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  • 1
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    Phase 1/2a study of the IRAK4 inhibitor CA-4948 as monotherapy or in combination with azacitidine or venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia or lyelodysplastic syndrome.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 7016-7016
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7016-7016
    Abstract: 7016 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). Methods: This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with CA-4948 monotherapy. Phase 1b includes 2 arms of combination therapy: CA-4948 + azacitidine (AZA) and CA-4948 + venetoclax (VEN). The primary objectives of this study are to assess the safety, clinical activity, and identify the Recommended Phase 2 Dose (RP2D) of CA-4948 as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for CA-4948 monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations. Results: As of December 16 th , 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30 th , allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of CA-4948 were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30 th , 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration 〉 6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to CA-4948. Conclusions: CA-4948 is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting CA-4948 may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing. Clinical trial information: 04278768.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.7016
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 2
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    Phase 1b study of venetoclax in combination with azacitidine in patients with treatment-naïve higher-risk myelodysplastic syndromes.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. TPS7082-TPS7082
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. TPS7082-TPS7082
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.TPS7082
    RVK:
    XA 52760
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Chromosomal Aberrations Identified in CD34+ Peripheral Blood Cells of MDS Patients by FISH- and SNP Array Analysis
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4872-4872
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4872-4872
    Abstract: Abstract 4872 Introduction: Chromosomal banding analysis (CBA) of bone marrow metaphases is the gold standard to identify chromosomal abnormalities in myelodysplastic syndromes (MDS). To detect and follow chromosomal abnormalities during the course of the disease without the need of repeated bone marrow biopsies, we are currently performing serial fluorescence in situ hybridization (FISH) analyses of CD34+ peripheral blood cells (PBC) in ongoing studies. To complement genetic analysis on peripheral blood we started a pilot study to establish SNP array analysis (SNP-A) on CD34+ PBC to identify chromosomal abnormalities not detectable by FISH. Methods: We analyzed eleven MDS and two AML-patients with known karyotypes and compared CBA with FISH and SNP-A of CD34+ peripheral blood and/or bone marrow cells. The FISH panel comprised up to 13 probes. The Affymetrix Genome-Wide Human SNP Array 6.0 and/or the Affymetrix Cytogenetics Whole-Genome 2.7M Array were used. We also included serial samples from a RAEB-II patient where bone marrow and/or peripheral blood were available from six time points collected over a period of 6 months. Results: In 13 patients analyzed using CBA, FISH, and SNP-A in parallel, 10/60 (17%) chromosomal abnormalities were exclusively detected by SNP-A. Using CBA and FISH we detected 28 chromosomal abnormalities in 12 patients. Additional SNP-A revealed 6 further aberrations (upd(7)(q11qter), upd(10)(q23.33q25.1), upd(17)(pterp11.2), del(9)(q22.33q31.1), del(13)(q12.3q22.2), del(15)(q15.1)). In one patient SNP-A increased the number of detectable chromosomal abnormalities from 22 to 26 (amplifications on 6p, del(15)(q11.2q21.1), del(18)(pterp11), upd(20)(q11.22q12)). Additional abnormalities were also detected in the serial sample: The major clone detectable by CBA at three different time points was 44,XX,del(5)(q13q33),-7,del(12)(p13p11.2),-17,-20,+der(20)t(17;20)(q10;p10). We could confirm all these abnormalities in CD34+ peripheral blood and bone marrow cells using a FISH panel that includes del(5q31)/EGR1, −7/CEP7, del(12p13)/TEL, del(17p13)/TP53, and del(20q12)/D20S108. FISH on CD34+ PBC confirmed a stable number of aberrant cells as 5q- was detectable in 94–98% of CD34+ PBC at all six available time points. We could also