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  • American Society of Hematology  (90)
  • 1
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    The Effects of Induction Chemotherapy and High-Dose Melphalan with Tandem Autologous Transplantation in Multiple Myeloma: The Prospective Randomized DSMM 2 Study.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 446-446
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 446-446
    Abstract: The concept of the DSMM 2 study was to give age-adjusted high-dose treatment to elderly myeloma patients in order to balance efficacy and toxicity. The value of conventional induction chemotherapy before high-dose melphalan and autologous stem cell transplantation and the durability of unmaintaned remissions afterwards was addressed. Between September 2001 and September 2006, 434 multiple myeloma patients 60–70 years of age with 0–1 cycle of pretreatment were recruited from 45 centers. The median age was 65 years. The patients were randomized to receive 4 cycles of conventional induction chemotherapy [A1] (n=216; VAD or idarubicin/Dex in 88%) or no induction chemotherapy [A2] (n=218). Instead of induction chemotherapy, patients in [A2] received only one short course of dexamethasone 40 mg orally (days 1–4 and 8–11). Subsequently, stem cells were mobilized after combination chemotherapy with ifosfamide, epirubicin and etoposide (IEV) followed by G-CSF; stem cells could be collected in 97% of the patients. Then the patients proceeded to tandem MEL140 (melphalan 140 mg/m2) and autologous peripheral blood stem cell transplantation with a time interval between high-dose cycles of 2 months. No consolidation or maintenance treatment was scheduled. Analyses were performed in an intent-to-treat approach. 87% of patients completed the first transplant, 74% the second. Overall, the treatment was well tolerated and grade 3/4 infections and stomatitis after high-dose melphalan occurred in 37% and 9% of patients, respectively. The overall mortality (tumor and/or toxicity) during treatment was 7.1%: 4.5% during the induction phase (6.1% in [A1] versus 2.9% in [A2]), 1.5% after mobilization and 1.1% after high-dose therapy. Notably, the best response (EBMT criteria) at the end of treatment in patients randomized to [A1] (16% CR, 64% PR) or [A2] (18% CR, 69% PR) was not different. An early loss of tumor control with disease progression occurred in 6% in [A1] versus 1% in [A2]. With a median follow-up time of 20 months, there was no significant difference in the median event-free survival (EFS) (22 months in [A1] versus 20 months in [A2]) and not in the overall survival (OS) at 4 years (63% in [A1] versus 65% in [A2]). In ≥ 50% of patients, the time between last treatment and progression was 〉 16 months. The EFS of patients 60–64 years of age and 65–70 years of age was the same. In conclusion, there was no benefit of conventional induction chemotherapy with VAD- or VAD-like regimens in patients receiving tandem MEL140 with autologous transplantation. This induction treatment therefore may be avoided. Tandem-MEL140 is feasible and well tolerated in the majority of elderly patients with symptomatic myeloma. Its profound and durable anti-tumor effect was demonstrated by prolonged unmaintained remissions. The addition of new agents given as consolidation or maintenance probably will further improve treatment results.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.446.446
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 2
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    The Efficacy and Safety of RAD (Lenalidomide, Adriamycin and Dexamethasone) In Newly Diagnosed Multiple Myeloma – First Results of a Phase II Trial by the German DSMM Group
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1945-1945
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1945-1945
    Abstract: Abstract 1945 Background Prognosis of patients with multiple myeloma (MM) has significantly improved by the introduction of autologous (auto) stem cell transplantation (SCT). The “novel drugs” which have shown activity in relapsed MM are increasingly used in first-line therapy aiming at maximized response prior to SCT. Whether allogeneic (allo) SCT adds to further disease control remains a matter of debate. Our group has shown the RAD regimen (lenalidomide, adriamycin and dexamethasone) to be highly effective and relatively well tolerated in relapsed and refractory MM. Therefore, we decided to explore RAD in the up-front management. Patients and Methods The current phase-II trial (DSMM XII) was designed to include patients (pts) up to the age of 65 years with newly diagnosed MM requiring treatment. We chose four cycles of RAD (lenalidomide 25 mg d-21; infusional adriamycin 9 mg/m2 per day d1-4; dexamethasone 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks for induction followed by chemomobilization of peripheral blood stem cells. Low molecular weight heparin is mandatory during RAD treatment for thromboprophylaxis. All pts are to undergo one cycle of melphalan 200 mg/m2 followed by auto SCT. A subsequent allo SCT after reduced intensity conditioning (treosulfan/fludarabin) is scheduled for pts featuring at least one previously identified (cytogenetic or serologic) risk factor. Those with very favourable risk are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance (10 mg per day) on a continuous basis. Here, we present results of a planned safety analysis. Results 75 pts with a median age of 57 (range, 35–66) years have been enrolled by 11 German centers between 9/2009 and 7/2010. Currently, 51 pts are evaluable for toxicity during RAD induction: In all, 25 severe adverse events (SAEs) were reported for 16 subjects (31%). 