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  • American Society of Hematology  (3)
  • 2005-2009  (3)
  • 1
    Online Resource
    Online Resource
    New Definition of Treatment Response in Adult Acute Lymphoblastic Leukemia (ALL): Use of Molecular Markers for Minimal Residual Disease (MRD).
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 90-90
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 90-90
    Abstract: Abstract 90FN2 Response to treatment measured by cytologic bone marrow evaluation has been so far the most important prognostic factor in adult ALL, and cytological complete remission (cyCR) and relapse (cyREL) are accepted endpoints for clinical trials. However, measurement of MRD is a more sensitive approach for assessment of response. In the past decade it has been confirmed that MRD is an independent, strong prognostic factor in ALL. The most widely applied method is based on quantative PCR evaluation of individual rearrangements of TCR and Ig genes. Methodology, interpretation and definitions are highly standardised and confirmed in different labs (e.g. van der Velden et al, Leukemia, 2007). Therefore it is essential to define and validate MRD based response criteria – namely complete molecular/complete MRD response (molCR), molecular failure/MRD persistence (molFAIL) and molecular relapse/MRD relapse (molREL) - as endpoints for clinical trials. Since 1999 the German Multicenter Study Group for Adult ALL (GMALL) has conducted two consecutive studies (GMALL 06/99 and 07/2003) with a risk and MRD adapted treatment strategy and prospective MRD evaluation. 1489 evaluable pts (15–55 y) with Ph-negative standard (SR) and high risk (HR) ALL have been included so far. MRD evaluation as described above has taken place in central labs. For analysis of molCR MRD evaluation was restricted to pts with cyCR (prerequisite: at least one marker with sensitivity and quantitative range of minimum 10−4 for negative results). MolCR was defined as negative MRD status after induction therapy. MolREL was defined as reappearance of MRD above 10−4 after achievement of molCR. MolCR after induction: The overall cyCR rate was 89% with differences between SR and HR (92% vs 84%;p 〈 .0001) and age 〈 vs 〉 35 yrs (90% vs 86%;p=.01) but not B vs T-lineage (89% vs 88%). As expected the molCR was lower (69%) in 479 evaluable pts. Significant differences were seen between SR vs HR (77% vs 46%;p 〈 .0001) and B vs T-lineage (63% vs 79%;p=.0005). The most rapid decrease of MRD was observed after induction phase I (34% molCR) and phase II (69%), whereas the effect of first consolidation was limited (72%) indicating a progressive selection of chemotherapy resistant leukemic clones. MolCR evaluation was also used to assess treatment modifications such as asparaginase intensification or addition of rituximab to induction therapy. Prognostic impact of molCR: SR pts were scheduled for chemotherapy. Those with molCR had a superior overall survival (OS) when compared to molFAIL (67% vs 38%;p 〈 .0001) which was mainly due to a lower relapse rate (RR) (26% vs 59%;p 〈 .0001) leading to better remission duration (RD) (57% vs 29%;p 〈 .0001). MolFAIL pts had a better OS with SCT in CR1 than without (60% vs 27%;p=.09). All HR pts were scheduled for SCT in CR1. OS was superior for MolCR vs MolFAIL (66% vs 42%; p=.003). The RR was higher for molFAIL vs molCR on chemotherapy (66% vs 18%;p=.04) and after SCT (34% vs 11%;p=.04). Even after SCT pts with molCR had a better OS (75% vs 58%; p=.03). MolREL: The incidence and outcome of molREL was evaluated in 432 pts with MRD tests during and after treatment. 