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  • 1
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    TP53 Mutations Detected By Next-Generation Deep-Sequencing In Patients With Myelodysplastic Syndrome and Isolated Deletion (5q): Results From a German Multicenter Trial
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2759-2759
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2759-2759
    Abstract: Beside cytogenetic aberrations, additional gene mutations are powerful predictors of outcome in myeloid diseases. Moreover, myelodysplastic syndromes with isolated deletion (5q) (MDS del(5q)) have been regarded as one of the most favorable entities among MDS. However, a substantial proportion of MDS del(5q) patients experience transformation into AML soon after diagnosis (Germing et al. Leukemia. 2012;26:1286-1292). Mutations of TP53 gene have early been recognized as an unfavorable prognostic biomarker in MDS in general and recent data suggest a role of TP53 mutations in the transformation of MDS del(5q) into AML. Lenalidomid (Len) is now approved in the US as well as in Europe for the treatment of MDS del(5q) it is of particular interest whether Lenalidomide can alter the course of pretreatment TP53 mutated MDS del(5q). Methods The Le-Mon-5 trial investigated the safety and efficacy of Len in patients with MDS and isolated deletion (5q). All patients gave their written informed consent to the clinical trial and to additional molecular genetic analyses. Bone marrow aspirates were performed at screening prior treatment initiation and during follow-up every 6 months. Only freshly extracted, high-quality DNA from ficollized mononuclear cells was used for next-generation deep-sequencing analysis. For generation of PCR amplicon libraries TP53 oligonucleotide primer plate assays were used and technically validated within the IRON-II (Interlaboratory Robustness Of Next generation sequencing) research study network. Amplicon deep-sequencing of TP53 (exons 4-11) was performed on a Roche 454 GS Junior system. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden. Results Central cytological, histological and cytogenetic review was performed in all patients establishing the diagnosis of MDS with isolated deletion (5q). A total of 68 patients (male: n=9) were analyzed with a median age of 71 years (range 41-88 years). TP53 mutations prior to treatment initiation with Len were found in 7 patients (10%). Mean mutation frequency was 38%. Notably, we did not find mutation frequencies lower than 15%. Of 4 evaluable patients, three patients became transfusion independent within 4 months of Len treatment. Of 2 patients we had follow-up samples available. Both patients showed no difference with regard to the mutation frequency after a follow-up of 4 and 17 months on Len treatment (27% and 51%, respectively). Noteworthy, one the two patients achieved a complete cytogenetic remission despite maintaining his TP53 mutation frequency. Conclusion Using freshly extracted DNA we achieved high-quality NGS results with a high mean coverage of the relevant coding region of TP53. However, prevalence of TP53 mutations in our patient cohort was lower as compared to previously published data and we did not find low-level allele burdens as published by other groups, which might be due to the different sample sources used. Transfusion independence as well as cytogenetic remissions can be achieved in patients with TP53 mutations who are treated with Lenalidomide. Disclosures: Platzbecker: Celgene: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Götze:Celgene Corp.: Honoraria. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bug:Celgene: Honoraria, Research Funding. Hofmann:Celgene: Research Funding. Germing:Celgene: Honoraria, Research Funding. Nolte:Celgene: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2759.2759
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 2
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    The Role of MSI2 Expression Levels on Outcome of MDS and AML Patients
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1734-1734
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1734-1734
    Abstract: Abstract 1734 Musashi (MSI) represents an evolutionarily conserved family of RNA-binding proteins. MSI2 is the predominant form in hematopoetic stem cells (HSC). Recently, overexpression of MSI2 in a mouse model was found to increase cell cycle progression and to cooperate with BCR-ABL1 to induce aggressive leukemia. The aim of this study was to analyze the prognostic importance of MSI2 expression in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML). Diagnostic bone marrow or peripheral blood samples were analyzed from 454 adult patients (aged 17–60 years) with de novo (n=406) or secondary AML (n=48) with French-American-British (FAB] classification M0-M2, or M4-M7, who were entered into the multicenter treatment trials AML SHG 0199 or AML SHG 0295. Additionally, we analyzed a cohort of 148 patients (aged 36–92 years) with MDS with low to high IPSS scores. Real-time reverse-transcriptase-polymerase