0000000000022549
AUTHOR
Hans Salwender
Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy.
Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell tr…
Monitoring of FLT3 Phosphorylation and FLT3 Ligand Levels in Patients with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) Treated with Midostaurin within the AMLSG 16-10 Trial of the German-Austrian Study Group
Abstract Background: Target inhibition of FLT3 by therapy with the recently FDA- and EMA-approved multi-targeted tyrosine kinase inhibitor (TKI) midostaurin can be monitored by plasma inhibitor activity (PIA) analysis by visualizing the level of target-dephosphorylation as previously described. When combining intensive chemotherapy with midostaurin, we have recently shown that the TKI achieves the lowest level of FLT3 phosphorylation (p-FLT3) at the end of the 1st induction cycle, indicating a deep target inhibition. However, sufficient inhibition could not be maintained during subsequent cycles by midostaurin in combination with chemotherapy, but it was reestablished during maintenance the…
Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial.
8508 Background: High-risk (HR) multiple myeloma (MM) still has a significant impaired prognostic outcome. Addition of CD38 monoclonal antibodies to standard-of-care regimens significantly improved response rates and depth of response in newly diagnosed (ND) and relapsed/refractory MM patients (pts). Here, we report the prespecified end of induction interim analysis (IA) of the investigator-initiated GMMG-CONCEPT trial (NCT03104842), evaluating the quadruplet regimen isatuximab plus carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in HR NDMM pts. Methods: 153 pts with HR NDMM are planned to be included into the trial. HR MM is defined by the presence of del17p or t(4;14) or t(14;16) o…
Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors
Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogene…
Impact Of The Pretreatment Characteristics As Well As Cyto- and Molecular-Genetic Profile On Outcome After Relapse In Acute Myeloid Leukemia
Abstract Background Cyto- and molecular-genetic abnormalities evaluated at initial diagnosis are the most powerful prognostic and in part also predictive markers in acute myeloid leukemia (AML) with regard to achievement of complete remission (CR) and survival. Nonetheless, after relapse the prognostic impact of clinical characteristics and genetic abnormalities assessed at initial diagnosis with respect to achievement of subsequent CR and survival are less clear. Aims To evaluate the probability of CR achievement and survival in relapsed AML patients in correlation to clinical characteristics and genetic abnormalities assessed at initial diagnosis as well as treatment strategy. Methods The…
T(11;14) and High BCL2 Expression Are Predictive Biomarkers of Response to Venetoclax in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Biomarker Analyses from the Phase 3 Bellini Study
Background: Overexpression of the anti-apoptotic BCL-2 protein promotes multiple myeloma (MM) cell survival. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis and has shown synergistic activity with bortezomib (B) and dexamethasone (d). Phase 1 studies in relapsed/refractory (RR) MM demonstrated encouraging clinical efficacy of Ven + d in t(11;14) MM and in a broader patient (pt) population in combination with Bd. Recent results from the Phase 3 BELLINI study of Ven vs placebo (Pbo) + Bd in pts with RRMM demonstrated that pts treated with Ven + Bd had improved clinical response rates and progression-free survival (PFS) vs Pbo, although the overall s…
Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma
Abstract Background: Multiple myeloma (MM) is a heterogenous cancer of terminally differentiated plasma cells that typically express elevated levels of antiapoptotic proteins, such as BCL-2. Venetoclax (Ven), a highly selective, potent, oral BCL-2 inhibitor, induces apoptosis in MM cells, and when combined with bortezomib and dexamethasone showed promising efficacy in patients (pts) with relapsed/refractory MM (RRMM; Moreau et al. Blood. 2017;130:2392-2400). The Phase 3 BELLINI study primary analysis showed significantly improved response rates and progression-free survival (PFS) in pts with RRMM treated with Ven added to bortezomib and dexamethasone versus placebo (Pbo); however, increased…
Kinetics of Renal Function during Induction in Newly Diagnosed Multiple Myeloma: Results of Two Prospective Studies by the German Myeloma Study Group DSMM
Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex
Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial.
