Publications by authors named "Arnold Ganser"

410 Publications

Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

Institute of Immunology, Hannover Mecial School, Germany.

Donor lymphocyte infusion (DLI) is a standard of care for relapse of AML after allogeneic hematopoietic stem cell transplantation (aHSCT). Currently it is poorly understood how and when CD8+ αβ T cells exert graft-versus-leukemia (GvL) activity after DLI. Also, there is no reliable biomarker to monitor GvL activity of the infused CD8+ T cells. Therefore, we analyzed the dynamics of CD8+ αβ T cell clones in DLI-patients. In this prospective clinical study of 29 patients, we performed deep T cell receptor β (TRB) sequencing of sorted CD8+ αβ T cells to track patients' repertoire changes in response to DLI. Upon first occurrence of GvL, longitudinal analyses revealed a preferential expansion of distinct CD8+ TRB clones (n=14). This did not occur in samples of patients without signs of GvL (n=11). Importantly, early repertoire changes 15 days after DLI predicted durable remission for the 36 months study follow-up. Furthermore, absence of clonal outgrowth of the CD8+ TRB repertoire after DLI was an early biomarker that predicted relapse at a median time of 11.2 months ahead of actual diagnosis. Additionally, unbiased sample analysis regardless of the clinical outcome revealed that patients with decreasing CD8+ TRB diversity at day 15 after DLI (n=13) had a lower relapse incidence (P=0.0040) compared to patients without clonal expansion (n=6). In conclusion, CD8+ TRB analysis may provide a reliable tool for predicting the efficacy of DLI and holds the potential to identify patients at risk for progression and relapse after DLI.
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http://dx.doi.org/10.1182/bloodadvances.2020004073DOI Listing
September 2021

Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT.

Br J Haematol 2021 Sep 12. Epub 2021 Sep 12.

CHU de Lille, INSERM U1286, Univ Lille, Lille, France.

Allogeneic haematopoietic-cell transplantation (allo-HCT) is a potentially curative therapy for high-risk myelodysplastic syndrome (MDS). Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM), higher relapse rate and similar overall-survival (OS) as myeloablative-conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced-toxicity regimen with intense anti-leukaemia activity and a favourable toxicity profile. We investigated post-transplant outcomes in 1722 MDS patients following allo-HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow-up was 64 months (1-171). Five-year relapse rates were 25% (21-30), 38% (34-42) and 25% (22-29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25-35), 27% (23-30) and 34% (31-38, P = 0·008), respectively. Five-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo-HCT in MDS.
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http://dx.doi.org/10.1111/bjh.17817DOI Listing
September 2021

Case Report: Convalescent Plasma Therapy Induced Anti-SARS-CoV-2 T Cell Expansion, NK Cell Maturation and Virus Clearance in a B Cell Deficient Patient After CD19 CAR T Cell Therapy.

Front Immunol 2021 12;12:721738. Epub 2021 Aug 12.

Institute of Immunology, Hannover Medical School, Hannover, Germany.

Here, we described the case of a B cell-deficient patient after CD19 CAR-T cell therapy for refractory B cell Non-Hodgkin Lymphoma with protracted coronavirus disease 2019 (COVID-19). For weeks, this patient only inefficiently contained the virus while convalescent plasma transfusion correlated with virus clearance. Interestingly, following convalescent plasma therapy natural killer cells matured and virus-specific T cells expanded, presumably allowing virus clearance and recovery from the disease. Our findings, thus, suggest that convalescent plasma therapy can activate cellular immune responses to clear SARS-CoV-2 infections. If confirmed in larger clinical studies, these data could be of general importance for the treatment of COVID-19 patients.
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http://dx.doi.org/10.3389/fimmu.2021.721738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387963PMC
September 2021

Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients.

Sci Rep 2021 Aug 12;11(1):16457. Epub 2021 Aug 12.

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

To date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen response and radiographic response (PSAR, RR), progression-free survival (PFS), FT/TT levels and safety. Median FT and TT serum levels were completely suppressed to below the detection limit during docetaxel treatment (FT: from 0.32 to < 0.18 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified requirement of non-narcotics, PSAR, complete FT suppression and FT nadir values < 0.18 pg/mL as independent parameters for PFS. Prior androgen-receptor targeted therapy (ART), soft tissue metastasis and complete FT suppression were independent prognostic factors for OS. FT was not predictive for treatment outcome in mPC patients with a history of ART.
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http://dx.doi.org/10.1038/s41598-021-95874-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361102PMC
August 2021

Prothrombotic immune thrombocytopenia after COVID-19 vaccination.