chain reaction (RT-PCR) was performed using patient-derived cDNA and ABL as an endogenous control. MSI-2 expression levels were quantified using the TaqMan Gene Expression Assay (Applied Biosystems, Assay ID MSI2: Hs01592567_m1). To define the MSI2 expression status patient cohorts were divided into four quartiles (Q) according to levels of MSI2/ABL expression and subsequently dichotomized into two groups including the three lower Qs (Q1, Q2, and Q3) and the upper Q (Q4) of MSI2/ABL values. Patients of the quartile with highest MSI2 expression levels were classified as high MSI2 expressing patients. In MDS, MSI2 high versus low expression was independent of transfusions (P=.55), cytogenetic risk (P=.6), and ASXL1 mutations (P=.99), but was associated with a higher blast percentage (p=.034). In AML, higher MSI2 expression correlated with increased peripheral blood blasts (P=.036), and inversely correlated with the favourable cytogenetic risk group defined by inv(16) and t(8;21) according to Medical Research Council criteria (P 〈 .001). Additionally, patients with higher MSI2 expression were likely to be FLT3-ITD positive (P 〈 .001), NPM1 (P 〈 .001), DNMT3A (P=.003), NRAS (P=.018) and CEBPA double mutated (P=.043). No association was found with other molecular markers including IDH1, IDH2 and WT1 mutations. Next, we evaluated the effect of MSI2 expression levels on patient outcome in MDS and AML. In MDS, high MSI2 expression predicted an increased likelihood of and more rapid progression to AML (HR 2.95, 95%CI 1.55–5.64, P=.001), but MSI2 expression levels did not affect overall survival (OS, HR 1.34, 95%CI 0.81–2.23, P=.25). In multivariate analysis when adjusting for karyotype, transfusion dependence, percentage of bone marrow blasts, ASXL1 frameshift mutation status and IDH1 mutation status, high MSI2 expression remained an independent prognostic factor for AML transformation in MDS (HR 2.33, 95%CI 1.16–4.67, P=.018). In AML, OS was shorter in AML patients with higher MSI2 expression as compared to low expression (HR 1.48, 95%CI 1.13–1.95, P=.005). However, relapse free survival (RFS) and complete remission (CR) rates were not influenced by high versus low MSI2 expression (RFS, HR 1.27, 95%CI.92–1.76, P=.15; CR, P=.39). In multivariate analysis, when considering MSI2 high versus low expression, DNMT3A mutations, age, platelet count, secondary versus de novo AML, cytogenetic risk group, NPM1/FLT3-ITD high vs. low risk group, and MLL5 expression levels, MSI2 expression did not remain an independent prognostic marker for OS (HR 1.31, 95%CI.98–1.76, P=.07). In patients with cytogenetically normal AML (CN-AML), MSI2 also presented a negative prognostic marker for OS (HR 1.59, 95%CI 1.08–2.33, P=.019) but did not influence RFS (HR 1.10, 95%CI 0.69–1.76, P=.68) and CR (P=.39). In multivariate analyses for CN-AML, when considering age, platelet count, DNMT3A mutations, NPM1FLT3-ITD high vs. low risk group, CEBPA mutation status and WT1 SNPrs16754, MSI2 did not independently predict OS (HR 144, 95%CI 0.94–2.19, P=.096). In summary, our data suggest that MSI2 expression might contribute to the transformation from MDS to AML. Whether MSI2 expression is dysregulated through other associated prognostic markers, or whether it is an independent event in AML pathogenesis remains to be determined. However, it may represent a valuable therapeutic target both in MDS and AML patients. Disclosures: Ottmann: Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Hofmann:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1734.1734
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 3
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    – Updated Results from the Bridge Trial: Long-Term Survival and Impact of Donor Availability – Clofarabine Salvage Therapy Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory AML
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1204-1204
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1204-1204
    Abstract: Background: In relapsed or refractory acute myeloid leukemia (AML), long-term disease-free survival may only be achieved with allogeneic hematopoietic stem cell transplantation (HSCT). Within the BRIDGE Trial, the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT was studied. Here, we report long-term survival data and the impact of donor availability at the time of study enrollment. The BRIDGE trial (NCT 01295307) was a phase II, multicenter, intent-to-transplant study. Patients and Methods: Between March 2011 and May 2013, 84 patients with relapsed or refractory AML older than 40 years were enrolled. Patients were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2, days 1-5). Patients with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2, day -6 to -3, and melphalan 140 mg/m2 on day -2. In patients with partially matched unrelated donors, ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil. Results: Forty-four patients suffered from relapsed AML and 40 patients had refractory disease. The median patient age was 61 years (range 40 – 75). According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as