Summary We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%)…
Survival of elderly patients with multiple myeloma-Effect of upfront autologous stem cell transplantation
Abstract Background The aim of this study was to determine the value of upfront autologous transplantation (ASCT) in elderly patients (60–79 years) with myeloma. Methods We analysed relative survival (RS) of patients diagnosed in 1998–2011 and treated with ASCT within 12 months after diagnosis in Germany (n = 3591; German Registry of Stem Cell Transplantation) and compare RS with survival of myeloma patients diagnosed in the same years in Germany (n = 13,903; population-based German Cancer Registries). Results Utilisation of ASCT has increased rapidly between 2000–2002 and 2009–2011 (60–64years: 7.0–43.0%; 65–69 years: 6.6–23.7%; 70–79 years: 0.4–4.0%). Comparison of 5-year RS of patients f…
Prediction of Early Death and Severe Infections during Novel Agent-Based Induction Therapy in Newly-Diagnosed Multiple Myeloma: An Intergroup Analysis from the German Speaking Myeloma Multicenter Group, the Dutch-Belgian Cooperative Trial Group for Hematology Oncology Foundation and the European Myeloma Network
Abstract Background: During the past decade, prognostic tools and outcomes of patients with newly-diagnosed multiple myeloma (NDMM) markedly improved. Data from clinical trials evaluating early morbidity and mortality including patients with transplant-eligible NDMM treated with novel agents are scarce. Thus, we aimed to analyze early morbidity and mortality in this patient cohort, devise and validate a predictive score to identify patients at risk. Patients and methods: Between July 2005 and January 2018, 1333 patients with transplant-eligible NDMM from three subsequent phase III trials, HD4, MM5 and HD6 from the German-speaking Myeloma Multicenter Group (GMMG), received a novel agent-base…
Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.
© 2018 The Authors.
Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma
Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells and has shown synergistic activity with the proteasome inhibitor (PI) bortezomib (B) and dexamethasone (d). Ven ± d had encouraging clinical efficacy in both t(11;14) MM and in pts irrespective of genetic background when administered with B, with a tolerable safety profile in Phase 1 studies. Here, we provide updated efficacy and safety of Ven vs placebo (Pbo) + Bd in pts with relapsed/refractory (RR) MM, including subgroup analyses, in the BELLINI study. Methods: BELLINI (NCT02755597) was a Phase 3, randomized, double-blind, multicenter study of Ven or Pbo…
Impact of Donor Type on Outcome after Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia Patients: Analysis of the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG)
Abstract Background:Despite recent advances in identifying novel molecular targets in AML patients, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) still remains a cornerstone of AML therapy. However, outcome of HSCT depends on the availability of a donor and the donor type. Prior studies comparing HSCT from HLA-matched related donors (MRD) with matched unrelated donors (MUD), demonstrated conflicting results with regards to outcome. These conflicting results might be attributed to the genetic heterogeneity of AML. Aims:To analyze outcome with respect to donor type of 952 AML patients who received HSCT in first complete remission (CR) and were tr…
Next-Generation Sequencing (NGS)-Based Measurable Residual Disease (MRD) Monitoring in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication (FLT3-ITD+ AML) Treated with Additional Midostaurin
Background: FLT3-ITD occurs in ~25% of adult AML patients (pts) and is associated with poor prognosis. MRD monitoring is of high prognostic relevance, but restricted to certain AML subtypes. FLT3-ITD represents an attractive target for MRD monitoring in particular in pts treated with a tyrosine kinase inhibitor. FLT3-ITD MRD monitoring is hampered by the broad heterogeneity of ITD length and insertion site (IS). NGS may overcome these limitations offering the opportunity for MRD monitoring in FLT3-ITD+ AML. Aims: To validate our recently established NGS-based FLT3-ITD MRD assay in a defined cohort of FLT3-ITD+ AML pts treated within the AMLSG16-10 trial (NCT01477606) combining intensive che…
Elotuzumab in Combination with Lenalidomide, Bortezomib, Dexamethasone and Autologous Transplantation for Newly-Diagnosed Multiple Myeloma: Results from the Randomized Phase III GMMG-HD6 Trial
