatment.

Study Design: Case series.

Methods: To describe experience on long-term systemic bevacizumab administration, we performed the underlying investigation. Clinical, radiological, and bronchoscopy data were collected.

Results: To date, a total of n = 5 patients has been treated with systemic bevacizumab at Muenster University Hospital. With a median follow-up since first systemic bevacizumab administration of 95.5 months long-term follow-up is illustrated. Following bevacizumab treatment partial remission or very good partial remission were achieved in all patients. After papilloma recurrence/progression due to bevacizumab discontinuation, further response was documented in all patients in whom bevacizumab was started again. In one patient, bevacizumab was discontinued due to loss of efficacy. Lung cancer developed in one patient with pulmonary papillomatosis prior to bevacizumab administration whereas three patients suffered from malignant transformation during bevacizumab treatment. Systemic bevacizumab led to long-term reduction in surgical interventions in all patients. Except from mild proteinuria and hypertension in two patients therapy was well tolerated.

Conclusions: Systemic bevacizumab represents a promising long-term treatment option for aggressive forms of papillomatosis. Rate of malignant transformation under bevacizumab treatment, optimal treatment schedule, and influence on survival should be further evaluated in clinical trials.

Level Of Evidence: 4 Laryngoscope, 131:E1926-E1933, 2021.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lary.29351DOI Listing
June 2021

Magnesium levels and outcome after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia.

Ann Hematol 2021 Jul 19;100(7):1871-1878. Epub 2020 Dec 19.

Department of Medicine A, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Low intake of magnesium has been associated with the occurrence of lymphomas and decreased magnesium levels suppress the cytotoxic function of T cells and natural killer cells in patients with "X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia" (XMEN) syndrome. These cell types are also important mediators of immune-mediated effects after allogeneic hematopoietic stem cell transplantation. Here, we show that high posttransplant magnesium levels independently associate with a lower incidence of relapse, a higher risk of acute graft-versus-host disease, and a higher non-relapse mortality in 368 patients with acute myeloid leukemia from our center. Magnesium serum levels might impact on donor-cell-mediated immune responses in acute myeloid leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04382-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195955PMC
July 2021

Animal Safety, Toxicology, and Pharmacokinetic Studies According to the ICH S9 Guideline for a Novel Fusion Protein tTF-NGR Targeting Procoagulatory Activity into Tumor Vasculature: Are Results Predictive for Humans?

Cancers (Basel) 2020 Nov 26;12(12). Epub 2020 Nov 26.

Department of Medicine A Hematology and Oncology, University Hospital Muenster, D-48149 Muenster, Germany.

Background: CD-13 targeted tissue factor tTF-NGR is a fusion protein selectively inducing occlusion of tumor vasculature with resulting tumor infarction. Mechanistic and pharmacodynamic studies have shown broad anti-tumor therapeutic effects in xenograft models.

Methods: After successful Good Manufacturing Practice (GMP) production and before translation into clinical phase I, ICH S9 (S6) guideline-conforming animal safety, toxicology, and pharmacokinetic (PK) studies were requested by the federal drug authority in accordance with European and US regulations.

Results: These studies were performed in mice, rats, guinea pigs, and beagle dogs. Results of the recently completed clinical phase I trial in end-stage cancer patients showed only limited predictive value of these non-clinical studies for patient tolerability and safety in phase I.

Conclusions: Although this experience cannot be generalized, alternative pathways with seamless clinical phase 0 microdosing-phase I dose escalation studies are endorsed for anticancer drug development and translation into the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759859PMC
November 2020

Blinatumomab or Inotuzumab Ozogamicin as Bridge to Allogeneic Stem Cell Transplantation for Relapsed or Refractory B-lineage Acute Lymphoblastic Leukemia: A Retrospective Single-Center Analysis.

Clin Lymphoma Myeloma Leuk 2020 10 3;20(10):e724-e733. Epub 2020 Jun 3.

Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany. Electronic address:

Background: Blinatumomab and inotuzumab ozogamicin are now widely used to treat relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).

Patients And Methods: We have reported the clinical course of 34 adult patients with r/r B-ALL receiving blinatumomab or inotuzumab ozogamicin at our institution from 2009 to 2019.