confirm all abnormalities of the major clone by SNP-A in CD34+ PBC in month 2 and in CD34+ bone marrow cells in month 6. Additional abnormalities occurring in sub-clones changed over time. A sub-clone exclusively detectable by CBA was identified in the first available sample in 2/25 (8%) metaphases: 44,idem,+der(3)t(3;6)(p10;q10),-6. Supplementary FISH and SNP-A revealed a 9.6 Mb del(13q14) in 44% of CD34+ PBC that was not detectable by CBA and had subsequently disappeared in the last available sample. SNP-A on CD34+ bone marrow cells of the last sample revealed two additional abnormalities in the absence of clinical signs of progression (del(2)(q31q32), del(4)(q24q26)). The del(4q)/TET2 could be confirmed by FISH. Conclusion: Detection and follow-up of chromosomal abnormalities during the course of the disease is possible without the need of bone marrow biopsies by parallel FISH and SNP-A of CD34+ peripheral blood cells. Detailed knowledge about the acquirement of chromosomal aberrations could be used to improve prognostication, to support therapy decisions and to unravel genetic evolutionary steps towards acute leukemia. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4872.4872
    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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    Safety and Efficacy of a Combination of 5-Azacitidine Followed by Lenalidomide in High-Risk MDS or AML Patients with Del(5q) Cytogenetic Abnormalities – Results of the “AZALE” Trial,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3799-3799
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3799-3799
    Abstract: Abstract 3799 Lenalidomide (LEN) has shown single agent activity in patients (pts) with low-risk MDS and a del(5q) cytogenetic abnormality although mutations of p53 have been recently associated with treatment failure. Further, the DNA methyltransferase inhibitor 5-azacytidine (AZA) is able to achieve responses in up to 50% of high-risk MDS (IPSS INT-2 or HIGH) and AML pts with a low rate of extramedullary toxicity compared to conventional induction chemotherapy (IC). Nevertheless, del(5q) abnormalities especially when part of a complex aberrant karyotype are associated with lower response rates compared to other cytogenetic aberrations. Therefore, studies combining both compounds are of interest in this population. We report results of a phase I clinical trial within the German MDS study group (GMDS-SG) evaluating the maximum tolerated dose (MTD) of LEN in combination with AZA in pts with either high-risk MDS, refractory/relapsed AML or de novo AML not eligible for conventional IC with del(5q) cytogenetic abnormalities. Given the mechanism of action of both drugs a sequential approach was chosen. To determine the MTD, a standard “3+3” design was used. In fact, induction therapy consisted of AZA (75mg/m2 days 1–5) followed by increasing doses (10, 15, 20 and 25mg) of LEN (starting with 10mg p.o., days 6–19). In pts achieving a complete remission (CR) this was followed by a combined maintenance therapy every 8 weeks until disease progression. Of 20 pts enrolled, median age was 69 years (range, 45 to 79 years), interval from MDS or AML diagnosis was 8 months (range, 1 to 100 months). IPSS categories were INT-2 (n = 5) or HIGH (n = 9) whereas 6 pts were included with advanced AML. Prior therapies included IC only (n=1), allogeneic HSCT (n=3), AZA (n=6), LEN (n=2) and/or low-dose cytarabine (n=2) while 10 pts had received supportive care only prior to study entry. It is of note, that the majority of pts (n=15, 75%) had a complex aberrant karyotype including a del(5q) abnormality. Further, p53 mutations could be detected in 7 (47%) out of 15 pts analyzed so far. A median of 2 induction cycles were administered within the 4 dose cohorts. The MTD of LEN was determined to be 20mg. DLTs were either infectious complications (n=2), thrombosis (n=1) or incomplete hematologic recovery (n=1). In fact, therapy-induced grade 3–4 neutropenia or thrombocytopenia occurred in 12 (60%) pts, respectively. Out of the 19 pts evaluable for response 6 pts (32%) achieved a hematologic (CR: n=2, CRi: n=2, PR: n=1, HI: n=1) and 7 pts (36%) a cytogenetic (CR: n=3, PR: n=4) response while 13 pts (68%) had stable disease. Interestingly, 5 out of 7 pts with p53 mutations responded to combination therapy. The combination of AZA and LEN is feasible and seems to be effective even in a very high risk patient group with advanced MDS or AML and a del(5q). Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hofmann:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Haase: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.V118.21.3799.3799