Abstract Background: Treatment regimens including a proteasome inhibitor, immunomodulating agent and a monoclonal antibody (moAb) play an emerging role in the treatment of newly-diagnosed multiple myeloma (NDMM). This multicenter phase III trial of the German-speaking Myeloma Multicenter Group (GMMG HD6) investigated the addition of the anti-SLAMF7 moAb elotuzumab to lenalidomide / bortezomib / dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible NDMM. Patients and Methods: Patients were equally randomized into four treatment arms, stratified by International Staging System (ISS). Treatment consisted of four 21-da…
DNMT3A mutations Predict for Inferior Outcome in NPM1-Wildtype and Molecular Unfavorable Cytogenetically-Normal Acute Myeloid Leukemia: A Study of the German-Austrian AMLSG
Abstract Abstract 415 Background: Alteration of DNA methylation, a hallmark of epigenetic modification, is currently discussed as one important pathomechanism in leukemogenesis. Using a next-generation sequencing approach, a frameshift mutation of the gene encoding the DNA methyltransferase (DNMT3A) in an acute myeloid leukemia (AML) case was identified. DNMT3A catalyses the addition of a methyl group to the cytosine residue of CpG dinucleotides, thereby affecting promoter methylation status and gene expression. Subsequent sequencing analysis in an independent cohort of 288 AML patients (pts) revealed DNMT3A mutations (DNMT3Amut) in 22% of the pts; mutations were associated with intermediat…
An Adapted Gating Strategy Integrating a Myelomonocytic Window Is Necessary For Correct Flow Cytometric Diagnosis In a Large Proportion Of AML With Mutated NPM1
Abstract Background Previously, it has been reported, that AML with mutated NPM1 is associated with a distinctive immunophenotype. In particular, low or absent expression of CD34 accompanied by high expression of CD33, and – at least in part of the cases - absence of HLA-DR expression was reported. CD45/side scatter (SSC) gating is widely used for the identification of blasts by flow cytometry (FC). Blast cell gates typically are defined by a low SSC and moderate CD45 expression. However, in a number of patients with NPM1mutation this typical blast cell gate comprises significantly lower blast percentages when compared to the morphological evaluation. In these patient samples a second popul…
Midostaurin Plus Intensive Chemotherapy for Younger and Older Patients with Acute Myeloid Leukemia and FLT3 Internal Tandem Duplications
Abstract BACKGROUND: Midostaurin is a first-generation, type I multi-targeted kinase inhibitor with inhibitory activity against FLT3-ITD and -TKD mutations. Midostaurin is approved by FDA and EMA in combination with intensive induction and consolidation chemotherapy for adult patients with AML exhibiting an activating FLT3 mutation; the EMA label also includes single-agent maintenance therapy following consolidation chemotherapy. We conducted a phase-II trial (AMLSG 16-10) to evaluate midostaurin with induction chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a one-year midostaurin maintenance therapy in younger and older patients with acute myeloid leukemia …
The prognostic and predictive value of IKZF1 and IKZF3 expression in T-cells in patients with multiple myeloma
Purpose: While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III. Experimental design: We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined in vivo observations with in vitro assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and…
Improved Outcome with ATRA-Arsenic Trioxide Compared to ATRA-Chemotherapy in Non-High Risk Acute Promyelocytic Leukemia - Updated Results of the Italian-German APL0406 Trial on the Extended Final Series
Abstract Background: We recently showed that the combination of ATRA and arsenic trioxide (ATO) is at least not inferior and possibly superior to standard ATRA and chemotherapy (CHT) in the front-line management of low/intermediate risk APL (Italian-German APL 0406 trial; Lo-Coco et al., NEJM 2013). We report herein on the extended and final series of 276 patients (162 were in the previous report) with the last case being enrolled into the study in January 2013. Methods: The APL0406 study was a prospective, open-label, randomized intergroup trial conducted by the Italian GIMEMA and the German SAL and AMLSG study groups. Eligible patients were adults aged 18-<71 years with newly diagnosed…
Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial
Background Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from …
Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.
