Publications by authors named "Michael Heuser"

165 Publications

Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin.

Blood 2021 Feb 17. Epub 2021 Feb 17.

Berlin Institute of Health (BIH), Berlin, Germany, Germany.

In the international randomized phase III RATIFY trial, the multi-kinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18-59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients on the midostaurin arm achieved protocol-specified complete remission (CR) and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD) positive AML who were entered on the RATIFY or the AMLSG 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD as well as whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative, but acquired mutations in signaling pathways (e.g. MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD-clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed suggesting either resistance mechanisms bypassing FLT3-inhibition or loss of midostaurin inhibitory activity due to inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD mutated AML under treatment with midostaurin in combination with intensive chemotherapy.
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http://dx.doi.org/10.1182/blood.2020007626DOI Listing
February 2021

[Treatment-refractory anaemia in a 35-year-old heart transplant recipient on chronic hemodialysis].

Internist (Berl) 2021 Feb 12. Epub 2021 Feb 12.

Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Deutschland.

This article presents a case of pure red cell aplasia in a 35-year-old heart transplant recipient on chronic hemodialysis. Elevated parvovirus B19 immunoglobulin M blood levels were detected along with a high viral load of 80 billion IU/ml quantified by polymerase chain reaction. Bone marrow examination revealed giant proerythroblasts confirming parvovirus B19 infection. High-dose intravenous immunoglobulin was used for treatment. Anaemia had significantly improved 4 weeks later. Parvovirus B19 infection should be excluded in organ transplant recipients with anaemia due to ineffective erythropoiesis.
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http://dx.doi.org/10.1007/s00108-021-00955-9DOI Listing
February 2021

Author Correction: Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2021 Feb 9. Epub 2021 Feb 9.

Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1038/s41591-021-01253-5DOI Listing
February 2021

Venetoclax and dexamethasone synergize with inotuzumab-ozogamicin induced DNA damage signaling in B-lineage ALL.

Blood 2020 Dec 23. Epub 2020 Dec 23.

Hannover Medical School, Hannover, Germany.

Adult patients with relapsed B- cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy we analyzed apoptosis induction by venetoclax and inotuzumab-ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry-based analyses of mitochondrial outer membrane permeabilization (MOMP) and Ataxia telangiectasia mutated (ATM) activation demonstrates rapid MOMP induction by venetoclax and DNA-damage signalling by inotuzumab-ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models venetoclax and inotuzumab-ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all ALL samples tested. In murine PDX models inotuzumab-ozogamicin but not venetoclax induced complete remission in a dose dependent manner but constantly failed to achieve relapse-free survival. In contrast combination therapy with venetoclax, dexamethasone and inotuzumab-ozogamicin induced long-term leukemia- and treatment-free survival in all three ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualifies for evaluation in clinical trials.
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http://dx.doi.org/10.1182/blood.2020008544DOI Listing
December 2020

Unbalanced translocation der(5;17) resulting in a TP53 loss as recurrent aberration in myelodysplastic syndrome and acute myeloid leukemia with complex karyotype.

Genes Chromosomes Cancer 2021 Jan 24. Epub 2021 Jan 24.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

A complex karyotype, detected in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), is associated with a reduced median survival. The most frequent chromosomal aberrations in complex karyotypes are deletions of 5q and 17p harboring the tumor suppressor gene TP53. The unbalanced translocation der(5;17) involving chromosome 5q and 17p is a recurrent aberration in MDS/AML, resulting in TP53 loss. We analyzed the karyotypes of 178 patients with an unbalanced translocation der(5;17) using fluorescence R-/G-banding analysis. Whenever possible, fluorescence in situ hybridization (FISH) (n = 138/141), multicolor FISH (n = 8), telomere length measurement (n = 9), targeted DNA sequencing (n = 13), array-CGH (n = 7) and targeted RNA sequencing (n = 2) were conducted. The der(5;17) aberration was accompanied with loss of genetic material in 7q (53%), -7 (27%), gain of 21q (29%), +8 (17%) and - 18 (16%) and all analyzed patients (n = 13) showed a (likely) pathogenic variant inTP53. The der(5;17) cohort showed significantly shortened telomeres in comparison to the healthy age-matched controls (P < .05), but there was no significant telomere shortening in comparison to MDS/AML patients with a complex karyotype without der(5;17). No fusion genes resulted from the unbalanced translocation. This study demonstrates that the unbalanced translocation der(5;17) is associated with a biallelic inactivation of TP53 due to a deletion of TP53 in one allele and a pathogenic variant of the second TP53 allele. Since the breakpoints are located within (near-) heterochromatic regions, alterations of DNA methylation or histone modifications may be involved in the generation of der(5;17).
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http://dx.doi.org/10.1002/gcc.22938DOI Listing
January 2021

Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial.

Blood 2020 Dec;136(26):3041-3050

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.
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http://dx.doi.org/10.1182/blood.2020005998DOI Listing
December 2020

Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication.

Blood Adv 2020 Dec;4(24):6342-6352

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.
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http://dx.doi.org/10.1182/bloodadvances.2020002673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757000PMC
December 2020

Newly diagnosed isolated myeloid sarcoma-paired NGS panel analysis of extramedullary tumor and bone marrow.

Ann Hematol 2021 Feb 27;100(2):499-503. Epub 2020 Oct 27.

Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Isolated myeloid sarcoma (MS) is a rare malignancy in which myeloid blast forms tumors at various locations while the bone marrow (BM) remains cytomorphologically free from disease. We analyzed isolated MS from four patients and their BMs at initial diagnosis and follow-up, using a custom next-generation sequencing (NGS) panel. We observed possible clonal evolution and a clonal hematopoiesis of indeterminate potential (CHIP)-like finding in the BM of one of three cases with detectable mutations. Clinical presentation of one patient suggested extramedullary confined homing of blasts to distal sites in the relapse situation still sparing the BM. In summary, our findings shall motivate future work regarding signals of extramedullary blast trafficking and clonal evolution in MS.
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http://dx.doi.org/10.1007/s00277-020-04313-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817572PMC
February 2021

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial.

Blood Adv 2020 Oct;4(19):4945-4954

Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy.

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556122PMC
October 2020

Long-Term Survival Benefit after Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia.

Biol Blood Marrow Transplant 2020 Oct 9. Epub 2020 Oct 9.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.007DOI Listing
October 2020

Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia.

Cancers (Basel) 2020 Sep 26;12(10). Epub 2020 Sep 26.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.

NUP98-NSD1-positive acute myeloid leukemia (AML) is a poor prognostic subgroup that is frequently diagnosed in pediatric cytogenetically normal AML. NUP98-NSD1-positive AML often carries additional mutations in genes including and . The purpose of our study was to characterize the cooperative potential of the fusion and its associated Neuroblastoma rat sarcoma (NRAS) mutation. By constitutively expressing NUP98-NSD1 and NRASG12D in a syngeneic mouse model and using a patient-derived xenograft (PDX) model from a NUP98-NSD1-positive AML patient, we evaluated the functional role of these genes and tested a novel siRNA formulation that inhibits the oncogenic driver NUP98-NSD1. NUP98-NSD1 transformed murine bone marrow (BM) cells in vitro and induced AML in vivo. While NRASG12D expression was insufficient to transform cells alone, co-expression of NUP98-NSD1 and NRASG12D enhanced the leukemogenicity of NUP98-NSD1. We developed a NUP98-NSD1-targeting siRNA/lipid nanoparticle formulation that significantly prolonged the survival of the PDX mice. Our study demonstrates that mutated NRAS cooperates with NUP98-NSD1 and shows that direct targeting of the fusion can be exploited as a novel treatment strategy in NUP98-NSD1-positive AML patients.
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http://dx.doi.org/10.3390/cancers12102766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600396PMC
September 2020

Evaluation of the Relationship of Glasdegib Exposure and Safety End Points in Patients With Refractory Solid Tumors and Hematologic Malignancies.