Results: Blinatumomab-based salvage therapy was applied for overt r/r B-ALL (n = 13) or minimal residual disease (MRD) positivity (n = 5). Of the 13 patients with r/r B-ALL, 9 (69%; 95% confidence interval [CI], 39%-91%) achieved complete remission (CR), with 78% of CR patients (95% CI, 40%-97%) reaching MRD negativity. MRD negativity was also achieved in all 5 patients treated for MRD positivity. The 1-year overall survival of patients receiving blinatumomab for r/r B-ALL and MRD positivity was 54% (n = 13; 95% CI, 26%-81%) and 80% (n = 5; 95% CI, 44-100), respectively. In the inotuzumab ozogamicin group, all 16 patients were treated for overt r/r B-ALL. The rate of CR was 94% (95% CI, 70%-100%), with 67% (95% CI, 38%-88%) of CR patients reaching MRD negativity. The 1-year OS after the first application of inotuzumab ozogamicin was 46% (95% CI, 18%-74%). Of those patients receiving blinatumomab and inotuzumab ozogamicin as a bridge-to-transplant strategy, 79% and 80%, respectively, proceeded to allogeneic stem cell transplantation. The most frequent drug-specific adverse events were similar to those previously reported, including cytokine release syndrome, capillary leak syndrome, and neurotoxicity for blinatumomab and transplant-associated veno-occlusive disease of the liver for inotuzumab ozogamicin.

Conclusion: Together with previous observations from phase III clinical trials, these data suggest that blinatumomab and inotuzumab ozogamicin are highly effective salvage regimens in r/r B-ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.05.022DOI Listing
October 2020

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study.

Cancers (Basel) 2020 Jun 7;12(6). Epub 2020 Jun 7.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, D-48149 Muenster, Germany.

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction.

Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts.

Results: MTD was 3 mg/m tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t of 8 to 9 h without accumulation in daily administrations.

Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12061488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352358PMC
June 2020

Low-density lipoprotein receptor (LDLR) is an independent adverse prognostic factor in acute myeloid leukaemia.

Br J Haematol 2021 02 8;192(3):494-503. Epub 2020 Jun 8.

Department of Medicine A, University Hospital Münster, Münster, Germany.

The low-density lipoprotein receptor (LDLR) is a membrane receptor that mediates the endocytosis of low-density lipoprotein (LDL). Uptake of LDL has been proposed to contribute to chemotherapy resistance of acute myeloid leukaemia (AML) cell lines in vitro. In the present study, we analysed LDLR expression and survival using bone marrow biopsies from 187 intensively treated patients with AML. Here, increasing LDLR expression was associated with decreasing overall (58·4%, 44·2%, and 24·4%; P = 0·0018), as well as event-free survival (41·7%, 18·1%, and 14·3%; P = 0·0077), and an increasing cumulative incidence of relapse (33·9%, 55·1%, and 71·4%; P = 0·0011). Associations of LDLR expression with survival were confirmed in 557 intensively treated patients from two international validation cohorts. In the analytic and validation cohorts, LDLR expression remained associated with outcome in multivariable regression analyses including the European LeukemiaNet genetic risk classification. Thus, LDLR predicts outcome of patients with AML beyond existing risk factors. Furthermore, we found low expression levels of LDLR in most healthy tissues, suggesting it as a promising target for antibody-based pharmacodelivery approaches in AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16853DOI Listing
February 2021

Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?

Blood 2020 08;136(7):823-830

Universitätsklinik und Poliklinik für Innere Medizin IV, Universitätsklinikum Halle (Saale), Halle (Saale), Germany.

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. All registered non-acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019004583DOI Listing
August 2020

Long-term survival and polyclonal immunoglobulin reconstitution after allogeneic stem cell transplantation in multiple myeloma.

Ann Hematol 2020 Aug 22;99(8):1907-1915. Epub 2020 May 22.

Department of Medicine A, University Hospital Münster, Münster, Germany.

