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  • 1
    Online Resource
    Online Resource
    Prognostic Factors in Patients Receiving An Allogeneic Stem Cell Transplantation for Relapsed AML. Results of the Prospective AML 295 and 01/99 Studies
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 344-344
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 344-344
    Abstract: In the prospective multicenter AML 295 and 01/99 trials, we treated 825 adult patients with acute myeloid leukemia (AML) up to 60 years. 719 patients had de novo disease and 106 had a secondary AML. Median age was 46 years. Patients with t(15;17) were excluded. Induction course I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with good response to IVA-I ( & lt;5% bone marrow blasts on day 15) continued with IVA-II on day 21 as double induction. Patients with bad response received an intensified second induction course with intermediate dose AraC (1g/m2, 8 doses) combined with mAMSA or fludarabine/idarubicine/G-CSF (FlAG-Ida). Double induction was followed by an early consolidation with intermediate dose AraC. Late consolidation was stratified according to risk factors (karyotype and response to IVA-I) and consisted of high dose AraC (3g/m2, 12 doses) + daunorubicine, autoPBSCT or an allogeneic stem cell transplantation. Overall complete remission (CR) rate was 75%. 278 patients relapsed after a median duration of first CR of 9 months. Of these 278 patients, 135 (48%) received an allogeneic stem cell transplantation (alloSCT) from related (n=65) or unrelated (n=70) donors. Median time from relapse to alloSCT was 3 months. 55% of the transplanted patients had achieved a second CR as best response to salvage therapy before alloSCT. Patients who received an alloSCT after relapse were younger (median 40 vs. 50 years) and had a longer duration of first CR (10 vs. 7.5 months) than those who did not. Patients with CBF-leukemias or normal karyotype were significantly more likely to receive an alloSCT after relapse than patients with other karyotypic aberrations. Median overall survival after alloSCT was 12 months and 5-year overall survival was 30%. Results did not differ between transplants from matched related or unrelated donors. In univariate and multivariate analysis, age above the median (HR 2.1, 95% CI 1.3 –3.2) and best response to salvage therapy (CR vs. no CR; HR 0.5, 95% CI 0.3 –0.9) were the only independent prognostic factors for overall survival after alloSCT. Patients aged below 46 years who achieved a CR as best response to salvage therapy had a 5-year overall survival after alloSCT of 53% (median not reached). All other patients had a 16% 5-year overall survival (median 7 months). There was no independent prognostic effect of WBC, platelets, peripheral blasts or extramedullary disease at initial diagnosis. Also, de novo vs. secondary AML, response to induction I, karyotype (CBF vs. normal vs. others), duration of CR1 (≥6 vs. & lt;6 months) and type of consolidation did not affect outcome after alloSCT in relapse. In conclusion, alloSCT from related or unrelated donors offers cure to selected patients with relapsed AML. Age and disease status after salvage therapy are critical prognostic factors for transplantation success. Strategies to increase the number of patients eligible for an alloSCT after relapse and age adapted transplantation protocols are required.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.344.344
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    Prospective Randomized Comparison of High Dose AraC and AutoPBSCT as Late Consolidation for Patients ≤60 Years with Standard Risk AML: Final Results of the AML SHG-Hannover 01/99 Trial.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 607-607
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 607-607
    Abstract: We treated 520 patients ≤60 years with de novo (n=414) or secondary (n=106) AML. Patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (≤5% blasts in d15 BM) were considered standard risk (SR), all others as high risk (HR). Patients with t(15;17) were excluded. Induction I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA–II on d21. In patients with bad response ( & gt;5% BM blasts on d15), the second cycle consisted of either IVA–II or FlAG/Ida. Induction was followed by early consolidation with intermediate dose araC. As late consolidation, SR patients with normal karyotype and an HLA-matched sibling received matched related donor (MRD) transplantation. The remaining SR patients were randomized between high dose (HD) araC (12 x 3g/m2)/daunorubicine (3 x 45mg/m2) or an autologous peripheral blood stem cell transplantation (autoPBCSCT) with PBSC mobilized after early consolidation. 