68% of SAEs were assessed to be drug-related. Most frequent events were venous thrombosis (VTE; n=4), pyrexia (n=3) and syncope (n=2). Neutropenia, extravasation, pleural effusion, and allergic dermatitis accounted for one SAE each. 17 patients, 10 of whom (59%) had ISS stage II/III disease, are evaluable for post-induction response. Ten subjects (59%) achieved VGPR or better: 6 pts had VGPR and 2 patients each CR and stringent CR as assessed by the investigator. Conclusions Our preliminary results suggest RAD to be a well tolerated and effective novel induction protocol in up-front treatment of MM. Notably, incidence of severe hematotoxicity observed so far is significantly lower than was in our previous study in relapsed/refractory pts. Incidence of VTE was acceptable while no neurotoxicity occurred. Updated results will be presented. Disclosures: Knop: Celgene Germany: Consultancy, Honoraria. Off Label Use: Lenalidomide in combination with doxorubicin in myeloma first-line therapy. Reichle:Celgene Germany: Research Funding. Einsele:Celgene Germany: Consultancy, Honoraria. Bargou:Celgene Germany: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1945.1945
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1637-1637
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1637-1637
    Abstract: Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality ( 〉 30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality ( 〉 30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1637.1637
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
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    Parallel Evolution of Multiple PSMB5 mutations in a Myeloma Patient Treated with Bortezomib
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 3282-3282
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3282-3282
    Abstract: Introduction: Proteasome inhibition is the backbone of various Multiple Myeloma (MM) treatment regimens, leading to durable responses and high quality remissions. However, under prolonged therapy patients eventually develop drug resistance and the underlying mechanisms have been poorly understood. Proteasome inhibitor resistant cell lines were generated by continuous exposure to proteasome inhibiting drugs. In these cell line models a number of variants within the PSMB5 gene were observed. This includes single point mutations, leading to conformational changes of the _5 subunit within the 20S proteolytic core of the proteasome, impairing its chymotryptic catalytic function and the binding of inhibitory drugs. However, no PSMB5 mutations could, so far, be identified in human disease, leaving the functional relevance of such mutations to be determined. Methods: We applied the MM Mutation Panel (M3P) and used the Personal Genome Machine (Life Technologies) to sequence CD138+ purified bone marrow plasma cells and peripheral blood germ line control from a MM patient in third relapse that had been previously treated by various proteasome inhibitor containing therapies (VTD-PACE, VCD, PAD-Rev). This patient was subsequently treated with a pomalidomide, bortezomib, adriamycin and dexamethasone combination therapy (Pom-PAD) and achieved a partial remission after 4 cycles of therapy. When being exposed to VCD at earlier relapse a complete remission was induced within 6 cycles of therapy, demonstrating excellent response to proteasome inhibition at this earlier disease stage. Results: We identified clonal missense mutations in this patient at known NRAS hotspot location (p.Gln61Arg) and in MAX (p.Arg35His). Most notably we found and validated four subclonal single point mutations in PSMB5, each of them in subclonal frequencies with variant reads (VR) ranging from 1.9%- 5.9% (average read depth 750X). All PSMB5 mutations occurred in a highly conserved region in exon 2 of the gene (p.Cys122Tyr, p.Met104Ile, p.Ala86Pro, p.Ala79Thr), with three of them being located within the proteasome inhibitor drug binding site. Our 400bp amplicon design allowed us to observe that each mutation identified in PSMB5 is exclusively present on a different sequencing read and no reads are shared between the mutations. This implies that the mutations are present on different subclones of the tumor, which means that, despite low VR frequencies of the single mutation, in sum more than a quarter of the whole tumor might be affected by mutated PSMB5. At a disease stage when the patient was well responsive to proteasome inhibitor treatment (at diagnosis and at first relapse), of note, none of the mutations in PSMB5 is detectable. Conclusion: Here we report the first in human PSMB5 mutation in a MM patient. These mutations evolved in parallel within different subclones of the disease under the selective pressure of bortezomib- containing treatment regimens, representing branching evolution. It is to speculate whether previous investigations negating the existence of PSMB5 mutations in proteasome inhibitor treated patients might not have sequenced deep enough or did set up a sensitivity cut-off too rigid to detect such subclonal mutations. Our finding suggests that the mutations identified may contribute to the development of proteasome inhibitor resistance, emphasizing the need for more detailed genomic characterization of tumors, including minor subclonal mutation detection. Functional analysis of the mutations is ongoing and results will be presented at the meeting. Figure Figure. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.3282.3282