Despite significant progress made in the treatment of patients with multiple myeloma (MM) in the last decade, for patients with early relapse or rapidly progressing high-risk disease, allogeneic hematopoietic stem cell transplantation (SCT) might be an option leading to long-term survival. Here, we retrospectively analyzed the outcomes of 90 MM patients who received allogeneic SCT in our center between 1999 and 2017. We specifically assessed the association of impaired humoral immune reconstitution, referred to as immunoparesis, and post-transplant survival. Sixty-four patients received allogeneic SCT in relapse following 2-7 lines of therapy; 26 patients received upfront tandem autologous-allogeneic SCT. With a median follow-up of 76 months, OS and PFS were 52.6% (95% CI 42.9-64.3) and 36.4% (95% CI 27.6-47.9) at 2 years and 38.6% (95% CI 29.2-51.1) and 25.3% (95% CI 17.5-36.4) at 5 years, respectively. Receiving more than two therapy lines prior to transplantation was an independent risk factor for OS (HR 3.68, 95% CI 2.02-6.70) and PFS (HR 3.69, 95% CI 2.09-6.50). In a landmark analysis at day 200, prolonged immunoparesis was associated with reduced OS (HR 3.22, 95% CI 1.14-9.11). Allogeneic stem cell transplantation offers an additional treatment element that may lead to long-term remission in selected patients with poor prognosis, probably exploiting graft-versus-myeloma effects. Immunoparesis could potentially serve as an indicator for impaired survival following allogeneic transplantation, an observation to be further studied prospectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04068-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340674PMC
August 2020

Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia.

Leukemia 2020 10 1;34(10):2621-2634. Epub 2020 May 1.

Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

Previous studies demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies with both clinical and functional implications. However, their aberrant splicing patterns in acute myeloid leukemia remain largely unexplored. In this study, we characterized mutations in SRSF2, U2AF1, and SF3B1, the most commonly mutated splicing factors. In our clinical analysis of 2678 patients, splicing factor mutations showed inferior relapse-free and overall survival, however, these mutations did not represent independent prognostic markers. RNA-sequencing of 246 and independent validation in 177 patients revealed an isoform expression profile which is highly characteristic for each individual mutation, with several isoforms showing a strong dysregulation. By establishing a custom differential splice junction usage pipeline, we accurately detected aberrant splicing in splicing factor mutated samples. A large proportion of differentially used junctions were novel, including several junctions in leukemia-associated genes. In SRSF2(P95H) mutants, we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Furthermore, we observed a validated impact on overall survival for two junctions overused in SRSF2(P95H) mutants. We conclude that splicing factor mutations do not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-0839-4DOI Listing
October 2020

Smoking and AML - another piece in the puzzle.

Br J Haematol 2020 07 27;190(2):143. Epub 2020 Apr 27.

Department of Medicine A, University Hospital Münster, Münster, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16683DOI Listing
July 2020

Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.

Leukemia 2020 12 30;34(12):3161-3172. Epub 2020 Mar 30.

Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

The revised 2017 European LeukemiaNet (ELN) recommendations for genetic risk stratification of acute myeloid leukemia have been widely adopted, but have not yet been validated in large cohorts of AML patients. We studied 1116 newly diagnosed AML patients (age range, 18-86 years) who had received induction chemotherapy. Among 771 patients not selected by genetics, the ELN-2017 classification re-assigned 26.5% of patients into a more favorable or, more commonly, a more adverse-risk group compared with the ELN-2010 recommendations. Forty percent of the cohort, and 51% of patients ≥60 years, were classified as adverse-risk by ELN-2017. In 599 patients <60 years, estimated 5-year overall survival (OS) was 64% for ELN-2017 favorable, 42% for intermediate-risk and 20% for adverse-risk patients. Among 517 patients aged ≥60 years, corresponding 5-year OS rates were 37, 16, and 6%. Patients with biallelic CEBPA mutations or inv(16) had particularly favorable outcomes, while patients with mutated TP53 and a complex karyotype had especially poor prognosis. DNMT3A mutations associated with inferior OS within each ELN-2017 risk group. Our results validate the prognostic significance of the revised ELN-2017 risk classification in AML patients receiving induction chemotherapy across a broad age range. Further refinement of the ELN-2017 risk classification is possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-0806-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685975PMC
December 2020

Renaissance of Radiotherapy in Intestinal Lymphoma? 10-Year Efficacy and Tolerance in Multimodal Treatment of 134 Patients: Follow-up of Two German Multicenter Consecutive Prospective Phase II Trials.