J Clin Pharmacol 2021 Mar 24;61(3):349-359. Epub 2020 Sep 24.

Pfizer Oncology, Collegeville, Pennsylvania, USA.

Glasdegib is approved for treating acute myeloid leukemia in elderly patients at 100 mg once daily in combination with low-dose cytarabine. Exposure-efficacy analysis showed that the survival benefit of glasdegib was not glasdegib exposure-dependent. The relationship between glasdegib exposure and adverse event (AE) cluster terms of clinical concern was explored in this analysis. The incidence and severity of dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged was modeled using ordinal logistic regression. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Estimated pharmacokinetic parameters were used to derive glasdegib exposure metrics. Demographic characteristics, disease factors, and other variables of interest as potential moderators of safety signals were evaluated. Clinical trial data from patients who received single-agent glasdegib (N = 70; 5-640 mg once daily); or glasdegib (N = 202, 100-200 mg once daily) with low-dose cytarabine, decitabine, or daunorubicin and cytarabine were analyzed. Glasdegib exposure was statistically significantly associated with the cluster term safety end points dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged. The impact of age on muscle spasms and baseline body weight and creatinine clearance on renal toxicity helped explain the AE grade distribution. At the 100 mg once daily clinical dose, the predicted probabilities of the highest AE grade were 11.3%, 6.7%, 7.7%, and 2.5% for dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged, respectively. Overall, the predicted probability of developing an AE of any severity for these safety end points was low. Therefore, no starting dose adjustments are recommended for glasdegib based on the observed safety profile.
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http://dx.doi.org/10.1002/jcph.1742DOI Listing
March 2021

Selection and management of older patients with acute myeloid leukemia treated with glasdegib plus low-dose cytarabine: expert panel review.

Leuk Lymphoma 2020 12 24;61(14):3287-3305. Epub 2020 Sep 24.

Hannover Medical School, Hannover, Germany.

Glasdegib, in combination with low-dose cytarabine (LDAC), is the first smoothened inhibitor approved for treatment of acute myeloid leukemia. Glasdegib plus LDAC is indicated for patients in whom therapy options are limited, e.g. older patients and those ineligible for intensive chemotherapy due to preexisting comorbidities. This review summarizes the recommendations of a panel of hemato-oncologists regarding the selection of patients best suited for treatment with glasdegib plus LDAC and the management during therapy with this combination. The panel considered the impact of concomitant medications and comorbidities during treatment with glasdegib plus LDAC, and discussed common adverse events (AEs) associated with glasdegib plus LDAC. Management strategies for AEs discussed by the panel included dose modifications, supportive care therapies, and prophylactic treatments. Finally, the panel highlighted the importance of patient communication and education regarding the possible AEs that may occur during treatment.
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http://dx.doi.org/10.1080/10428194.2020.1817445DOI Listing
December 2020

IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction-a retrospective propensity score analysis.

Leukemia 2020 Sep 18. Epub 2020 Sep 18.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to leukemia gene mutations and associates with an increased risk for coronary artery disease and poor prognosis in ischemic cardiomyopathy. Two recurrently mutated genes in CHIP and adult acute myeloid leukemia (AML) encode for isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). Global expression of mutant IDH2 in transgenic mice-induced dilated cardiomyopathy and muscular dystrophy. In this retrospective observational study, we investigated whether mutant IDH1/2 predisposes to cardiovascular disease in AML patients. Among 363 AML patients, IDH1 and IDH2 mutations were detected in 26 (7.2%) and 39 patients (10.7%), respectively. Mutant IDH1 patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p = 0.002). Applying inverse probability-weighting analysis, patients with IDH1/2 mutations had a higher risk for a declining cardiac function during AML treatment compared to IDH1/2 wild type patients [left ventricular ejection fraction pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (p < 0.001) vs 58.5% to 55.4% (p = 0.27), respectively]. Mechanistically, RNA sequencing and immunostaining in hiPS-derived cardiomyocytes indicated that the oncometabolite R-2HG exacerbated doxorubicin mediated cardiotoxicity. Evaluation of IDH1/2 mutation status may therefore help identifying AML patients at risk for cardiovascular complications during cytotoxic treatment.
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http://dx.doi.org/10.1038/s41375-020-01043-xDOI Listing
September 2020

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2020 10 3;26(10):1549-1556. Epub 2020 Aug 3.

Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.
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http://dx.doi.org/10.1038/s41591-020-1008-zDOI Listing
October 2020

Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results.

Leukemia 2020 11 30;34(11):2903-2913. Epub 2020 Jul 30.

Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.
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http://dx.doi.org/10.1038/s41375-020-0996-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584476PMC
November 2020

Risk of tumor lysis syndrome in patients with acute myeloid leukemia treated with venetoclax-containing regimens without dose ramp-up.

Ann Hematol 2021 Feb 23;100(2):595-599. Epub 2020 Jul 23.

Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Straße 1, 30625, Hannover, Germany.

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http://dx.doi.org/10.1007/s00277-020-04181-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817590PMC
February 2021

Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy.

J Hematol Oncol 2020 07 14;13(1):92. Epub 2020 Jul 14.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Background: The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015).

Methods: This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR.

Results: In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41-0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively.

Conclusions: Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR.

Trial Registration: ClinicalTrials.gov NCT01546038 (March 7, 2012).
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http://dx.doi.org/10.1186/s13045-020-00929-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362563PMC
July 2020

Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia.

Leukemia 2020 11 24;34(11):2951-2963. Epub 2020 Jun 24.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

To establish novel and effective treatment combinations for chronic myelomonocytic leukemia (CMML) preclinically, we hypothesized that supplementation of CMML cells with the human oncogene Meningioma 1 (MN1) promotes expansion and serial transplantability in mice, while maintaining the functional dependencies of these cells on their original genetic profile. Using lentiviral expression of MN1 for oncogenic supplementation and transplanting transduced primary mononuclear CMML cells into immunocompromised mice, we established three serially transplantable CMML-PDX models with disease-related gene mutations that recapitulate the disease in vivo. Ectopic MN1 expression was confirmed to enhance the proliferation of CMML cells, which otherwise did not engraft upon secondary transplantation. Furthermore, MN1-supplemented CMML cells were serially transplantable into recipient mice up to 5 generations. This robust engraftment enabled an in vivo RNA interference screening targeting CMML-related mutated genes including NRAS, confirming that their functional relevance is preserved in the presence of MN1. The novel combination treatment with azacitidine and the MEK-inhibitor trametinib additively inhibited ERK-phosphorylation and thus depleted the signal from mutated NRAS. The combination treatment significantly prolonged survival of CMML mice compared to single-agent treatment. Thus, we identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and propose its clinical development.
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http://dx.doi.org/10.1038/s41375-020-0929-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116758PMC
November 2020

A Phase II study of selinexor plus cytarabine and idarubicin in patients with relapsed/refractory acute myeloid leukaemia.

Br J Haematol 2020 08 9;190(3):e169-e173. Epub 2020 Jun 9.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1111/bjh.16804DOI Listing
August 2020

SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS.

Blood 2020 07;136(2):157-170

Department of Molecular Medicine, University of Pavia & Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

The 2016 revision of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues is characterized by a closer integration of morphology and molecular genetics. Notwithstanding, the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality. Approximately half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one. SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course. A large body of evidence supports recognition of SF3B1-mutant MDS as a distinct nosologic entity. To further validate this notion, we interrogated the data set of the International Working Group for the Prognosis of MDS (IWG-PM). Based on the findings of our analyses, we propose the following diagnostic criteria for SF3B1-mutant MDS: (1) cytopenia as defined by standard hematologic values, (2) somatic SF3B1 mutation, (3) morphologic dysplasia (with or without RS), and (4) bone marrow blasts <5% and peripheral blood blasts <1%. Selected concomitant genetic lesions represent exclusion criteria for the proposed entity. In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overt MDS with RS, suggesting that this genetic lesion might provide presumptive evidence of MDS in the setting of persistent unexplained cytopenia. Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making. In fact, this condition has a relatively good prognosis and may respond to luspatercept with abolishment of the transfusion requirement.
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http://dx.doi.org/10.1182/blood.2020004850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362582PMC
July 2020

CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia.