intermediate I, 17% as intermediate II and 20% as adverse risk. The overall response rate assessed at day 15 after start of CLARA was 80% (defined as at least a marked reduction in BM blasts or BM cellularity and absence of blasts in the peripheral blood) with 31% of patients having less than 5% BM blasts at that time. Seventeen patients did not respond to CLARA, and were subsequently treated off-study. Due to early death, three patients were not evaluable for treatment response. Overall, 66% of the patients received HSCT within the trial. Donors were HLA-identical siblings in eight cases (14%), HLA-compatible unrelated donors in 30 cases (55%) and unrelated donors with one mismatch in 17 cases (31%). Treatment success was defined as complete remission (CR), CR with incomplete recovery (CRi) or CRchim (BM donor chimerism 〉 95% and absolute neutrophil count 〉 0.5/nL) on day 35 after HSCT. Treatment success was achieved in 61% of the patients. With a median follow up of 25 months, the OS for all enrolled patients at two years was 42% (95% CI, 32% to 54%). (Figure 1) The Leukemia-free survival at two years for those 51 patients who achieved the primary endpoint was 52% (95% CI, 40% to 69%). (Figure 2) At the time of enrollment, 14% of patients had a related donor and 33% had an unrelated donor available. In 46% of the patients, donor search was initiated at the time of enrollment. For 7% of patients, donor search was unsuccessful prior to enrollment and reinitiated. The OS at 2 years for patients with a related or an unrelated donor available was 75% (95% CI, 54% to 100%) and 47% (95% CI, 31% to 71%), respectively, while it was 29% (95% CI, 18% to 48%) for patients for whom donor search was initiated at time of enrollment (p = .09). Conclusions: Salvage therapy with CLARA, and subsequent conditioning with clofarabine and melphalan prior to allogeneic HSCT, provides good anti-leukemic activity in patients with relapsed or refractory AML. Fast unrelated donor search and work up, with conditioning in aplasia allowed a high rate of successful HSCTs. The leukemia-free survival for this group of elderly, high risk AML patients is very promising. Figure 1 Figure 1. Overall survival for all patients, n=84 Figure 2 Figure 2. Leukemia-free survival for all patients with primary treatment success, n=51 Disclosures Middeke: Genzyme: Speakers Bureau. Off Label Use: Clofarabine for AML. Schetelig:Genzyme: Research Funding; DKMS German Bone Marrow Donor Center: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1204.1204
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
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    Syk and Btk Transduce Survival and Proliferation-Inducing Signals By Activating Distinct Signaling Pathways and Transcriptional Programs in AML Cells
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3594-3594
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    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3594-3594
    Abstract: Acute myeloid leukemia (AML) is a genetically heterogeneous disease where multiple driver mutations coincide in branching hematopoietic subclones leading to malignant transformation. One important class of mutations alters the function of signaling intermediates such as FLT3, thereby helping AML cells to overcome the physiological communication with their microenvironment. To investigate, if also non-mutated signaling molecules might be potential drug targets in AML, we performed an unbiased proteomic kinase activity profiling. Our (phospho)proteomic and functional analyses revealed spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK) as novel non-mutated drug targets in AML. By immunohistochemical analyses we identified expression of both kinases in more than 70% of analyzed AML cases. Oncogenic SYK signaling in AML cells turned out to be critically regulated by beta-integrins upon intercellular contact formation between AML cells and bone marrow stroma cells. BTK, however, turned out to act downstream of FLT3-ITD to activate MYC-dependent oncogenic transcriptional programs. FLT3-ITD expression induced activation of BTK in cell culture models and patient-derived AML cultures and sensitized them towards BTK inhibitors. This newly identified FLT3-ITD/BTK signaling axis can be therapeutically exploited by combining FLT3 and BTK inhibitors resulting in additive apoptosis-inducing effects. As in some cases also FLT3-ITD-negative AML cells showed response to BTK inhibition, we characterized the BTK interactome and its downstream signaling networks by quantitative proteomic techniques and identified the apoptosis sensor Toll-like receptor 9 (TLR9) as an upstream activator of BTK in FLT-ITD-negative cells. In the absence of FLT3-ITD, TLR9 activates BTK to induce cell survival through NFkB as revealed by transcriptome sequencing and cell biological studies. While TLR9 stimulation enhanced AML cell proliferation, knock-down of TLR9 induced a partial cell cycle arrest and apoptosis. Thus, we here describe a novel microenvironment-derived signaling axis that may represent an important mechanism of AML maintenance in various important clinical settings including efficient FLT3-ITD inhibition and cytotoxic therapy. Taken together, these data highlight the importance of interactions between AML cells and their microenvironment and unravel cooperative dependencies between mutant oncoproteins and wild-type kinases in AML pathogenesis. They also provide a rationale for the clinical evaluation of SYK- and BTK inhibitors in AML. Disclosures Beck: Chronic Biomedical: Employment. Schuetz:Chronix Biomedical: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3594.3594