Oncologist 2020 05 27;25(5):e816-e832. Epub 2020 Mar 27.

Department of Radiation Oncology, University Hospital of Muenster, Muenster, Germany.

Purpose: This article reports on the long-term impact of radiotherapy adapted to stage, histology, and previous resection in a large cohort of patients with intestinal lymphoma (iL) treated with definitive or adjuvant curative-intent radiation therapy (RT) ± chemotherapy (CHOP, MCP, or COP).

Patients And Methods: In two consecutive prospective study designs, 134 patients with indolent (stage IE-IIE) or aggressive (stage IE-IVE) iL were referred to 61 radiotherapeutic institutions between 1992 and 2003. Patients with indolent iL received extended field (EF) 30 Gy (+10 Gy boost in definitive treatment); patients with aggressive iL received involved field (IF) (EF) 40 Gy by means of stage-, histology-, and operation-adapted radiation fields.

Results: The patients had median age 58 years and were predominantly male (2:1). Histology showed aggressive prevalence (1.6:1), stage IE-to-stage IIE ratio of iL 1.04:1, and localized stages-to-advanced stages ratio of aggressive lymphoma 23:1. Median follow-up was in total 11.7 years: 10.0 years in the first study, GIT (GastroIntestinal-Tract) 1992, and 11.8 years in the second study, GIT 1996. Lymphoma involvement was predominantly a single intestinal lesion (82.1%). Decrease of radiation field size from EF to IF in stage I aggressive iL from GIT 1992 to GIT 1996 resulted in a nonsignificant partial reduction of chronic toxicity while maintaining comparable survival rates (5-year overall survival 87.9 vs. 86.7%, 10-year overall survival 77.4 vs. 71.5%) with nonsignificant difference in event-free survival (5-year event-free survival 82.6 vs. 86.7%, 10-year event-free survival 69.7 vs. 71.5%) and lymphoma-specific survival (5-year lymphoma-specific survival 90.1 vs. 91.9%, 10-year lymphoma-specific survival 87.6% vs. 91.9%). Comparative dose calculation of two still available indolent duodenal lymphoma computed tomography scans revealed lower radiation exposure to normal tissues from applying current standard involved site RT (ISRT) 30 Gy in both cases.

Conclusion: RT adapted to stage, histology, and resection in multimodal treatment of iL, despite partially decreasing field size (EF to IF), achieves excellent local tumor control and survival rates. The use of modern RT technique and target volume with ISRT offers the option of further reduction of normal tissue complication probability.

Implications For Practice: Although patients with intestinal lymphoma (iL) are heterogeneous according to histology and subtype, they benefit from radiotherapy. Prospective study data from 134 patients with indolent iL (stage IE-IIE) or aggressive iL (stage IE-IVE) show 100% tumor control after definitive or adjuvant curative-intent radiation therapy ± chemotherapy. Radiation treatment was applied between 1992 and 2003. Median follow-up in total was 11.7 years. No radiotherapy-associated death occurred. Relapse developed in 15.7% of the entire cohort; distant failure was more frequent than local (4:1). Normal tissue complication probability can be further improved using modern involved site radiation therapy techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2019-0783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216456PMC
May 2020

Radiation synergizes with antitumor activity of CD13-targeted tissue factor in a HT1080 xenograft model of human soft tissue sarcoma.

PLoS One 2020 21;15(2):e0229271. Epub 2020 Feb 21.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, Muenster, Germany.

Background: Truncated tissue factor (tTF) retargeted by NGR-peptides to aminopeptidase N (CD13) in tumor vasculature is effective in experimental tumor therapy. tTF-NGR induces tumor growth inhibition in a variety of human tumor xenografts of different histology. To improve on the therapeutic efficacy we have combined tTF-NGR with radiotherapy.

