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  • 1
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2030-2030
    Abstract: Abstract 2030 HSCT after reduced or minimal intensity conditioning is increasingly used to treat AML patients not eligible for conventional HSCT. Short term outcome has been reported frequently and risk factors have been identified; long term results still await in depth evaluation. We report here 5 years follow up results from a prospective phase II study conducted by two AML study groups in Europe. Patients were recruited from AML protocols HOVON/SAKK AML 43 and the OSHO AML 1997 study. The regimen consisted of fludarabine (FLU), 30 mg/m2/d on days −4, −3, and −2, 2 Gy TBI on day 0 (the day of HSCT) with mycophenolate mofetil, [15 mg/kg p.o. b.i.d. from 5 hours after HSCT to day +40], and cyclosporine, [CSP; 6.25 mg/kg p.o. bid from day –3 to day +180] after HSCT. Cyclosporine was adjusted to trough levels and reduced according to a predetermined tapering schedule and donor type. A total of 96 patients were recruited between 5/2002 and 8/2005 in the study. Age was median 62 (range 40 – 74) years, 54 patients were male (56%) and 73 patients (76%) had de novo AML. The remission status on entry was CR1 in 83 (86%) patients and CR2 in 13 (14%). Of the 96 patients, 20% had high risk cytogenetics and SCT was performed a median of 75 days after chemotherapy. There were no statistical differences in the above described characteristics except for more secondary AML (p=0.04) and more CR2 patients (p=0.07) among the 59 unrelated SCT (61%) as compared to the 37 related SCT (39%). Graft rejection at two years was observed in 6% of the patients. Absence of chronic GvHD was diagnosed in 40% and limited chronic GvHD in 29% of the patients, with no difference between related and unrelated SCT. Probability of overall survival (OS) at 6 years with a median follow up of 64 (49–92) months reaches a plateau after 5 years at 0.33±0.05 and was not significantly better in CR1 than in CR2. However, there was a trend towards better OS at 6 years for unrelated 0.41±0.11 as compared to related 0.29±0.07 SCT (p=0.08) in CR1 only. This difference was significant for disease free survival (DFS) (0.48±0.09 unrelated vs 0.27±0.06 related; p=0.04), the major reason being a higher relapse rate in related as compared to unrelated SCT (0.62±0.08 vs 0.40±0.09). The overall non-relapse mortality at 6 years was 0.21±0.05. We conclude that OS and DFS reach a stable plateau from 5 years after SCT to more than 8 years after SCT. In CR1 patients, DFS is superior after unrelated as compared to related SCT. Accordingly, strategies designed to decrease relapse, especially after related SCT, have already been implemented in the ongoing protocols. The preferential use of unrelated rather than related donors may be beneficial and should be considered in future protocols. Disclosures: Off Label Use: Transplantation in elderly patients.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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    detail.hit.zdb_id: 80069-7
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  • 2
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 53, No. 8 ( 2012-08), p. 1561-1568
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2012
    detail.hit.zdb_id: 2030637-4
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  • 3
    In: Current Opinion in Oncology, Ovid Technologies (Wolters Kluwer Health), Vol. 21, No. Suppl 1 ( 2009-06), p. S17-S22
    Type of Medium: Online Resource
    ISSN: 1040-8746
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
    detail.hit.zdb_id: 2026986-9
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  • 4
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1921-1921
    Abstract: AML patients with unfavourable cytogenetics generally have a poor outcome. Over the last decade a number of strategies to improving survival have been assessed by the East German Study Group (OSHO). Here, we analyse the results of three protocols (AML 93, AML 96 and AML 2002) for effects on outcome in younger patients ( 〈 60 years) with unfavourable cytogenetics. Methods: Unfavourable cytogenetics, defined as abn 3q26, -5/5q-, -7/7q-, abn 11q23 or a multiaberrant clone were present in 20 (12,3%), 76 (20,5%) and 60 (26,3%) patients from the AML 93/96/2002 respectively. In the AML 93 protocol, therapy consisted of double induction (Idarubicin and standard dose AraC 3+7), followed by consolidation (Mitoxantron, Etoposide) and re-induction (Idarubicine + high dose AraC). In both AML 96 and AML 2002, a single course of induction therapy (intermediate dose AraC and Idarubicine 3+7) was repeated as the first consolidation for all patients achieving CR. In AML 96, patients in PR after the first induction received intermediate dose AraC and Mitoxantrone as a 2nd induction therapy. In AML 2002, both non-responders and those achieving PR were randomized between the same induction therapy or a more intensive regime (Mitoxantrone, Fludarabin and intermediate dose AraC). Results: Of all patients with unfavourable cytogenetics (n=156), 40%, 50%, and 65% achieved CR in the AML 93, 96 and 2002 studies respectively, with no statistically significant difference between the CR rates in the three studies (p=0,19). OS