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 5
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    Successful High-Dose Ribavirin Treatment of Respiratory Syncytial Virus-Induced Tracheobronchitis and Pneumonia Occuring Pre-Engraftment in Allogeneic Hematopoietic Stem Cell Transplant Recipients.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1163-1163
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    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1163-1163
    Abstract: Abstract 1163 Poster Board I-185 Introduction Respiratory syncytial viruses (RSV) frequently cause severe respiratory disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Within the first post-transplant month, progression of upper respiratory tract infection to life-threatening bronchiolitis and pneumonia is common and mortality rates of up to 80% have been reported if left untreated. Aerosolized ribavirin plus/minus immunoglobulins is considered the treatment of choice for RSV pneumonia. With this regimen, the 30-day all cause mortality is still 40% in immunosuppressed HSCT patients. In addition, nebulizing ribavirin may induce toxic side effects on patients and staff. Patients and treatment Concurrent with an outbreak in the community, RSV infection was diagnosed in 10 out of 29 patients (34%) undergoing allogeneic HSCT in the winter season 2008. Diagnosis was based on RSV-specific PCR of routinely collected throat swaps. Intravenous ribavirin was dosed according to Schleuning et al., 2003 (day 1: 33 mg/kg, day 2-5: 4×16 mg/kg, day 6-10: 3×8 mg/kg) for 8-10 days, followed by oral ribavirin (1800 mg per day) until recovery from symptoms. Airflow obstruction (AFO) was defined as a FEV1/FVC ratio 〈 0.7 or a drop in FEV1 〉 20% from baseline. All RSV-infected patients (median age 60 years) had undergone reduced-intensity conditioning HSCT for high-risk acute myeloid leukemia (1st CR: n=2; subsequent CR: n=3; untreated or refractory relapse: n=5). GvHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil with (n=8) or without (n=2) antithymocyte globulin. Donors were HLA-idential siblings (n=1), matched (n=8) or mismatched unrelated donors (n=1). Results Median time from HSCT to detection of RSV was 15 (range, 1-40) days. In 7 out of 10 patients, RSV infection was diagnosed pre-engraftment during neutropenia. Four patients had bronchiolitis or pneumonia and 6 patients suffered from tracheobronchitis. High-dose intravenous ribavirin was administered to all patients with pneumonia and/or diagnosis of RSV infection within 7 days after transplantation (n=5). These patients had hypoxia and required oxygen supplementation. Treatment with oral ribavirin was initiated in the other five patients with tracheobronchitis diagnosed on days 12-40 after HSCT. With a median follow up of 6 months, 9 out of 10 patients are alive and in complete remission of their AML. All 9 patients became RSV-negative in throat swabs after a median time of 22 days from start of therapy. Severe AFO caused by RSV pneumonia occurred in 2 patients and improved after treatment. Despite severe lymphopenia, no patient treated for tracheobronchitis progressed to RSV pneumonia. Neutrophil recovery was delayed in the three patients diagnosed with RSV pneumonia pre-engraftment until days 26, 28+ and 111 after HSCT, due to high-dose intravenous ribavirin and/or RSV infection itself. One of these patients died of septic shock associated with pseudomonas aeruginosa-induced pneumonia on day 28 after HSCT in prolonged neutropenia. No other ribavirin-associated toxicity such as hepatotoxicity or clinically relevant hemolysis was observed. Three patients developed acute intestinal GvHD, 2 of them recovering upon steroid treatment and one proceeding to chronic disease despite salvage therapy. One additional patient had steroid-responsive acute GvHD of the skin. Conclusions High-dose intravenous or oral ribavirin therapy appears to be safe and effective even if administered to neutropenic allogeneic HSCT recipients. None of these patients with RSV infection in the early post-transplant period developed bronchiolitis obliterans or persistent AFO. Based on our favourable results, further studies are required. Meanwhile, we suggest to treat all patients with symptomatic RSV infections in the early post-transplant phase with oral or intravenous ribavirin. Disclosures Off Label Use: Ribavirin is approved for inhalative treatment of RSV infections but not for systemic therapy..