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
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    Imatinib and Leptomycin B Are Effective in Overcoming Imatinib-Resistance Due to Bcr-Abl Amplification or Clonal Evolution but Not Due to Bcr-Abl Kinase Domain Mutation.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2003-2003
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2003-2003
    Abstract: Constitutive activity of the Bcr-Abl kinase has been shown to be the causative event in the molecular pathogenesis of CML and Ph+ ALL. Even though Imatinib, a small molecule inhibitor of the Abl kinase, is very effective in treating the disease, development of resistance to this drug is a common phenomenon in advanced stage disease. Using Leptomycin B (LMB), a nuclear export blocker, Vigneri et al. have shown that Bcr-Abl kinase activity trapped in the nucleus induces cell death, thus being a new potential treatment option for Bcr-Abl expressing diseases. To test whether this approach might be effective in the case of imatinib resistant leukaemia several Bcr-Abl positive, imatinib-resistant Ba/F3 clones were established and characterized: 1. Ba/F3 cells resistant due to a point mutation in the Abl kinase domain at position T315I. 2. Ba/F3 cells resistant due to amplification of the Bcr-Abl kinase. 3. Ba/F3 cell clones resistant to imatinib with clear features of clonal evolution. All four cell lines were tested for the efficacy of a combined treatment approach with imatinib and leptomycin B. This combination was very effective in inducing apoptosis in imatinib resistant Ba/F3 cells displaying Bcr-Abl amplification. One out of two cell lines with signs of clonal evolution also responded to this combination treatment. However, imatinib resistant cells expressing the Bcr-AblT315I mutant kinase were completely resistant to this approach. Thus, these results are in agreement with the proposed hypothesis of Vigneri and wang that the combined effect of leptomycin B and imatinib requires Bcr-Abl kinase inhibition (which is not achieved in cells expressing Bcr-Abl T315I) by imatinib and nuclear entrapment by LMB To check the feasibility of this combined treatment for purging purposes, in vitro colony forming assays were performed with mixed cultures of Bcr-Abl positive BaF3 cells and primary murine bone marrow. All colonies formed after combined treatment with imatinib and LMB were derived from BM cells, indicating selective toxicity towards Bcr-Abl positive cells while sparing primary murine bone marrow cells. We are currently evaluating the effectivity of the combined LMB/imatinib treatment as purging strategy in a murine bone marrow transplantation model.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2003.2003
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 6
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    Sorafenib Monotherapy Is Effective In Relapsed and RefractoryFlt3-ITD Positive Acute Myeloid Leukemia, Particularly After Allogenic Stem Cell Transplantation
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3314-3314
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3314-3314
    Abstract: Abstract 3314 Introduction: The FLT3-internal tandem duplication is the most frequent genetic aberration in normal karyotype acute myeloid leukemia (NK-AML) and associated with a poor prognosis. Patients with FLT3-ITD positive AML relapsing after allogenic stem cell transplantation (allo-SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor, which is approved in Europe for the treatment of metastatic renal cell and hepatocellular carcinoma. It inhibits the FLT3 receptor tyrosine kinase, and, at low nanomolar concentrations also the mutated variant of FLT3, FLT3-ITD. Sorafenib also inhibits Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR). We have previously reported that sorafenib monotherapy is effective in relapsed FLT3-ITD positive AML (Metzelder et al., Blood 2009; Metzelder et al., ASH 2009, poster #2060). Here we significantly extend these compassionate use experiences by reporting on clinical response details from 39 relapsed or refractory FLT3-ITD positive AML patients treated with sorafenib monotherapy. Methods: A questionnaire was developed and sent to 60 centers in Germany, Singapore and the United States, where FLT3-ITD-positive patients had been treated with sorafenib monotherapy. 26 centers returned information on therapy details of 55 patients. These included data on age, FAB-classification, karyotype, FLT3-ITD molecular testing, type and duration of response to prior therapy and to sorafenib, sorafenib dosing and tolerability. 