and EFS were analyzed both with and without censoring HCT. OS and EFS in patients censored at the time of transplant was not different between the three AML studies although intensity of chemotherapy differed widely (standard, intermediate and high dose AraC). The same analysis performed without censoring allogenic HCT revealed OS at 3 years of 10% for the AML 93, 14% for the AML 96 and 34% for the AML 2002 study (log rank p 〈 10 −2). EFS at 3 years was 9%, 10% and 32% in the AML 93, 96 and 2002 respectively (log rank p 〈 0,10−3). In AML 96, 32% of the patients with unfavourable karyotype underwent HCT, 40 % of these in CR1. In AML 2002, 60% of such patients were transplanted and 75% of them were in CR1. The interval from diagnosis to HCT decreased from median 204 (range 142–329) days in the AML 96 to median 125 (range 47–321) days in the AML 2002 (p=0,001). This decrease was associated with fewer cycles of chemotherapy prior to transplant: Patients in the AML 96 protocol received a median of 3 courses (range 2–4) and those in AML 2002 a median of 2 courses (p= 0,002). Conclusion: We conclude that intensity of induction and consolidation chemotherapy is not crucial for CR rate, OS or EFS in patients with unfavourable karyotype,. Improvement in OS and EFS was observed only using HCT as early as possible after CR1.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    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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  • 5
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4904-4904
    Abstract: Abstract 4904 Background: Prognostic molecular markers are expected to be of increasing value in stratifying treatment of patients with AML lacking cytogenetic abnormalities. While specific DNA-level mutations such as those in the FLT-3 or NPM1 genes clearly identify informative genotypes, phenotypic characterization of gene expression should be a more direct indicator of cell function. However, of the prognostic mRNA levels identified to date, such as BAALC, ERG or NME1/2, none appear to be superior to DNA mutation as indicators of prognosis. Because of the lability of mRNA expression, it is common practice to quantify levels only in freshly processed or direct-lysed samples in order to provide a snapshot of gene expression as close as possible to that of fresh tissue. However, characteristics of leukemic cells relevant to prognosis might become more apparent under challenging conditions, such as the stress environment developing in a bone marrow sample during transport or storage. The NME1 and -2 mRNAs have been reported to be prognostic indicators in AML and are multifunctional proteins coordinating metabolism, signalling and gene expression. To see how storage related stress affects the prognostic power of NME mRNA, we have assessed their prognostic relevance in CN-AML bone marrow samples which had originally been processed either directly, or following ≥ 2 days of transport from collaborating centers. Methods: A total of 78 archived CN-AML BMMNC samples were available for this analysis. All samples were taken at presentation from patients under 60ys treated within the AML 96 (OSHO #033) or AML 2002 (OSHO #061) protocols of the East German Study Group (OSHO). Of the 78 samples, 25 (32%) originated locally and had been freshly processed to cryopreserved MNC, while the remaining 53 (68%) had been submitted as bone marrow from other centers with an associated delay of 2–3 days. NME1 and NME2 mRNA levels were determined by triplicate qRT-PCR determinations normalized to RPLP0. The mean NME1 and NME2 expression values from each patient were expressed relative to the corresponding mean NME expression of 17 healthy donor BM samples (control group).To investigate directly the effects of delayed processing on NME mRNA expression, aliquots of 11 fresh CN-AML bone marrow samples were removed for analysis either immediately or following storage at room temperature for ≥ 2 days. Results: Both NME1 and -2 mRNA were increased relative to controls in 84% (21/25) of fresh samples with no prognostic relevance of expression above or below the median. Comparable results were obtained from a cohort of 59 freshly processed CN-AML samples from a separate study. In contrast, the transported samples yielded a heterogeneous pattern of NME mRNA expression above and below control levels, with a significant correlation between NME2 mRNA and event-free survival (p=0.009) independently of FLT-3ITD status. Direct analysis of aliquoted AML bone marrow samples confirmed that a delay in processing of ≥ 2 days resulted in a universal decrease in NME1 mRNA with variable changes in NME2 mRNA. Conclusion: NME1/2 mRNA levels are not indicative of prognosis in freshly processed bone marrow from CN-AML patients 〈 60ys. However, delayed processing is associated with the development of an NME2 expression pattern with high prognostic relevance, maintenance of high NME2 in samples with reduced NME1 being a strong indicator of increased event-free survival. These results suggest that subjecting leukemic cells to defined challenges ex-vivo may reveal phenotypic properties of high relevance to treatment optimization. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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