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1163.1163
    RVK:
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
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    Phase I/II Study of Volasertib (BI 6727), an Intravenous Polo-Like Kinase (Plk) Inhibitor, in Patients with Acute Myeloid Leukemia (AML): Results From the Randomized Phase II Part for Volasertib in Combination with Low-Dose Cytarabine (LDAC) Versus LDAC Monotherapy in Patients with Previously Untreated AML Ineligible for Intensive Treatment
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 411-411
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 411-411
    Abstract: Abstract 411 Background: LDAC is an established treatment option for patients (pts) with AML considered ineligible for intensive remission induction treatment. However, the outlook for pts who receive LDAC remains unsatisfactory, and novel therapeutic strategies are needed to improve clinical outcome in these pts. Plk1 plays a key role in mitosis and cell cycle progression and is an attractive target for novel therapeutic approaches in cancer. Volasertib (V) is a first-in-class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plks. The phase I part of this trial determined the maximum tolerated dose of V in combination with LDAC (V + LDAC) to be 350 mg and demonstrated antileukemic activity of V and V + LDAC in pts with relapsed/refractory AML ineligible for intensive therapy (Bug et al, ASH 2010 and 2011). Here we present preliminary phase II data for the randomized comparison of V + LDAC vs LDAC in pts with newly diagnosed AML ineligible for intensive treatment. Methods: In the phase II part of this open-label study, eligible pts were randomized to receive V (350 mg 1-hr intravenously, days 1, 15 Q4W) + LDAC (20 mg bid subcutaneously, days 1–10 Q4W), or LDAC alone until progression/relapse or intolerance. The primary endpoint was objective response (complete remission [CR] or CR with incomplete blood count recovery [CRi] ); secondary endpoints included event-free survival (EFS), overall survival (OS), safety and pharmacokinetics (PK). Results: 87 pts were treated with V + LDAC (n=42) or LDAC (n=45). Pt characteristics (V + LDAC/LDAC) were largely balanced: median age, 75/76 yrs; secondary AML, 40.5%/64.4%; adverse cytogenetic group, 35.7%/33.3%. At time of analysis (February 22 2012) 15 pts were still on treatment (12 with V + LDAC). Pts received a median (range) of 2 (1–12) cycles of V + LDAC and 2 (1–11) cycles with LDAC. A significantly greater proportion of pts who received V + LDAC achieved a CR or CRi compared with pts who received LDAC (31.0% vs 11.1%; odds ratio 3.59 [95% CI: 1.15, 11.18]; P = 0.0277), with a median (range) time to remission of 71 (29–158) days and 69 (34–125) days, respectively. Remissions with V + LDAC were observed across genetic groups, including pts with adverse cytogenetics. A trend for longer median EFS was observed for pts who received V + LDAC compared with those who received LDAC (HR 0.61 [95% CI: 0.35, 1.05]; P = 0.0725; Figure). Follow-up for OS was ongoing at the time of this analysis. Among pts achieving CR/CRi, only 2 had experienced recurrence or death at the time of analysis (1 in each arm after a remission duration of 57 [V + LDAC] or 67 [LDAC] days). For all other pts ongoing in remission, the remission duration was censored after 53–407 days (LDAC + V) or 32–282 days (LDAC), consistent with prolonged duration of remission in some pts. The most frequent all grade adverse events (AEs) in the V + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%) and anemia (40.5%). In the LDAC arm, the most common all grade AEs were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), and constipation, asthenia and diarrhea (26.7% each). More pts who received V + LDAC experienced ≥ grade 3 AEs than those who received LDAC (95.2% vs 68.9%), particularly for blood and lymphatic system disorders (81.0% vs 44.4%), gastrointestinal disorders (21.4% vs 6.7%), and infections and infestations (45.2% vs 22.2%). The early death rates (V + LDAC/LDAC) at 30, 60 and 90 days were comparable between the two treatment arms: 30 days, 9.5%/8.9%; 60 days, 21.5%/17.8%; 90 days, 28.9%/33.4% (rates calculated using Kaplan-Meier method). PK analyses demonstrated that V is a moderate clearance drug with multi-compartmental PK behavior, a large volume of distribution and a long terminal half-life. Preliminary data suggest no drug-drug interactions following combination of V with LDAC. Conclusions: These preliminary phase II data demonstrate a significantly improved CR/CRi rate and a trend for EFS benefit with V + LDAC compared with LDAC alone in pts with newly diagnosed AML ineligible for intensive treatment. An increased frequency of AEs was observed with the addition of V, which was expected given its myelosuppressive mechanism of action; available data do not suggest increased early mortality for V + LDAC vs LDAC. A confirmatory phase III trial is needed to determine the clinical benefit of V + LDAC in pts with AML ineligible for intensive treatment. Disclosures: Off Label Use: Volasertib is an investigational agent. Fiedler:Pfizer, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Tidow:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer-Ingelheim: Employment. Döhner:Celgene, Amgen, Ambit, Astellas, Lilly: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.411.411