16 patients were excluded from further analysis because of FLT3-ITD negativity or application of chemotherapy concomitant to sorafenib. Results: There were 39 evaluable patients (20 male, 19 female), grouped into i) primary refractory patients (PR-P) (n=11), receiving one (n=5) or two cycles (n=6) of chemotherapy before commencing sorafenib, ii) relapsing patients (REL-P) (n=12) with hematological recurrence after between one and four cycles of prior chemotherapy, syngenic, or autologous SCT, and iii) patients relapsing after allogenic SCT (SCT-P) (n=16). One patient was treated first line with sorafenib. One patient was treated before and after allo-SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 71 days (range, 13 to 270) for PR-P, 76 days (range, 9 to 160 days) for REL-P, and 76 days (range, 20 to 489 days) for SCT-P. All reported patients in this cohort responded to sorafenib. In the PR-P group, there were 6 hematological remissions (HR), characterized by complete (n=4) or near complete peripheral blast clearance (n=2), 4 complete remissions (bone marrow blasts 〈 5% with (CR) or without (CRp) normalization of peripheral blood counts) and one complete molecular remission (CMR, molecular negativity for FLT3-ITD). Six of these 11 PR-P underwent allo-SCT after responding to sorafenib induction. In the REL-P group there was one patient with a partial blast clearance (PR), 8 HR, 2 bone marrow responses (which includes a HR) and 1 CRp. In the SCT-P group there were 3PR, 2HR, 7 BMR and 4 CMR. Notably, the median time to treatment failure due to frank clinical sorafenib resistance was 119 days for PR-P and REL-P, but was not reached in the SCT-P group. This difference was statistically significant (p-value 0.0217). Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant but manageable side effects. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion: This analysis on a large cohort of 39 FLT3-ITD positive patients confirms our previous reports on the remarkable clinical activity of sorafenib monotherapy in FLT3-ITD positive AML. Evidence is accumulating that sorafenib may be particularly effective in the context of allo-SCT, where long-term responses were seen. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3314.3314
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 7
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    Prognostic Impact of Mutant to Wild-Type Ratio and Insertion Site in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 785-785
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 785-785
    Abstract: Abstract 785 Background: FLT3 internal tandem duplications (FLT3-ITD) occur in about 25% of acute myeloid leukemia (AML), are associated with cooperating gene mutations (NPM1, DNMT3A), and confer an adverse prognosis. Several studies have indicated that the unfavorable impact of FLT3-ITD is influenced by a number of factors, such as the mutant to wild-type ratio (allelic ratio), insertion site of FLT3-ITD in the beta1 sheet of the tyrosine kinase domain 1, and the molecular background of cooperating mutations. Aims: To evaluate the relative impact of FLT3-ITD allelic ratio and insertion site, as well as cooperating genetic lesions on prognosis and treatment decision making in a large cohort of homogeneously treated younger adult patients. Methods: The basis of the study were 2377 younger adults (median age, 48 years; range, 16–62 years) with newly diagnosed AML enrolled on three prospective treatment trials of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. Patients with acute promyelocytic leukemia (n=99), core-binding factor AML (n=279) and AML with adverse-risk cytogenetics (n=436) according to the European LeukemiaNet recommendations were excluded. Based on material availability, the presence of FLT3-ITD could be analyzed in 1414 patients; NPM1 and DNMT3A mutational status was available in 97% and 84% of the patients, respectively. In FLT3-ITD positive AML (n=394), the allelic ratio, determined by Genescan-based fragment-length analysis, was available in 86% and the insertion site in 72%. Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission was performed in 41% and 29% of FLT3-ITD positive and negative patients, respectively. Results: We first evaluated the prognostic impact of the different FLT3-ITD characteristics within the subgroup of FLT3-ITD positive patients. The allelic ratio was categorized into quartiles ranging from low to high. For the endpoints event-free (EFS), relapse-free (RFS) and overall survival (OS), only the fourth quartile with the highest allelic ratio showed a prognostic impact for all endpoints, whereas no difference was identified between the other three quartiles. For further analyses, the allelic ratio was dichotomized comparing the fourth quartile versus the other three quartiles. FLT3-ITD insertion site in the beta1 sheet was significantly associated with an unfavorable outcome for all endpoints. Additionally, FLT3-ITD size was directly correlated with the insertion site: the more C-terminal the ITD inserted in the FLT3 gene the longer the FLT3-ITD size. There was no prognostic impact of FLT3-ITD size neither as continuous nor as quartile-categorized variable. Multiple FLT3-ITDs, present in 13% of AMLs, were associated with an unfavorable prognosis. The presence of either NPM1 and/or DNMT3A mutations in FLT3-ITD positive patients did not alter the original FLT3 prognosis. In multivariable models for the endpoint OS of the total cohort of intermediate-risk AML, an independent prognostic impact beyond the variable FLT3-ITD was shown for the allelic ratio (fourth quartile) [HR, 1.4; p=0.037] and in trend for insertion site in the beta1 sheet [HR, 1.33; p=0.06] . Survival of patients exhibiting a high allelic ratio (n=43) or insertion site in the beta1 sheet (n=60) was comparable, with a median of 10 and 13 months and 4-year survival of 19% and 24%, respectively. Of note, outcome of patients with both high allelic ratio and insertion site in the beta1 sheet (n=21) was very poor with a median OS of 10 months and 4-year OS of 5%, respectively. In patients with FLT3-ITD positive AML without these unfavorable factors (n=144), median and 4-year OS were 15 months and 42%, respectively. Of note, a clear benefit of allogeneic HSCT in first CR was only seen in FLT3-ITD positive patients without these two unfavorable factors, with a 4-year OS of 63%. In comparison, the 4-year OS of the same subgroup of patients achieving a CR after induction therapy without proceeding to allogeneic HSCT during first CR was 35%. In contrast, outcome in patients with high allelic ratio and/or insertion site in the beta1 sheet remained poor despite allogeneic HSCT in first CR. Conclusion: High FLT3-ITD allelic ratio and ITD insertion site in the beta1 sheet presented as prognostic indicators for poor outcome in patients with the presence of a FLT3-ITD. Only patients without these unfavorable FLT3-ITD features significantly benefitted from allogeneic HSCT. Disclosures: Schlenk: Roche: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.785.785
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 8
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    CD34+ FISH As a New Method for Molecular-Cytogenetic Diagnostic From Peripheral Blood in MDS: Update of the Multicenter German Prospective Diagnostic Study
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3816-3816
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3816-3816
    Abstract: Abstract 3816 Background Conventional chromosome banding (CCB) analyses of bone marrow (bm) metaphases represent the gold standard of cytogenetic diagnostics in myelodysplastic syndromes (MDS), but they are not suitable for frequent follow-up analyses. Most aberrations can also be detected by fluorescence in situ hybridisation (FISH), and they are provable in CD34+ cells from peripheral blood (pb). In our prospective multicenter German diagnostic study “Screening and genetic monitoring of patients with MDS under different treatment modalities by cytogenetic analyses of circulating CD34+cells” (ClinicalTrails.gov NCT01355913) we followed MDS pts by sequential FISH analyses. Methods CD34+ pb cells were enriched by immunomagnetic cell sorting (MACS®) and analysed by FISH using a “Superpanel” (D7/CEP7, EGR1, CEP8, CEP XY, D20, TP53, IGH/BCL2, TEL/AML1, RB1, MLL, 1p36/1q25, CSF1R, all Abbott® Products) at initial screening, every 12 months during follow-up and in case of suspected disease progression and a “Standardpanel” (EGR1, D7/CEP7, CEP8, TP53, D20, TEL/AML1, CEP XY, plus -if necessary- another informative probe) every 2 months in the 1st and every 3 months in the 2nd and 3rd year. If bm aspirate was available, additional CCB and FISH analysis of CD34+ and native bm cells were performed. Cut-off values for each FISH probe were evaluated in our lab. Cytogenetics, bm morphology, clinical course and therapies were documented in a database. All pts gave their written informed consent. The study was approved by all local ethic committees. Results After 3 years of study time, 361 patients (25 AZALE (University of Dresden), 110 LEMON5 (University of