36 molREL without additional extramedullary relapse were observed. The OS was 36% and the probability of cyREL was 82% with median of 75 d from molREL to cyREL. All pts not treated at molREL relapsed (N=12). Only 1/11 (9%) pts who were transferred to SCT in cyCR1 after additional treatment, including experimental drugs, relapsed compared to 21/25 (84%) pts without SCT in cyCR1 (p 〈 .0001). Overall these data show in the largest cohort of adult ALL pts with MRD analysis reported so far, the proof of principle for molecular response evaluation. In a study with high cyCR rate it allows to detect differences between subgroups and treatment approaches and thereby refines the evaluation of treatment efficacy. It is a clinically relevant endpoint since molFAIL is associated with significantly poorer RD and OS even after subsequent SCT. Detection of molFAIL and molREL identifies pts with resistance to conventional drugs and the need for targeted, experimental drugs and SCT in cyCR1 before occurrence of cyREL. Molecular response evaluation with standardised methods provides new refined endpoints for future trials, including pivotal trials with new drugs with the major advantage of early decision points and strong correlation to clinical outcome. Supported by Deutsche Krebshilfe 702657Ho2 and BMBF 01GI9971/8 Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.90.90
    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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  • 2
    Online Resource
    Online Resource
    High Survival Rate in Adult Burkitt’s Lymphoma/Leukemia and Diffuse Large B-Cell Lymphoma with Mediastinal Involvement.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 518-518
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 518-518
    Abstract: With short intensive chemotherapy mainly based on HDMTX, fractionated alkylators and HDAC outcome of Burkitt’s NHL and mature B-ALL (B-ALL) in adults could be improved substantially to CR rates of 80% and overall survival (OS) of 50–70% (Hoelzer et al, Blood, 1996). Further intensification - namely increase of MTX dose - failed to improve these results. Therefore the German Multicenter Study Group for Adult ALL (GMALL) invented in 2002 a new protocol for mature B-ALL/Burkitt and other high-grade NHL, namely primary mediastinal (med) DLBCL, including 6x Rituximab® 375 mg/m2 before each chemo cycle and two R maintenance cycles. In addition 2 cycles based on HDAC 2 g /m2 were included. HDMTX was 1,5 g/m2 in the protocol for younger pts ( 〈 55 yrs). Older pts ( 〉 55 yrs) received a dose reduced regimen without HDAC and with MTX at 500 mg/m2. 227 pts with Burkitt (27=Burkitt-like), B-ALL or med DLBCL aged between 16 and 78 enrolled between 09/02 and 12/06 were evaluable for response after the first two cycles. The median age was 36 yrs for Burkitt, 46 for B-ALL and 35 for med DLBCL; 18%, 41% and 12% were older than 55 yrs respectively. The subgroups were characterised as follows: 115 Burkitt (stage III–IV 52%, extranodal inv. 78%, aaIPI 〉 1 47%), 70 B-ALL, 42 med DLBCL (stage III–IV 55%, extranodal inv. 71%, aaIPI 〉 1 61%). The CR rate was 90% in Burkitt, 83% in B-ALL and 69% in med DLBCL; death under therapy occurred in 3%, 11% and 0% respectively. The overall survival at 3 yrs was 91% for Burkitt, 79% for B-ALL and 90% for med DLBCL in pts at the age of 15–55 yrs and 84%, 39% and 67% (N=5) respectively in pts 〉 55 yrs. CNS relapses were observed in 3 out of 22 older CR patients with B-ALL whereas in younger pts the CNS relapse rate was 0. CNS relapses are among the reasons for inferior outcome in elderly B-ALL in contrast to elderly pts with Burkitt or med DLBCL. CNS relapse rate may hopefully be reduced by inclusion of an intermediate dose ARAC cycle in the elderly B-ALL. There was no difference in OS between pts with Burkitt (92%) vs Burkitt-like NHL (86%). Since no prognostic factors could be identified in younger pts, there was no need for SCT in CR1. Major grade III/IV toxicity was hematological (28–37%) and mucositis (36%, 37%, 28% in cycles A1, B1, C1 respectively). Compared to the previous GMLL trial B-NHL90 (without Rituximab) with 270 pts the OS of 272 patients (including LBL, LCAL, DLBCL) at 3 yrs improved significantly from 54% to 80% (p 〈 .0001) overall, 56% to 85% (p 〈 .0001) in younger and 39% to 65% (p=.01) in older pts. In this largest prospective study of adult Burkitt’s lymphoma/leukemia and med DLBCL the combination of Rituximab and 6 short intensive chemo cycles was feasible and lead to an OS of 90% in NHL and 79% in mature B-ALL in the younger patient cohort. Even in older pts with Burkitt’s NHL survival was 84%. The further aim is now to reduce toxicity, namely mucositis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.518.518