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 5
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    BPI A645G SNP but Not NOD2 Genotype Predicts for Acute Lung Injury After Allogeneic Stem Cell Transplantation
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2324-2324
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2324-2324
    Abstract: Abstract 2324 Introduction: Infectious as well as non-infectious pulmonary complications are key determinants of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Single nucleotide polymorphisms (SNP) in two genes coding for nucleotide-binding oligomerization domain containing 2 (NOD2) and bactericidal/permeability-increasing protein (BPI) have been shown to predict for the occurrence of GvHD and chronic pulmonary complications after allo-HSCT. We aimed at determining the effect of SNPs in these genes on the occurrence of acute lung injury (ALI) after allo-HSCT. Patients and Methods: We retrospectively analyzed a cohort of 272 patients undergoing allo-HSCT and their respective related and unrelated donors. ALI was functionally defined as a drop of the oxygenation index (OI = partial pressure of oxygen in arterialized capillary blood/inhaled oxygen concentration) below 300. Genotyping for NOD2 SNP 8, 12 and 13 and BPI SNP A645G was done using Real Time-PCR. The incidence of ALI was assessed by univariate competing events statistics and by a multivariate model according to Fine and Gray. Results: Overall, 115 of 272 (42.3%) patients suffered from ALI at least once during the first 100 days post allo-HSCT. Median time to onset was 11 days. Neither NOD2 polymorphisms in the donor nor in the recipient correlated with the occurrence of ALI. Further, BPI recipient genotype was not associated with an increased incidence of this complication. On the other hand, ALI was more frequent in patients receiving a transplant from a donor homozygous for the G allele of the BPI A645G SNP (Figure 1). This association was confirmed in multivariate analysis (OR 1.46, p = 0.048). Other independent risk factors for the occurrence of ALI were age (as continuous variable, OR 1.03, p = 0.002) and transplantation from an unrelated vs. related donor (OR 1.66, p = 0.018) whereas the use of intensive conditioning was a risk factor of borderline significance (OR 1.59, p = 0.077). In spite of its association with ALI, BPI donor genotype did not correlate with cumulative incidence of NRM at 100 days (G/G: 6.7%, 95% CI: 1.0 – 12.4% vs. A/A or A/G: 10.2%, 95% CI: 6.0 – 14.4%; p = 0.380) or overall survival. Conclusion: In contrast to other investigators we found no correlation between NOD2 genotype and the occurrence of acute pulmonary complications after allo-HSCT. On the other hand, BPI A645G SNP in the donor was identified as an independent risk factor for ALI in these patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2324.2324
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
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    Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 23 ( 2016-12-08), p. 2666-2670
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 23 ( 2016-12-08), p. 2666-2670
    Abstract: We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia ( & lt;2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%] ). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P = .022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2016-03-704528
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 7
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    Treatment of Indolent Non-Hodgkin’s Lymphoma in Germany - Results of a Representative Population-Based Survey.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1353-1353
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1353-1353
    Abstract: In advanced stage indolent lymphoma, therapeutic approaches may vary from watch and wait, antibody monotherapy, conventional chemotherapy or dose-intensified consolidation up to allogeneic strategies. In this nation-wide survey, representative hematological/oncological centers monitored current treatment strategies under routine conditions. 495 centers involved in the treatment of indolent lymphoma including university hospitals (UH), community hospitals (CH), and office-based hematologists (OBH) were contacted. 