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 7
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    Clinical Impact of TP53 Mutations in Patients with MDS and Isolated Deletion 5(q) Treated with Lenalidomid: Results from the German Prospective Le-Mon-5 Trial
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1920-1920
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1920-1920
    Abstract: Introduction: MDS with isolated deletion 5(q) accounts for approximately 5% of all MDS cases. A recent retrospective analysis has found a cumulative progression rate of 18% after 5 years in patients with MDS deletion 5(q) without an increased medullary blast count[1]. Retrospective analyses have indicated that mutations in TP53 have an adverse impact on the clinical course of affected patients and their response to Len treatment. Here we report on the results of the German multi-center, prospective Le-Mon-5 trial that investigated the safety and efficacy of lenalidomide (Len) in patients with MDS and isolated deletion 5(q). Methods: Le-Mon-5 is a trial of Len in patients with MDS with isolated 5q abnormality, a blast count of 〈 5% in the bone marrow, a platelet count 〉 50.000/µl and absolute neutrophil counts of 〉 500/µl in the peripheral blood. Patients were treated with the standard dose of 10 mg Len for 21 days q28 days. The primary endpoint was safety. Secondary endpoints included response according to IWG criteria (2000), time to response, duration of transfusion independency and incidence and time to AML-transformation, respectively. All patients gave written informed consent to the trial including additional molecular genetic analyses. Central cytologic, cytogenetic and histologic review was performed. Mutational analysis of TP53 was done by next generation sequencing (NGS). For generation of PCR amplicon libraries TP53 primer plate assays were used and technically validated within the IRON-II (Interlaboratory Robustness Of Next generation sequencing) study network. Amplicon sequencing of TP53 was performed on a Roche 454 GS Junior system. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden. Results: A total of 91 patients were enrolled into the trial. Of those, 71 patients (male, n=13) were analyzed for TP53 mutations. Median age was 71 years (range 40-88 years). TP53 mutations prior to treatment initiation with Len were found in 7 patients (10%). There was no difference between the TP53 mutated (TP53mut) versus TP53 wildtype patients (TP53WT) with regard to age, IPSS risk, hemoglobin levels, absolute neutrophil counts and platelet counts at baseline. Transfusion independence was achieved in a significantly lower proportion of patients in the TP53mut group versus TP53WT group (43% vs. 62%, p=0.036). Moreover, median survival was significantly shorter in the TP53mut group as compared to TP53WT group (533 days vs. not reached, p=0.0002). No difference was seen with regard to cytologic and cytogenetic response. Data on evolution into AML are currently being collected. Of 2 patients we had follow-up samples available. Both patients showed no difference with regard to the mutation frequency after a follow-up of 4-17 months on Len treatment (27% and 51%, respectively), although one of the patients achieved a complete cytogenetic response during Len treatment. Conclusions: Using the NGS technique on a routine basis, we achieved high quality runs with a high mean coverage of analyzed exons of TP53. Presence of TP53 mutations adversely affected response to Len with regard to transfusion independence. Moreover, TP53mut patients had a shorter overall survival as compared to TP53WT patients underlining the prognostic relevance of TP53 mutations in this patient cohort. Therefore, mutation analysis of TP53 might guide treatment decisions in the future, e.g. consideration of combination regimens. Since the TP53 clone obviously prevails during Len treatment, careful monitoring for signs of transformation should be performed. Disclosures Platzbecker: Celgene Corp.: Honoraria, Research Funding. Götze:Celgene Corp, Novartis Pharma: Honoraria. Schlenk:Celgene Corp.: Research Funding, Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bug:Celgene: Honoraria, Research Funding. Germing:Celgene Corp.: Honoraria, Research Funding. Nolte:Celgene Corp., Novartis Pharma: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1920.1920
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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    Sorafenib As Maintenance Therapy Post Allogeneic Stem Cell Transplantation for FLT3-ITD Positive AML: Results from the Randomized, Double-Blind, Placebo-Controlled Multicentre Sormain Trial
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 661-661
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 661-661