Blood 2021 07;138(4):350-353

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

We report 5 cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and thrombotic microangiopathy. All patients had thrombocytopenia and markedly elevated D-dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients, although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependent manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in 3 patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.
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http://dx.doi.org/10.1182/blood.2021011958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084604PMC
July 2021

Impact of sarcopenia in advanced and metastatic soft tissue sarcoma.

Int J Clin Oncol 2021 Jul 27. Epub 2021 Jul 27.

Klinik Für Hämatologie, Hämostaseologie, Onkologie Und Stammzelltransplantation, Medizinische Hochschule Hannover, OE 6860, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.

Introduction: Advanced or metastatic soft tissue sarcoma (a/mSTS) is associated with a dismal prognosis. Patient counseling on treatment aggressiveness is pivotal to avoid over- or undertreatment. Recently, evaluation of body composition markers like the skeletal muscle index (SMI) became focus of interest in a variety of cancers. This study focuses on the prognostic impact of SMI in a/mSTS, retrospectively.

Methods: 181 a/mSTS patients were identified, 89 were eligible due to prespecified criteria for SMI assessment. Baseline CT-Scans were analyzed using an institutional software solution. Sarcopenia defining cut-off values for the SMI were established by optimal fitting method. Primary end point was overall survival (OS) and secondary endpoints were progression free survival (PFS), disease control rate (DCR), overall response rate (ORR). Descriptive statistics as well as Kaplan Meier- and Cox regression analyses were administered.

Results: 28/89 a/mSTS patients showed sarcopenia. Sarcopenic patients were significantly older, generally tended to receive less multimodal therapies (62 vs. 57 years, P = 0.025; respectively median 2.5 vs. 4, P = 0.132) and showed a significantly lower median OS (4 months [95%CI 1.9-6.0] vs. 16 months [95%CI 8.8-23.2], Log-rank P = 0.002). Sarcopenia was identified as independent prognostic parameter of impaired OS (HR 2.40 [95%-CI 1.4-4.0], P < 0.001). Moreover, DCR of first palliative medical treatment was superior in non-sarcopenic patients (49.2% vs. 25%, P = 0.032).

Conclusion: This study identifies sarcopenia as a prognostic parameter in a/mSTS. Further on, the data suggest that sarcopenia shows a trend of being associated with first line therapy response. SMI is a promising prognostic parameter, which needs further validation.
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http://dx.doi.org/10.1007/s10147-021-01997-7DOI Listing
July 2021

Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.

Leukemia 2021 Jul 28. Epub 2021 Jul 28.

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

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.
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http://dx.doi.org/10.1038/s41375-021-01323-0DOI Listing
July 2021

Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT.

Bone Marrow Transplant 2021 Jul 10. Epub 2021 Jul 10.

EBMT Paris study office / CEREST-TC, Paris, France.

Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P = 0.36) and 84% in UD 9/10 patients (P = 0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P < 0.001), male gender (P < 0.001), second complete remission (CR2) versus CR1 (P = 0.05), secondary AML (P = 0.01), antecedent of chronic GVHD (P < 0.001) and poor-risk cytogenetics (P = 0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.
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http://dx.doi.org/10.1038/s41409-021-01387-7DOI Listing
July 2021

Induced dendritic cells co-expressing GM-CSF/IFN-α/tWT1 priming T and B cells and automated manufacturing to boost GvL.

Mol Ther Methods Clin Dev 2021 Jun 9;21:621-641. Epub 2021 Apr 9.