13% of identified centers provided information on 741 patients corresponding to 10% of the expected national prevalence. Detailed data on 576 unselected patients (median age 67 years, range 17 to 95) with treatment decision in the second and third quarter of 2006 (start, change or end of therapy) of 46 representative centers (2 UH, 25 CH, and 19 OBH) were included in this analysis. Data were verified by monitoring anonymized patients source data. Median age was 67 with hypertension (28%), coronary heart disease (14%), diabetes (11%), heart failure (8%), cardiac arrhythmia (7%) and renal impairment (7%) being the most frequent concomitant diseases at time of diagnosis. Histology included 39% follicular lymphoma, 26% chronic lymphocytic leukemia (CLL), 10% marginal zone, 9% mantle cell lymphoma, and 16% other histologies. Aim of initial therapy was curative in 35%, aiming at improved survival in 62% and palliation in 54% of patients. Radiation (10%), antibody monotherapy (4%), chemotherapy (33%) and combined immuno-chemotherapy (31%) were the most frequent approaches. Applied chemotherapies included CHOP (46%), fludarabine combinations (F/FC/FCM: 15%), chlorambucil (14%), CVP/COP (9%), Bendamustin (4%), with maintenance (12%) and autologous/allogeneic stem cell consolidation both in 3% of patients. In first relapse, complex regimen including immuno-chemotherapy (49%), maintenance therapy (16%), and autologous/allogeneic transplantation (14%/4%) were more frequently planned. As expected, significant differences were observed between follicular, mantle cell lymphoma and CLL. Interestingly, supportive measures including antibiotics (34%), erythrocyte transfusions (32%), G-CSF (22%), immunoglobulins (19%), antifungal drugs (13%), and erythropoietin (10%) were frequently applied already in first line therapy. Overall response was 83% (FL: 97%, MCL: 95%, CLL: 74%) with a 39% CR rate. Only 10% of first line patients were treated within studies (UH: 19%, CH: 5%, OBH: 13%). In this population-based survey, patient characteristics differed significantly from published study cohorts as did clinical strategies and therapeutic approaches. Thus, clinical studies more relevant to the treatment of medically compromised patients are urgently warranted.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1353.1353
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 8
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    Novel Genomic Structural Variations in Relapsed Childhood ETV6/RUNX1 (TEL/AML1) Acute Lymphoblastic Leukemias Identified by Next Generation Sequencing
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 518-518
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 518-518
    Abstract: Abstract 518 Introduction The chimeric fusion gene ETV6/RUNX1 generated by the interchromosomal translocation t(12;21) presents the most frequent chromosomal aberration in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of all patients. This ALL subtype is associated with an overall favorable prognosis, nevertheless 10–20% of children will suffer from relapse. ETV6/RUNX1-positive preleukemic clones arise already in utero, but require additional cooperating oncogenic lesions for the development of overt leukemia. The nature of the assisting genetic alterations and the mechanisms driving the development of leukemia and recurrent disease are still not well understood. Methods We applied state-of-the-art whole genome and whole exome next-generation-sequencing to comprehensively analyze the assisting oncogenic alterations in pediatric patients with initial and/or recurrent ETV6/RUNX1+ ALL (primary disease n=11, recurrent disease n=7). Matched sample sets taken at initial diagnosis, remission and relapse were compared. Mate pair and/or paired end sequencing was carried out for whole genome analysis with inserts spanning 2 kb or 500 kb, respectively. Constructed libraries were sequenced from both ends with 36- or 50-bp reads on a Genome Analyzer IIx or a HiSeq 2000 (Illumina/Solexa), respectively. Reads were aligned against the human reference genome (GRCh37) using BWA. Duplicate reads were removed. Unique reads with high mapping quality (q 〉 35) served as input for GASV which detected translocations and inversions based on the mapping coordinates, insert sizes and read orientation. Variations covered by at least three reads in the tumor sample and not detected in the remission sample or the Database of Genomic Variants were reported. For detection of copy number variations, the program FREEC carried out coverage normalization, computation of copy number ratios between paired leukemia and remission samples (with up to 10 kb resolution) and subsequent segmentation. A subset of six selected patients was further investigated by targeted enrichment of whole exomic regions employing SeqCap EZ libraries (Roche) and 100 bp single read next-generation-sequencing on a HighSeq 2000. Mutations were called using GATK and further processed by an in-house bioinformatic pipeline. Putative somatically acquired mutations were validated by PCR, Sanger sequencing and FISH analysis. Results Genomes were sequenced to at least 13× physical coverage (mate pair) and 6.7× sequence coverage (paired-end). Exome sequencing achieved a minimum of 25× sequence coverage. In silico we detected 155 tumor-specific intragenic translocations. On average each tumor harbored 9 acquired translocations. With the exception of one case (13 translocations at diagnosis, 9 at relapse), the number of translocations was higher in relapse than in the matched diagnosis sample (additional 3 translocations on average). Ongoing validation studies confirmed the defining ETV6/RUNX1 translocation t(12;21) and identified 13 novel translocations. The genes affected are involved in essential signaling pathways, such as cytokine signaling (LIFR), calcium signaling (RCAN2), insulin and anti-apoptotic signaling (PHIP). Interestingly, also a factor essential for pre-mRNA splicing (IBP160) and genes encoding regulatory