    Abstract: Introduction: Most patients with FLT3-ITD-positive AML, who relapse after allogenic stem cell transplantation (allo-SCT) die from their disease. Whether prophylactic FLT3-ITD inhibition with sorafenib can prevent AML relapse and improve outcome of patients in complete hematological remission (CHR) after allo-SCT is unknown and was tested in the SORMAIN trial. Methods: This randomized, double blind, placebo-controlled study was done at 14 centers in Germany and Austria. Patients with FLT3-ITD+ AML, aged 18 years or older, who had undergone allogenic stem cell transplantation from a HLA-matched sibling donor, 10/10 or 9/10 HLA-matched unrelated donor, and who were in confirmed CHR at the time of screening between day +30 and day +100 post allo-SCT, were included. Patients were randomly assigned (1:1) to receive either sorafenib (starting dose: 2 x 1 tbl. [2 x 200mg] qd, increasing every 14d to up to 2 x 2 tbl. [2 x 400mg] qd according to tolerability) or placebo (2 x 1 or 2 tbl. qd) for up to 24 months. Randomization was done centrally. In case of drug related adverse events, study medication could be interrupted, stepwise reduced to a minimum of 2 x 1 tbl. qd, temporarily withheld and recommenced at a lower dose level. FLT3-ITD diagnostics was done centrally at baseline and at time of relapse. In relapsing patients, off-label compassionate use of sorafenib was possible. The primary endpoint was relapse-free survival (RFS) as defined by either hematological relapse or death from any cause. The secondary endpoint was overall survival (OS). We here report the final RFS analysis. The OS results will be unblinded only prior to the ASH meeting and will be reported there. The SORMAIN study was terminated prior to full recruitment because of slow accrual. SORMAIN was registered with the European Clinical Trials Database (EudraCT 2010-018539-16) and the German Clinical Trials Register (DRKS00000591). Results: Between October 29, 2010, and May 17, 2016, 83 patients (41 males, 42 females) were randomized and included in the primary analysis (placebo, n=40; sorafenib, n=43). Median age was 54 years (IQR 47.75 - 61.33) for the entire study population and not significantly different between sorafenib and placebo groups. With a median follow up of 41.8 months after randomization (IQR 24.1 - 42.5), median RFS was 30.9 months (lower bound of 95% CI 5.2 months) in the placebo group versus not reached in the sorafenib group, corresponding to a 2-year RFS of 53,3 % (95% CI 36.5-67.5) in the placebo versus 85.0 % (69.5-93.0) in the sorafenib group (hazard ratio [HR] 0.39, 95% CI; 0.18 -0.85; P=0.0135) (Fig. 1). Overall, sorafenib was well tolerated. The most common grade 3-4 adverse event in both groups was acute GvHD (seven [ 17.5%] in the placebo group vs. nine [20.9%] in the sorafenib group. Conclusion: Sorafenib maintenance therapy after allo-SCT is feasible and significantly reduces the risk of relapse or death in patients with FLT3-ITD positive AML. OS results will be presented at the meeting. Figure 1. Figure 1. Disclosures Burchert: Bristol Myers Squibb: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; AOP Orphan: Honoraria, Research Funding; Novartis: Research Funding. Bug:Amgen: Honoraria; Neovii: Other: Travel Grant; Novartis Pharma: Honoraria, Research Funding; Astellas Pharma: Other: Travel Grant; Jazz Pharmaceuticals: Other: Travel Grant; Celgene: Honoraria; Janssen: Other: Travel Grant. Finke:Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Rollig:Bayer: Research Funding; Janssen: Research Funding. Wäsch:Pfizer: Honoraria. Lang:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Serve:Bayer: Research Funding. Kroeger:Neovii: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding. Schmid:Jazz Pharma: Honoraria, Other: Travel grant, Speakers Bureau. Wolf:BMS: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-112614
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 9
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    Monitoring of Donor Chimerism in CD34+ Peripheral Blood Progenitors Allows to Detect Minimal Residual Disease after Allogeneic Stem Cell Transplantation -Results of a Randomized Trial
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 340-340
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 340-340
    Abstract: Relapse of hematological malignancy remains a major complication after allogeneic stem cell transplantation. This is especially true for patients receiving minimal or reduced-intensity conditioning therapy. Analysis of donor chimerism (DC) is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. The sensitivity of a standard PCR assay amplifying short-tandem-repeat sequences can be improved significantly by investigating sorted CD34+ peripheral blood cells. We prospectively compared the serial analysis of DC in selected CD34+ cells and unmanipulated whole blood (WB) within a randomised study in 131 patients with CD34+ hematological malignancies (AML, ALL and MDS) surviving more than 100 days after transplantation. The primary end-point was the association between decreasing CD34+ DC and haematological relapse. Whenever a decreasing CD34+ or WB DC was confirmed and no signs of active GvHD were present, a rapid taper of CsA or tracolimus (50% every 5–7 days) was suggested. If no GvHD occurred within 14 days after the stop of CsA or tacolimus, patients were scheduled to receive donor lymphocyte infusions (DLI) in incremental doses. The cumulative incidence of relapse was significantly increased in patients with decreasing or incomplete CD34+ DC (62% vs. 38%, p=0.01). This was associated with a lower probability of overall survival (20% vs. 39%, p=0.03). The interval between the decrease in CD34+ DC and hematological relapse was 35 days (range 0–567) in the study group compared to only 8 days (range 0–63) in the control group monitored by WB DC analysis (p=0.05). The median time between a decrease in CD34+ DC and WB DC was 14 days (range, 0 to 445). Patients receiving preemptive therapy triggered by decreasing CD34+ DC had a significantly higher probability of disease-free survival compared to cases monitored and treated according to WB DC (19% vs. 0%, p=0.009). Multivariate analysis revealed age, disease-risk and decreasing CD34+ DC as independent risk-factors for overall survival in the study group. In summary, we could demonstrate that the quantification of DC in CD34+ selected cells is a sensitive method to predict relapse and survival after allogeneic SCT. Although this technology opens a window for preemptive therapy, new treatment approaches have to be employed to improve the overall outcome of patients with recurrence of residual disease after allogeneic stem cell transplantation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.340.340