90% of the 262 SR patients achieved CR in contrast to only 59% of the 249 HR patients (overall CR rate 74%). After 75 months, overall survival (OS) and relapse free survival (RFS) was significantly better for SR than for HR patients. Within the SR group, OS for patients with CBF leukemia (n=62) at 56 months was significantly better than for patients with normal karyotype (n=200). RFS was similar for both groups. 57 SR patients (14 with CBF leukemia) were randomized to receive HD araC and 62 (16 with CBF leukemia) to undergo autoPBSCT. At 70 months, OS and RFS was not different for the patients treated with autoPBSCT and for those receiving HD araC. This was true for patients with normal karyotype as well as CBF leukemias. Median duration of neutropenia ( & lt;500/μl) was 9 days for autoPBSCT and 19 days for HD araC (p & lt;0.01) with a significantly higher rate of septicemia (21% vs. 11%) and pneumonia (14% vs. 3%) after HD araC. Duration of thrombocytopenia was 21 days for HD araC and 11 days for autoPBSCT (p & lt;0.01). In SR patients with normal karyotype, OS and RFS after MRD transplantation did not significantly differ from HD araC or autoPBSCT. However, when looking at the FLT3 status in patients with normal karyotype (n=49), chemoconsolidation resulted in an inferior survival (17%) in patients with mutated FLT3 as compared to autotransplantation (67%). In conclusion, outcome is similar in SR AML patients after autoPBSCT, HD araC or MRD transplantation. In SR patients without an HLA-identical sibling donor, autoPBSCT instead of HD araC as used in our study is recommended for late consolidation due to the reduced treatment related toxicity and should be studied prospectively in patients with mutated FLT3.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.607.607
    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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  • 3
    Online Resource
    Online Resource
    Treatment of Patients up to 60 Years with High Risk AML: Final Results of the AML SHG-Hannover 01/99 Trial.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 433-433
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 433-433
    Abstract: In this prospective multicenter trial, we treated 520 patients with AML ≤60 years (414 with de novo and 106 with secondary AML). Patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (≤5% blasts in day 15 BM) were considered standard risk (SR), all other patients as high risk (HR). Patients with t(15;17) were excluded. Induction course I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21. In patients with bad response (BR; & gt;5% BM blasts on day 15), the second cycle consisted of either IVA-II or FlAG/Ida. Double induction was followed by early consolidation with intermediate dose araC. As late consolidation, HR patients with an HLA-matched sibling were scheduled for a matched related donor (MRD) transplantation; patients without a family donor should undergo autologous peripheral blood stem cell transplantation (autoPBSCT). PBSC were mobilized after early consolidation. An interim analysis showed superior results for allogeneic transplants compared to patients who had undergone autoPBSCT. Therefore, since 2003 all HR patients without a sibling donor were scheduled for matched unrelated donor (MUD) transplantation. 147 of 249 HR patients (59%) achieved complete remission. 33 (13%) of the HR patients died during induction. After 75 months, overall survival (OS) was significantly worse for HR patients (24%) than for SR patients (53%). For HR patients, there was no difference in OS and relapse-free survival (RFS) between patients classified as HR because of BR to IVA-1 (n = 83), unfavourable karyotype (n = 87) or both characteristics (n = 79). RFS was neither different between HR patients with de novo or secondary AML nor between HR patients with normal karyotype, complex karyotype or other high risk cytogenetics. Regarding late consolidation, the “as treated” analysis revealed that OS and RFS was significantly better after an MRD transplantation (n=41, OS 67%, RFS 62%) than after autoPBSCT (n=27, OS 14%, RFS 7%). Patients who received a MUD transplantation (n=32) showed a significantly better RFS (52%) than after autoPBSCT. RFS and OS after MUD transplantation did not differ significantly from MRD transplants. OS of patients after autoPBSCT was not significantly different from patients who received no transplant at all after entering CR. Of the 69 HR patients who did not enter CR after induction, 44 received an MRD or MUD transplantation. 15 of these patients (35%) are alive in CR. In conclusion, HR patients as defined in our study do not benefit from an autologous PBSCT and an allogeneic MRD or MUD transplantation should be performed. Moreover, allogeneic transplants are a viable salvage option for HR patients not entering CR.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.433.433