Blood 2020 07;136(4):387-400

Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria.

Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.
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http://dx.doi.org/10.1182/blood.2019003267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115844PMC
July 2020

Combination treatment of an IDH1 inhibitor with chemotherapy in IDH1 mutant acute myeloid leukemia.

Ann Hematol 2020 Jun 15;99(6):1415-1417. Epub 2020 Apr 15.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1007/s00277-020-04001-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237524PMC
June 2020

Synergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia.

Haematologica 2021 Feb 1;106(2):565-573. Epub 2021 Feb 1.

Hannover Medical School, Hannover, Germany.

Mutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P<.005). The sequential combination treatment depleted leukemia stem cells (LSC) by 470-fold. Interestingly, the simultaneous combination treatment depleted LSCs by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and RB/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.
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http://dx.doi.org/10.3324/haematol.2019.236992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849562PMC
February 2021

Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study.

Leukemia 2021 01 16;35(1):62-74. Epub 2020 Mar 16.

Department of Haematology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia.

Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6-3.6; p = 0.44). Median (95% CI) OS was 5.36 (4.27-7.95) months for combination therapy versus 7.26 (6.47-8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79-1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee's recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.
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http://dx.doi.org/10.1038/s41375-020-0773-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787975PMC
January 2021

Gemtuzumab Ozogamicin in -Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study.

J Clin Oncol 2020 02 18;38(6):623-632. Epub 2019 Dec 18.

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Purpose: High CD33 expression in acute myeloid leukemia (AML) with mutated provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in -mutated AML.

Patients And Methods: Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all--retinoic acid with or without GO. The early ( = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment.

Results: Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm ( = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm ( = .005), with no difference in the cumulative incidence of death ( = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and internal tandem duplication-negative patients with respect to EFS and CIR.

Conclusion: The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.
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http://dx.doi.org/10.1200/JCO.19.01406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030890PMC
February 2020

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Blood 2020 01;135(5):371-380

The Ohio State University Comprehensive Cancer Center, Columbus, OH.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
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http://dx.doi.org/10.1182/blood.2019002697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993016PMC
January 2020

Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial.

J Clin Oncol 2020 01 3;38(3):257-270. Epub 2019 Dec 3.

University Hospital of Ulm, Ulm, Germany.

Purpose: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML).

Patients And Methods: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety.

Results: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided = .06). For valproate, no effect was observed (17.8% with valproate 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided = .44). Median overall survival was 8.2 months with ATRA 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms.

Conclusion: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
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http://dx.doi.org/10.1200/JCO.19.01053DOI Listing
January 2020

The Actin Binding Protein Plastin-3 Is Involved in the Pathogenesis of Acute Myeloid Leukemia.

Cancers (Basel) 2019 Oct 26;11(11). Epub 2019 Oct 26.

Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Leukemia-initiating cells reside within the bone marrow in specialized niches where they undergo complex interactions with their surrounding stromal cells. We have identified the actin-binding protein Plastin-3 (PLS3) as potential player within the leukemic bone marrow niche and investigated its functional role in acute myeloid leukemia. High expression of PLS3 was associated with a poor overall and event-free survival for AML patients. These findings were supported by functional in vitro and in vivo experiments. AML cells with a PLS3 knockdown showed significantly reduced colony numbers in vitro while the PLS3 overexpression variants resulted in significantly enhanced colony numbers compared to their respective controls. Furthermore, the survival of NSG mice transplanted with the PLS3 knockdown cells showed a significantly prolonged survival in comparison to mice transplanted with the control AML cells. Further studies should focus on the underlying leukemia-promoting mechanisms and investigate PLS3 as therapeutic target.
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http://dx.doi.org/10.3390/cancers11111663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895973PMC
October 2019