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    Improved Outcome in High Risk and Very High Risk ALL by Risk Adapted SCT and in Standard Risk ALL by Intensive Chemotherapy in 713 Adult ALL Patients Treated According to the Prospective GMALL Study 07/2003.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 12-12
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 12-12
    Abstract: In 2003 the German Multicenter ALL Study Group (GMALL) initiated the trial GMALL 07/2003. Major aims were improvement of outcome by shortened, intensified induction, intensified consolidation, risk adapted and extended SCT indication and minimal residual disease (MRD) based treatment stratification. 8drug-induction was followed by uniform 1st consolidation based on HDARAC and HDMTX. Further treatment was stratified according to the following risk factors (RF): WBC 〉 30.000 in B-prec. ALL, late CR ( 〉 3wks), proB-, earlyT and mature T-ALL, Ph/BCR-ABL and t(4;11)/ALL1-AF4. The risk groups were defined as follows: standard risk (SR, no RF), high risk (HR, 〉 = 1RF) and very high risk (VHR,Ph/BCR-ABL). HR and VHR pts were scheduled for SCT in CR1 with the following priorities: allo sibling, allo matched unrelated and autologous. VHR pts mostly received Imatinib according to different schedules. SR pts received 5 consolidation cycles (HDMTX/ASPx3, VP16/ARAC, CYCLO/ARAC) and reinduction. SR pts with high MRD after consolidation I were allocated to SCT. In the remaining SR pts decision on maintenance therapy was based on MRD. Between 04/03-12/06 713 evaluable (15–55 yrs) pts were included. The median age was 34 yrs. The CR rate after induction was 89% with 5% early death and 6% failure. 50%, 33% and 17% were allocated to SR (N=353), HR (N=235) and VHR (N=117) with similar CR rates of 92%, 88% and 85%. CR rate was not different in pts 〈 vs 〉 35 yrs (90% vs 89%). 5 year overall survival (OS) was 54% and survival of CR (S-CR) pts was 59%. HR and VHR pts obtained 55% and 49% S-CR at 3 yrs resp. HR subgroups showed different S-CR for early T (58%), mature T (70%), pro B (66%) and other B-lineage ALL (37%). 68% and 71% of HR and VHR pts received SCT in CR1 as scheduled which thus contributed substantially to improved outcome. In SR- ALL S-CR was 69% (68% c/preB, 66% thymicT). The CCR probability was 52% at 3 yrs. CNS prophylaxis was very effective since only 2% of the CR pts had CNS involvement at relapse. Univariate analysis confirmed a significant prognostic impact of immunphenotype, WBC in B-lin ALL, time to CR and Ph/BCR-ABL. WBC was no prognostic factor in T-lin-ALL. Age was highly significant for survival with 64% survival 〈 35 yrs vs 48% above 35 yrs. In adolescents below 25 years the most favourable survival of 67% was achieved. In standard risk pts below 35 yrs the survival was 73% without SCT in CR1. Overall the study yielded improved CR rates (89%) and survival (54%). Risk adapted SCT indication was feasible (realised in 70% of HR/VHR pts) and lead to improved survival particularly in early/mature T-ALL and pro B-ALL. In standard risk (SR) the survival is favourable, even above 70% in young pts; however, the relapse rate is still high. Further intensification of therapy during the first year seems required. By definition of new risk factors additional SR patients could be allocated to SCT in CR1. There is however no intention to transfer all SR patients to SCT. Future improvement will be attempted by further inclusion of subtype specific and targeted therapies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.12.12
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
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