Duesseldorf), 226 CD34+FISH) have been included in the study, resulting in a total number of 19,516 FISH analyses: Median age, gender distribution and MDS subtypes were typical for the disease, median follow-up at the time of analysis was 8.2 (1–36) months. Chromosomal aberrations could be detected by FISH of CD34+ pb cells in 71.5% of pts (55% of CD34+FISH-cohort, 99% of LEMON5-trial pts, 100% of AZALE-trial pts). FISH and CCB were highly correlated: p 〈 0.01 for CD34+ pb FISH vs CCB and p 〈 0.01 for CD34+ bm vs CCB. The clone sizes were significantly larger in CD34+ cells compared to native pb (p 〈 0.01). Discussion Our interim results demonstrate that FISH analysis of circulating CD34+ pb cells provides relevant cytogenetic informations. It is a reliable novel method for screening and cytogenetic monitoring of MDS pts during the course of disease and under different therapies, and helps in cases where a bm biopsy is not possible or not successful. Disclosures: Braulke: Celgene: This study was supported by Celgene. Other. Götze:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bug:Celgene: Honoraria, travel support, advisory board Other; Novartis: Honoraria, travel support, advisory board, travel support, advisory board Other; Boehringer Ingelheim: Honoraria, travel support, advisory board, travel support, advisory board Other. Schafhausen:Novartis: Honoraria, travel support Other; BMS: Honoraria, travel support, travel support Other; Roche: Honoraria, travel support, travel support Other; Celgene: Honoraria, travel support, travel support Other; Alexion: Honoraria, travel support Other. Haase: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.V120.21.3816.3816
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 9
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    A Phase I Study of a Combination of 5-Azacyitidine Followed by Lenalidomide In High-Risk MDS or AML Patients with Chromosome 5 Abnormalities – Interim Results of the “AZALE” Trial
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4000-4000
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4000-4000
    Abstract: Abstract 4000 Lenalidomide has shown single agent activity in patients with MDS (Myelodysplastic Syndromes) and a del(5q) cytogenetic abnormality. Further, studies with the DNA methyltransferase inhibitor 5-azacytidine (5-aza) have been conducted in high-risk MDS (IPSS INT-2 or HIGH) and patients with acute myeloid leukemia (AML) resulting in considerable responses with a low rate of extramedullary toxicity compared to conventional induction chemotherapy (IC). Given the poor outcome of high-risk MDS and AML patients with chromosome 5 abnormalities, there is a significant clinical need to perform studies with new regimens in this patient population. We report first results of an ongoing phase I clinical trial evaluating the maximum tolerated dose (MTD) of lenalidomide in combination with 5-aza in patients with either high-risk MDS, refractory/relapsed AML or de novo AML not eligible for conventional IC with chromosome 5 abnormalities including monosomy 5 or del(5q). Given the mechanism of action of both drugs and also in contrast to a recent study in non-del(5q) MDS patients, a sequential approach was chosen. In fact, induction therapy consisted of 5-aza (75mg/m2 days 1–5) followed by increasing doses of lenalidomide (starting with 10mg p.o., days 6–19). In patients achieving a complete remission this was followed by a combined maintenance therapy every 8 weeks until disease progression. To determine the MTD, a standard “3+3” design was used. The dose limiting toxicity (DLT) is determined during the first cycle only and is defined as either inability to deliver the full dosing schedule of lenalidomide due to any ≥ Grade 3 non-hematologic toxicity or absence of hematological recovery after completing the 1st cycle despite complete marrow blast clearance or treatment delay of ≥ 4 weeks as a result of unresolved grade 4 non-hematological toxicity. Of 8 patients currently enrolled, median age was 67 years (range, 45 to 74 years), interval from primary MDS or AML diagnosis was 9 months (range, 1 to 100 months). IPSS categories were INT-2 (n = 1) and HIGH (n = 3) whereas 4 patients were included with advanced AML. It is of note, that all but two patients had a complex karyotype including a del(5q) abnormality. Prior treatment included IC (n=1), IC plus allogeneic HSCT (n=3) and/or single agent 5-aza (n=3) while 4 patients had received supportive care only prior to study entry. A median of 2 induction cycles were administered. During the first cycle of cohort I (10mg lenalidomide) and