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

Acute myeloid leukemia (AML) patients with minimal residual disease and receiving allogeneic hematopoietic stem cell transplantation (HCT) have poor survival. Adoptive administration of dendritic cells (DCs) presenting the Wilms tumor protein 1 (WT1) leukemia-associated antigen can potentially stimulate T and B cell development to harness the graft-versus-leukemia (GvL) effect after HCT. We established a simple and fast genetic modification of monocytes for simultaneous lentiviral expression of a truncated WT1 antigen (tWT1), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon (IFN)-α, promoting their self-differentiation into potent "induced DCs" (iDCtWT1). A tricistronic integrase-defective lentiviral vector produced under good manufacturing practice (GMP)-like conditions was validated. Transduction of CD14 monocytes isolated from peripheral blood, cord blood, and leukapheresis material effectively induced their self-differentiation. CD34 cell-transplanted Nod.Rag.Gamma (NRG)- and Nod.Scid.Gamma (NSG) mice expressing human leukocyte antigen (HLA)-A∗0201 (NSG-A2)-immunodeficient mice were immunized with autologous iDCtWT1. Both humanized mouse models showed improved development and maturation of human T and B cells in the absence of adverse effects. Toward clinical use, manufacturing of iDCtWT1 was up scaled and streamlined using the automated CliniMACS Prodigy system. Proof-of-concept clinical-scale runs were feasible, and the 38-h process enabled standardized production and high recovery of a cryopreserved cell product with the expected identity characteristics. These results advocate for clinical trials testing iDCtWT1 to boost GvL and eradicate leukemia.
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http://dx.doi.org/10.1016/j.omtm.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142053PMC
June 2021

What can Heraclitus tell us about AML?

Authors:
Arnold Ganser

Blood 2021 May;137(20):2719-2720

Hannover Medical School.

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http://dx.doi.org/10.1182/blood.2021011264DOI Listing
May 2021

Measurable residual disease status and outcome of transplant in acute myeloid leukemia in second complete remission: a study by the acute leukemia working party of the EBMT.

Blood Cancer J 2021 May 12;11(5):88. Epub 2021 May 12.

Hematology Division, Chaim Sheba Medical Center, Tel Hashomer, Israel.

Measurable residual disease (MRD) prior to hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) in first complete morphological remission (CR1) is an independent predictor of outcome, but few studies address CR2. This analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation registry assessed HCT outcomes by declared MRD status in a cohort of 1042 adult patients with AML CR2 at HCT. Patients were transplanted 2006-2016 from human leukocyte antigen (HLA) matched siblings (n = 719) or HLA 10/10 matched unrelated donors (n = 293). Conditioning was myeloablative (n = 610) or reduced-intensity (n = 432) and 566 patients (54%) had in-vivo T cell depletion. At HCT, 749 patients (72%) were MRD negative (MRD NEG) and 293 (28%) were MRD positive (MRD POS). Time from diagnosis to HCT was longer in MRD NEG than MRD POS patients (18 vs. 16 months (P < 0.001). Two-year relapse rates were 24% (95% CI, 21-28) and 40% (95% CI, 34-46) in MRD NEG and MRD POS groups (P < 0.001), respectively. Leukemia-free survival (LFS) was 57% (53-61) and 46% (40-52%), respectively (P = 0.001), but there was no difference in terms of overall survival. Prognostic factors for relapse and LFS were MRD NEG status, good risk cytogenetics, and longer time from diagnosis to HCT. In-vivo T cell depletion predicted relapse.
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http://dx.doi.org/10.1038/s41408-021-00479-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116335PMC
May 2021

Posttransplantation MRD monitoring in patients with AML by next-generation sequencing using DTA and non-DTA mutations.