Methods: Serum-stimulated human umbilical vein endothelial cells (HUVEC) and human HT1080 sarcoma cells were irradiated in vitro, and upregulated early-apoptotic phosphatidylserine (PS) on the cell surface was measured by standard flow cytometry. Increase of cellular procoagulant function in relation to irradiation and PS cell surface concentration was measured in a tTF-NGR-dependent Factor X activation assay. In vivo experiments with CD-1 athymic mice bearing human HT1080 sarcoma xenotransplants were performed to test the systemic therapeutic effects of tTF-NGR on tumor growth alone or in combination with regional tumor ionizing radiotherapy.

Results: As shown by flow cytometry with HUVEC and HT1080 sarcoma cells in vitro, irradiation with 4 and 6 Gy in the process of apoptosis induced upregulation of PS presence on the outer surface of both cell types. Proapoptotic HUVEC and HT1080 cells both showed significantly higher procoagulant efficacy on the basis of equimolar concentrations of tTF-NGR as measured by FX activation. This effect can be reverted by masking of PS with Annexin V. HT1080 human sarcoma xenografted tumors showed shrinkage induced by combined regional radiotherapy and systemic tTF-NGR as compared to growth inhibition achieved by either of the treatment modalities alone.

Conclusions: Irradiation renders tumor and tumor vascular cells procoagulant by PS upregulation on their outer surface and radiotherapy can significantly improve the therapeutic antitumor efficacy of tTF-NGR in the xenograft model used. This synergistic effect will influence design of future clinical combination studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034830PMC
May 2020

Monitoring minimal residual/relapsing disease after allogeneic haematopoietic stem cell transplantation in adult patients with acute lymphoblastic leukaemia.

Bone Marrow Transplant 2020 07 30;55(7):1410-1420. Epub 2020 Jan 30.

Department of Medicine A/Haematology and Oncology, University of Muenster, Muenster, Germany.

Relapse after allogeneic haematopoietic stem cell transplantation (SCT) is a major cause of death in patients with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed the contributions of lineage-sorted donor cell chimerism (sDCC) and quantitative PCR (qPCR) targeting disease-specific genetic rearrangements to detect minimal residual/relapsing disease (MRD) and predict impending relapse in 94 adult ALL patients after SCT. With a median follow-up of surviving patients (n = 61) of 3.3 years, qPCR and/or sDCC measurements turned positive in 38 patients (40%). Of these, 22 patients relapsed and 16 remained in complete remission. At 3 years, qPCR and/or sDCC positive patients showed an increased incidence of relapse (50% vs. 4%, p < 0.0001), decreased relapse-free survival (RFS, 40% vs. 85%, p < 0.0001), and decreased overall survival (OS, 47% vs. 87%, p 0.004). Both, qPCR and sDCC pre-detected 11 of 21 relapses occurring within the first two years after SCT and, overall, complemented for each other method in four of the relapsing and four of the non-relapsing cases. Patients receiving pre-emptive MRD-driven interventions (n = 11) or not (n = 10) showed comparable median times until relapse, RFS, and OS. In our single centre cohort, qPCR and sDCC were similarly effective and complementary helpful to indicate haematological relapse of ALL after SCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0801-0DOI Listing
July 2020

The clinical mutatome of core binding factor leukemia.

Leukemia 2020 06 2;34(6):1553-1562. Epub 2020 Jan 2.

Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-019-0697-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266744PMC
June 2020

Chromosomal Abnormalities and Prognosis in -Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts.

J Clin Oncol 2019 10 20;37(29):2632-2642. Epub 2019 Aug 20.

St Vincent's Hospital, Melbourne, Australia.

Purpose: Nucleophosmin 1 () mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene () is absent (-ITD) or present with a low allelic ratio (-ITD). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

Methods: We analyzed associations between karyotype and outcome in intensively treated patients with /-ITD AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

Results: Among 2,426 patients with /-ITD AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with /-ITD AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors ( < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the mutational status on outcome.

Conclusion: Karyotype abnormalities are significantly associated with outcome in /-ITD AML. When adverse-risk cytogenetics are present, patients with share the same unfavorable prognosis as patients with wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in /-ITD AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.00416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462529PMC
October 2019
-->