8509 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B…
Treatment Results In Acute Myeloid Leukemia Over a Time Period Of 20 Years: Analysis Of The German-Austrian Acute Myeloid Leukemia Study Group (AMLSG)
Abstract Background Overall survival (OS) in acute myeloid leukemia (AML) treated with intensive chemotherapy has improved over the last 20 year especially in younger adults (18-60 years) but still remains poor in older patients (>60 years) (Döhner et al. Blood 2010). The German-Austrian AMLSG performed controlled prospective treatment trials since 1993 starting with a risk-adapted approach (phase I, 1993-1997), followed by randomized and risk-adapted treatment strategies based on cytogenetic risk groups (phase II, 1997-2002); since 2003 addition of differentiating agents and HiDAC inhibitors to intensive induction therapy was evaluated (phase III, 2003-2007). Of note, until 2007 younger…
All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.
Abstract Introduction: Response to first induction therapy is one of the most important prognostic factors in patients with adult myeloid leukemia (AML). Induction of CR or PR is the primary aim in these patients. Methods: Between 1993 and 2005 225 consecutive patients (median age: 48.4 yrs, range 16–60 yrs) treated within the AMLHD93 (n=45), AMLHD98A (n=157) and AMLSG 05-04 (n=23, still active) trials were evaluated. All patients had primary refractory AML after one cycle of ICE. The different salvage therapies were as follows: AMLHD93 sequential-HAM (S-HAM) for patients <55 years of age [cytarabine 3g/m2 bid. days 1,2,8,9, mitoxantrone 10mg/m2 days 3,4,10,11], HAM for patients >=55 …
All-Trans Retinoic Acid Improves Outcome in Younger Adult Patients with Nucleophosmin-1 Mutated Acute Myeloid Leukemia – Results of the AMLSG 07-04 Randomized Treatment Trial
Abstract Abstract 80 Background: Mutations in the nucleophosmin-1 gene (NPM1) are the most common genetic abnormalities in acute myeloid leukemia (AML) and define a provisional AML entity in the current WHO classification. In a retrospective biomarker study within a randomized trial of older patients with AML, we demonstrated that patients with mutated NPM1 and absence of a FLT3 internal tandem duplication (ITD) benefit from all-trans retinoic acid (ATRA) as adjunct to conventional chemotherapy (Schlenk et al. Haematologica 2009;94:54–69). Aims: To evaluate the impact of ATRA in combination with conventional chemotherapy on outcome, and to assess the NPM1 mutational status as predictive mar…
Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone As Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial
Abstract Background: In newly-diagnosed multiple myeloma (NDMM), lenalidomide/bortezomib/dexamethasone (RVd) is one of the most widely used combination regimens. Anti-CD38 monoclonal antibodies (CD38-moAb) increase efficacy when added to standard-of-care regimens. Here we present the first primary endpoint of the randomized, open-label, multicenter, phase III GMMG-HD7 trial, comparing RVd without (arm IA) or with the CD38-moAb isatuximab (Isa, arm IB) with regard to the rate of minimal residual disease (MRD) negativity after induction therapy in patients with transplant-eligible NDMM. Patients and Methods: Patients with transplant-eligible NDMM at 67 sites in Germany were equally randomized…
All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18–60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6–8; 15 mg/m2, days 9–21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred pati…