Blood Adv 2021 05;5(9):2294-2304

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

Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML) is widely applicable and prognostic prior to allogeneic hematopoietic cell transplantation (alloHCT). We evaluated the prognostic role of clonal hematopoiesis-associated DNMT3A, TET2, and ASXL1 (DTA) and non-DTA mutations for MRD monitoring post-alloHCT to refine MRD marker selection. Of 154 patients with AML, 138 (90%) had at least one mutation at diagnosis, which were retrospectively monitored by amplicon-based error-corrected NGS on day 90 and/or day 180 post-alloHCT. MRD was detected in 34 patients on day 90 and/or day 180 (25%). The rate of MRD positivity was similar when DTA and non-DTA mutations were considered separately (17.6% vs 19.8%). DTA mutations had no prognostic impact on cumulative incidence of relapse, relapse-free survival, or overall survival in our study and were removed from further analysis. In the remaining 131 patients with at least 1 non-DTA mutation, clinical and transplantation-associated characteristics were similarly distributed between MRD-positive and MRD-negative patients. In multivariate analysis, MRD positivity was an independent adverse predictor of cumulative incidence of relapse, relapse-free survival, and overall survival but not of nonrelapse mortality. The prognostic effect was independent of different cutoffs (above limit of detection, 0.1% and 1% variant allele frequency). MRD log-reduction between diagnosis and post-alloHCT assessment had no prognostic value. MRD status post-alloHCT had the strongest impact in patients who were MRD positive prior to alloHCT. In conclusion, non-DTA mutations are prognostic NGS-MRD markers post-alloHCT, whereas the prognostic role of DTA mutations in the posttransplant setting remains open.
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http://dx.doi.org/10.1182/bloodadvances.2021004367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114555PMC
May 2021

Severe allo-immune antibody-associated peripheral and central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

Sci Rep 2021 Apr 19;11(1):8527. Epub 2021 Apr 19.

Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren's syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors' and patients' blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT ("neuro-GvHD"). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.
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http://dx.doi.org/10.1038/s41598-021-87989-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055885PMC
April 2021

Second allogeneic haematopoietic cell transplantation using HLA-matched unrelated versus T-cell replete haploidentical donor and survival in relapsed acute myeloid leukaemia.

Br J Haematol 2021 05 10;193(3):592-601. Epub 2021 Apr 10.

Department of Hematology, Hôpital Saint Antoine, Sorbonne University and INSERM UMRs 938, Paris, France.

Optimal donor choice for a second allogeneic haematopoietic cell transplant (allo-HCT) in relapsed acute myeloid leukaemia (AML) remains unknown. We compared overall survival (OS) using registry data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) involving 455 adults who received a second allo-HCT from a human leucocyte antigen (HLA)-matched unrelated (MUD) (n = 320) or a haploidentical (n = 135) donor. Eligibility criteria required adults aged ≥18 years who received a second allo-HCT for treating AML relapse between 2005 and 2019. The primary end-point was OS. There was no statistically significant difference in the median (interquartile range) age between the groups, MUD 46 (35-58) versus haploidentical 44 (33-53) years (P = 0·07). The median OS was not different between the MUD and the haploidentical groups (10 vs. 11 months, P = 0·57). Similarly, the 2-year OS was 31% for the MUD and 29% for the haploidentical donor groups. The OS was worse if the procedure was performed with active AML [hazard ratio (HR) 1·42, 95% confidence interval (CI) 1·07-1·89; P = 0·02]. Conversely, a longer time from first allo-HCT to relapse (>13·2 months) was associated with better OS (HR 0·50, 95% CI 0·37-0·69; P < 0·0001). The results of the present analysis limit the ability to recommend one donor type over another when considering a second allo-HCT for relapsed AML. Our findings highlight that best OS is achieved when receiving the second allo-HCT in complete remission.
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http://dx.doi.org/10.1111/bjh.17426DOI Listing
May 2021

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

Leukemia 2021 09 2;35(9):2539-2551. Epub 2021 Mar 2.

Novartis Pharma AG, Basel, Switzerland.

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.
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http://dx.doi.org/10.1038/s41375-021-01179-4DOI Listing
September 2021

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

Blood 2021 Jun;137(22):3093-3104

Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany.

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in 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 in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 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 and 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 (eg, 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 because of 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233666PMC
June 2021

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

Blood 2021 May;137(19):2657-2661

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation.

Adult patients with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy, we analyzed induction of apoptosis 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 activation demonstrate rapid induction of MOMP by venetoclax and DNA damage signaling 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 tested samples of ALL. 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-free survival and treatment-free survival in all 3 ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualify for evaluation in clinical trials.
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http://dx.doi.org/10.1182/blood.2020008544DOI Listing
May 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 12;136(26):3041-3050

Division of Biostatistics, German Cancer Research Center, Heidelberg, 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 12;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

F-FDG PET/CT of off-target lymphoid organs in CD19-targeting chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma.

Ann Nucl Med 2021 Jan 11;35(1):132-138. Epub 2020 Nov 11.