cohort II (15mg lenalidomide) grades 3 to 4 non-hematologic toxicities included febrile neutropenia (n = 3), enterocolitis (n = 1) and pneumonia (n=3) whereas therapy-induced grade 3–4 neutropenia or thrombocytopenia occurred in four and five patients, respectively. The MTD has not been reached yet. One patient (12.5%) with AML showed rapid progression while receiving the 1st cycle. Out of the remaining seven patients, one (12.5%) achieved a marrow CR together with a partial cytogenetic remission, and six patients (75%) had stable disease. Interestingly, two out of these achieved a partial cytogenetic remission. These preliminary data of an ongoing phase I trial demonstrate the safety and the potential of a combination of 5-aza and lenalidomide in patients with advanced MDS or AML and a del(5q). Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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.V116.21.4000.4000
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 10
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    Risk-Adapted Therapy in Younger Adults with Acute Myeloid Leukemia: Results of the AMLHD98A Trial of the AMLSG.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 14-14
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 14-14
    Abstract: Objective: To evaluate outcome of younger adult patients with acute myeloid leukemia (AML) allocated to different treatment strategies according to the risk factors “karyotype” and “response to first induction cycle”. Methods: Between 1998 and 2004, 871 patients (age 16–60 yrs) were enrolled. 77% of pts had de novo AML, 16% s-AML, and 7% t-AML. Risk stratification was based on cytogenetics and response to first induction therapy: i) low-risk: t(8;21); ii) intermediate-risk: normal karyotype, inv(16), t(11q23) or other rare aberrations; iii) high-risk: abn(3q), −5/5q-, −7/7q-, abn(12p), abn(17p) or complex karyotype and/or all pts having refractory disease (RD) after the 1st or not achieving complete remission (CR) after the 2nd induction. All pts received first induction with ICE (idarubicin, cytarabine, etoposide) followed by a second cycle ICE in case of CR/PR; pts with RD after first induction were assigned to high-dose cytarabine based salvage therapy. Pts achieving CR after response-adapted induction received first consolidation therapy with HAM. Second consolidation therapy was stratified according to the risk definition: i) low-risk pts were assigned to a second course of HAM; ii) intermediate-risk pts with an MRD were assigned to a HLA-matched related donor (MRD) stem cell transplantation (SCT), whereas the remaining pts were either randomized between autologous SCT and a second course of HAM in case of normal karyotype or assigned to autologous SCT if cytogenetic aberrations were present; iii) all high-risk pts were assigned to allogeneic SCT from a MRD or unrelated donor (MUD). Results: Response after response-adapted double induction therapy was as follows: CR 70%, RD 18%, death 12%. In 69 pts risk assessment could not be performed due to unsuccessful cytogenetics; 701 (91%) were assigned to a specific risk: i) high-risk n=255 (36%); ii) intermediate-risk: 408 (58%) pts, comprising 254 pts with normal karyotype and 154 with aberrations; iii) low-risk: 38 pts. (5%) with t(8;21). The median follow-up time was 47 months. Overall survival (OS) for the whole study population at 4 years was 40% (95%-CI 37-42%). All 38 low-risk pts received intensive chemotherapy translating in an OS of 75% (95%-CI 61%-92%). Intention to treat-analysis for intermediate-risk patients exhibiting a normal karyotype revealed a relapse free survival (RFS) of 63%, 38% and 46% for patients assigned to MRD-SCT, autologous SCT and HAM, respectively (p=0.01). However, this difference in RFS did not translate into a difference (p=0.36) in OS due to effective salvage treatment, i.e. mainly MUD-SCT. Within the intermediate-risk group defined by cytogenetic abnormalities no difference in RFS (p=0.16) and OS (p=0.61) was evident between the intended MRD-SCT and autologous SCT. High-risk: 93 pts received MUD-SCT, 57 MRD-SCT, and 93 no allogeneic SCT, resulting in a feasibility of 58% and an OS of 28%, 29% and 5%, respectively (p & lt;0.0001). Conclusions: In this prospective study, allogeneic SCT from MRD or MUD improved outcome of patients with high-risk features. In addition, pts with normal karyotype had a significant better RFS after allogeneic SCT.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.14.14
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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