RNAs (miRNAs, lincRNAs and RNAs involved in splicing) were rearranged. A validated intragenic deletion of 836 bp leading to a frameshift and premature stop affected a calcium ion sensor of the ferlin protein family. Recurrent deletions in 9 of 11 cases (82%) ranging from 5 to 200 kb were detected in the immunoglobulin lambda variable gene cluster (IGLV) on chromosome 22q11. Some of the deletions were extending into the pre-B lymphocyte 1 gene (VPREB1) locus. In silico the probabilty of illegitimate RAG-mediated recombination at the breakpoint sites was determined by evaluation of RIC scores. RIC scores indicated that aberrant V(D)J rearrangements involving cryptic recombination sequence signals had caused the deletions on chromosome 22q11. Conclusion We present somatic mutations that are promising novel candicate genes (e.g. LIFR, RCAN2, PHIP, IBP160) for cooperating secondary mutations in ETV6/RUNX1+ ALL and discuss their impact on the molecular pathology of primary and recurrent disease. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.518.518
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 9
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    New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling
    American Society of Hematology ; 2009
    In:  Blood Vol. 113, No. 11 ( 2009-03-12), p. 2488-2497
    Details
    In: Blood, American Society of Hematology, Vol. 113, No. 11 ( 2009-03-12), p. 2488-2497
    Abstract: Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype–specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell–like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2008-04-152900
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Ex Vivo Generated Cytotoxic T Cells (CTL) for Adoptive Immunotherapy across MHC Barriers Retain Anti-Leukemic Capacity (GVL) without Eliciting Graft Versus Host Disease (GVHD): Crucial Role of Recipient-Derived Antigen Presenting Cells (APC).
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3168-3168
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3168-3168
    Abstract: BACKGROUND: While recipient-derived APC have proven to be crucial in mediating GVL after allogeneic hematopoietic stem cell transplantation (HCT), this desired effect seemed to be inevitably linked to the risk of developing severe GVHD. It has been elegantly shown in murine models that delayed donor lymphocyte infusions (DLI) into mixed rather than full hematopoietic chimeras produce dramatically improved GVL effects and virtually no GVHD. However, avoidance of GVHD has been more difficult when this intelligent concept was transferred into the clinical setting. Here we demonstrate that donor-derived T cells of MHC-mismatched origin retain strong anti-leukemic activity and lose nonspecific alloreactivity upon specific in vitro priming and consecutive short term expansion. METHODS: We chose a fully MHC-mismatched allogeneic bone marrow transplantation model using B10.A mice (H-2a) as donors and C57BL/6 (H-2b) mice as recipients to produce either full (controls) or stable mixed hematopoietic chimeras. After full hematopoietic recovery mice were challenged with a lethal dose of a C57BL/6-derived leukemic cell line (C1498) and consecutively injected with either naive DLI, ex vivo generated CTL or PBS only. CTL were generated by specifically priming lymphocytes of MHC-mismatched donor origin on bone marrow-derived dendritic cells (DC) (either donor- or recipient-derived) that had been pulsed with recipient-derived leukemia cell lysates. This was followed by expansion using αCD3/αCD28 coated microspheres. RESULTS: We show that ex vivo generated CTL of allogeneic origin can mediate anti-leukemic effects only when primed on recipient-derived DC that had been pulsed with leukemia cell lysates (CTL versus controls, p 〈 0.05 ). In contrast, loading recipient-derived leukemia lysates on donor-derived DC (T cells and DC syngeneic to each other) abrogates the anti-leukemia effect of adoptively transferred CTL in vitro and in vivo. CTL exhibit a strong proliferative response in vitro when stimulated with irradiated leukemic cells of allogeneic origin (C1498), however, this response is significantly weaker (3-fold) when compared to naive DLI. Remarkably, the nonspecific proliferative response (alloreactivity) of CTL is completely abolished when irradiated C57BL/6 splenocytes are used as stimulators. CTL maintain their responsiveness to leukemia in vivo as demonstrated by cure rates from leukemia in up to 40% of mice. Importantly, upon adoptive transfer into leukemia bearing mice after MHC-mismatched HCT, CTL lose their unspecific alloreactivity in vivo as well as proven on microscopic sections of GVH target organs. Anti-leukemia effects of CTL across MHC-barriers are comparable to naive DLI in leukemia bearing mice (40% versus 50% cure rate). CTL are able to convert mixed hematopoietic chimerism into full hematopoietic chimerism (30% donor →100% donor). In contrast, mixed chimerism remains unchanged when CTL are transferred that had been primed ex vivo on donor-derived DC. This data is encouraging in that it provides further evidence that strong GVL effects can be obtained across MHC barriers without eliciting severe GVHD.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3168.3168
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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