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

Objective: The interplay between systemic inflammation, activity of lymphoid organs and lymphoma activity in CD19-targeting chimeric antigen receptor (CAR)-T-cell immunotherapy, and its significance for response and toxicity, is not well defined.

Methods: Using serial F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), metabolic parameters of lymphoma and lymphoid organs were analyzed in ten patients receiving Tisagenlecleucel (an autologous CD19 CAR-T cell product) for relapsed or refractory diffuse large B-cell lymphoma. The prevalence and severity of toxicity (e.g., neurotoxicity) were noted.

Results: Achieving remission required early metabolic response (P = 0.0476). Early suppression of metabolic activity of lymphoid organs (spleen, P = 0.0368; lymph nodes, P = 0.0470) was associated with poor outcome. Lymphoma metabolic activity was significantly higher in patients with neurotoxicity (P = 0.0489).

Conclusions: Early metabolic changes in lymphoma lesions and off-target lymphoid organs parallel medium-term response to CAR-T-cell therapy. PET can identify patients at risk for severe toxicity.
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http://dx.doi.org/10.1007/s12149-020-01544-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796875PMC
January 2021

Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia.

Cancers (Basel) 2020 Oct 27;12(11). Epub 2020 Oct 27.

Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with transcript levels were associated with cell cycle arrest, while APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high expression was correlated with reduced leukocyte count ( = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; < 0.001). Functionally, -knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count ( = 0.001) and decreased overall survival ( = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.
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http://dx.doi.org/10.3390/cancers12113134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693375PMC
October 2020

A multicenter prospective, randomized, placebo-controlled phase II/III trial for preemptive acute graft-versus-host disease therapy.

Leukemia 2021 06 20;35(6):1763-1772. Epub 2020 Oct 20.

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

Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2-2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66-4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.
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http://dx.doi.org/10.1038/s41375-020-01059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179847PMC
June 2021

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

Blood Adv 2020 10;4(19):4945-4954

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

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

Evaluation of six different types of sequential conditioning regimens for allogeneic stem cell transplantation in relapsed/refractory acute myelogenous leukemia - a study of the Acute Leukemia Working Party of the EBMT.

Leuk Lymphoma 2021 02 11;62(2):399-409. Epub 2020 Oct 11.

Department of Hematology and Cell Therapy, Hopital Saint-Antoine, Paris, France.

The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients <55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences compared to FLAMSA-TBI4 and Mel-Flu-TBI8. Furthermore, best NRM rates were obtained with the two FLAMSA regimens groups. Our study suggests that in younger (<55 years) patients a more intense regimen might be used whereas in older (≥55 years) patients the focus might be more on tolerability.
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http://dx.doi.org/10.1080/10428194.2020.1827248DOI Listing
February 2021

Hepatic toxicity during regorafenib treatment in patients with metastatic gastrointestinal stromal tumors.

Mol Clin Oncol 2020 Dec 21;13(6):72. Epub 2020 Sep 21.

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

Regorafenib is a multi-target tyrosine kinase inhibitor that has been approved for the treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors (GIST). Severe hepatobiliary toxicity has been reported in patients with colorectal cancer treated with regorafenib, but not in those with GIST. Therefore, the aim of the present study was to investigate the incidence and clinical course of regorafenib-associated hepatic toxicity (HT) in patients with GIST in a real-world setting. Patients with metastatic GIST treated with regorafenib between September 2012 and May 2014 at three German tertiary care centers were followed up until August 2017. Patient records were retrospectively analyzed and descriptive statistics were employed. HT was defined as alterations in the serum values of aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase and bilirubin (according to the Common Terminology Criteria for Adverse Events, version 4.0), and/or corresponding clinical signs. The time to clinical progression and the overall survival were calculated by Kaplan-Meier curves. Overall, 21 patients were treated with regorafenib and 5 (23.5%) of those heavily pretreated patients suffered from severe HT during regorafenib treatment. In 4 (80%) of these cases, regorafenib treatment was continued, optimizing individual treatment benefit. Clinical monitoring and adequate therapy management are crucial for ensuring continuation of regorafenib treatment in order to achieve an optimal clinical outcome.
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http://dx.doi.org/10.3892/mco.2020.2143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523284PMC
December 2020
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