    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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  • 4
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    Online Resource
    Impact of IDH1 R132 Mutations and an IDH1 Single Nucleotide Polymorphism in Cytogenetically Normal Acute Myeloid Leukemia: SNP rs11554137 Is an Adverse Prognostic Factor
    American Society of Clinical Oncology (ASCO) ; 2010
    In:  Journal of Clinical Oncology Vol. 28, No. 14 ( 2010-05-10), p. 2356-2364
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 14 ( 2010-05-10), p. 2356-2364
    Abstract: We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. Patients and Methods IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified. Results IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3–internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles. Conclusion IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2009.27.6899
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2010
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Online Resource
    Role of Etoposide in Combination with All-Trans Retinoic Acid in the Treatment of Elderly Patients with Acute Myeloid Leukemia and NPM1 Mutation
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 559-559
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 559-559
    Abstract: Rationale: In a previous randomized trial (AML HD98B) in elderly ( & gt;60 yrs) patients with AML (excluding APL), we could demonstrate that all-trans retinoic acid (ATRA) given as adjunct to intensive induction therapy with idarubicin, cytarabine and etoposide significantly improved outcome; this beneficial effect appeared to be restricted to patients having NPM1 mutation without concomitant FLT3-ITD (NPM1mut/FLT3-ITDneg). In our subsequent trial in elderly patients (AMLSG 06-04), all patients received ATRA with a similar backbone of chemotherapy, except that for induction therapy idarubicin was intensified and etoposide was omitted. NPM1mut AML is associated with myelomonocytic/monocytic differentiation, and etoposide is believed to have a particular effect in these morphologic subtypes of AML. Aims: To evaluate the impact of etoposide in combination with ATRA in elderly patients with AML exhibiting NPM1 mutation enrolled into two consecutive AMLSG protocols. Methods: 171 patients with NPM1mut AML were included in this retrospective analysis; 78 patients from trial AML HD98B (trial A; accrual from 1998 to 2004); and 95 patients from trial AMLSG 06-04 (trial B, 2004–2008). Twenty-nine of 78 (37%) patients and 87 of 93 (94%) received ATRA in trials A and B, respectively. Results: Initial patient characteristics, such as median age (67.8 and 67.9 years for trial A and B, respectively), type of AML (de novo, secondary or therapy-associated), white blood cell count (WBC), LDH, and FLT3-ITD mutation status (41% and 47%), were not significantly different between the two cohorts. The rates of complete remission (CR) were 68% and 71% for NPM1mut patients in trial A and B, respectively. Lower age and lower WBC counts were significantly associated with achievement of CR; study, treatment with ATRA, type of AML, and FLT3-ITD mutation status had no impact. Univariable survival analyses revealed no significant difference for the end points event-free (EFS), relapse-free (RFS) and overall survival (OS) between the two patient cohorts from trial A and B. However, when restricting the analysis to patients who had received ATRA, a significant better EFS (p=0.05) and RFS (p=0.03) was found for patients with the genotype NPM1mut/FLT3-ITDneg in trial A (that included etoposide) compared to trial B (in which etoposide was omitted); there was no difference in EFS (p=0.18) and RFS (p=0.09) for patients with the genotype NPM1mut/FLT3-ITDpos. In addition, no difference was seen either in patients with the genotype NPM1mut/FLT3-ITDpos or in patients with the genotype NPM1mut/FLT3-ITDneg in terms of OS mainly due to a high second CR rate in patients with the genotype NPM1mut/FLT3-ITDneg. Conclusion: The data from this retrospective subgroup analysis suggest that etoposide in combination with ATRA may exert a beneficial synergistic effect in elderly patients with AML having NPM1 mutation without concurrent FLT3-ITD.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.559.559
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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