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 10
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    Phase II Study of Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) As First Salvage Therapy in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (allo-SCT): Final Results From the AZARELA-Trial (NCT-00795548)
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 656-656
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 656-656
    Abstract: Abstract 656 Background: Relapse after allo-SCT is a major cause of treatment failure in patients (pts) with myeloid malignancies and is associated with a poor prognosis. As therapeutic options are limited, treatment of these pts is challenging. Indeed, there is a need for novel strategies which ideally target the leukemic clone and direct the immune system towards an enhanced GvL effect without aggravating GvHD. The hypomethylating agent Aza might provide these properties, and results from retrospective studies investigating Aza+/−DLI in pts with AML/MDS relapsing after allo-SCT were encouraging. Design/Methods: We here report the final results from a prospective single-arm EBMT multicenter phase II trial which aimed to investigate the efficacy and safety of a combination of Aza and DLI as 1st salvage therapy in pts with AML or MDS with hematological relapse after allo-SCT. Treatment schedule contained up to 8 cycles Aza (100 mg/m2/d d1-5, every 28 d) followed by DLI with increasing dosages (1-5×106–1-5×108cells/kg) after every 2ndAza cycle. Results: A total of 30 pts (19 f/11 m, median age 56 years, range 29–71) from 6 German transplant centres were included between January 2009 and May 2010. The majority of pts (n=28, 93%) suffered from AML, while 2 pts (8%) had MDS or MDS/MPN, respectively. At transplant, 16 pts (53%) had active disease (6 induction failure, 7 relapse I/II, 3 untreated) and 14 pts (47%) were in remission (12 CR1, 2 CR2). Following standard-dose (n=4, 13%) or dose-reduced conditioning (n=26, 87%), 10 pts (33%) received a graft from MSD and 20 pts (67%) from MUD. PBSC were used in 29 pts (97%), while 1 pt (3%) received BM. Acute GvHD occurred in 13 pts (46%) and 4 pts (13%) had chronic GvHD prior inclusion. None of the pts had active GvHD at the time of relapse, but 6 pts were still on immunosuppressive therapy. All pts had hematological relapse (median BM blasts: 34%, median chimerism: 67%) at a median time of 160 days (range 19–1699) following allo-SCT. A median of 3 courses Aza (range 1–8) were administered, and 22 of 30 pts (73%) received DLI (median: 1, range: 1–4, median CD3 dose 5×106/kg/DLI, range: 1–100×106). Overall response rate was 47%. Seven pts (23%) achieved CR or CRi, 2 pts (7%) PR, and 5 pts (17%) had stable disease (SD). Median time and median number of Aza cycles to best response were 79 days (range 28–299) and 3 cycles (range 1–8) respectively. Of the 7 pts who achieved a CR, 5 pts continue in CR for a median of 605 days (range 307–763) without any additional treatment, while 1 pt relapsed after 490 days and 1 pt died from GvHD. By July 2011 median follow-up of surviving pts is 645 days (range 564–857) and 5 of 30 pts (17%) are currently alive. Twelve pts have died due to progressive disease (PD), while 7 pts died during (n=3, 2 infection, 1 bleeding) or after the end of therapy (n= 4, 1 GvHD, 2 infection, 1 bleeding). All 5 pts who underwent 2nd allo-SCT died. Median overall survival (OS) of all pts is 117 days (95% CI 66–168 days). Patients with CR/CRi had a significant longer OS than pts not reaching CR/CRi (not reached vs. 83 days, p 〈 .001). Eleven pts (37%) developed aGvHD, while cGvHD was observed in 5 pts (17%). Any type of GvHD was seen in 78% of pts with CR/PR as opposed to 33% in pts with SD/PD (p=.03). Cytopenias grade III/IV occurred in all pts, but were considered to be drug-related in only 11 pts (37%). The most common drug-related grade III/IV non-hematological toxicities were infection and bleeding. Conclusion: Aza and DLI as first salvage therapy is a safe and active approach for pts with AML or MDS who relapse after allo-SCT, and induces durable remissions in a subgroup of pts. Further research to better define target patient groups and combination partners for AZA+DLI is needed. Disclosures: Schroeder: Celgene: Financial travel support. Bug:Celgene: Lecture fees, Membership on an entity's Board of Directors or advisory committees. Luft:Celgene: Research Funding. Kobbe:Celgene: Financial travel support, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.656.656
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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