Acute Myeloid Leukemia (AML): Different Treatment Strategies Versus a Common Standard Arm—Combined Prospective Analysis by the German AML Intergroup

Büchner, Thomas; Schlenk, Richard F.; Schaich, Markus; Döhner, Konstanze; Krahl, Rainer; Krauter, Jürgen; Heil, Gerhard; Krug, Utz; Sauerland, Maria Cristina; Heinecke, Achim; Späth, Daniela; Kramer, Michael; Scholl, Sebastian; Berdel, Wolfgang E.; Hiddemann, Wolfgang; Hoelzer, Dieter; Hehlmann, Rüdiger; Hasford, Joerg; Hoffmann, Verena S.; Döhner, Hartmut; Ehninger, Gerhard; Ganser, Arnold; Niederwieser, Dietger; Pfirrmann, Markus

doi:10.1200/jco.2012.42.2907

Cited by 122 publications

(91 citation statements)

References 21 publications

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“…As in allogeneic transplantation, veno-occlusive disease is an uncommon complication after an autograft using intravenous busulfan. Antonio Torres Gomez, 7 Simona Lapusan, 3 Giuseppe Irrera, 8 Jose E Guimaraes, 9 Aida Botelho Sousa, 10 Angelo M. Carella, 11 Norbert Vey, 12 William Arcese, 13 Avichai Shimoni, 1 Raanan Berger, 1 Vanderson Rocha, fan pharmacokinetics, an intravenous formulation of busulfan has recently been developed. In adults, intravenous busulfan has shown predictable and consistent pharmacokinetic profiles with acceptable toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

et al. 2014

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International audienceOral busulfan is the historical backbone of the busulfan+cyclophosphamide regimen for autologous stem cell transplantation. However intravenous busulfan has more predictable pharmacokinetics and less toxicity than oral busulfan; we, therefore, retrospectively analyzed data from 952 patients with acute myeloid leukemia who received intravenous busulfan for autologous stem cell transplantation. Most patients were male (n=531, 56%), and the median age at transplantation was 50.5 years. Two-year overall survival, leukemia-free survival, and relapse incidence were 67±2%, 53±2%, and 40±2%, respectively. The non-relapse mortality rate at 2 years was 7±1%. Five patients died from veno-occlusive disease. Overall leukemia-free survival and relapse incidence at 2 years did not differ significantly between the 815 patients transplanted in first complete remission (52±2% and 40±2%, respectively) and the 137 patients transplanted in second complete remission (58±5% and 35±5%, respectively). Cytogenetic risk classification and age were significant prognostic factors: the 2-year leukemia-free survival was 63±4% in patients with good risk cytogenetics, 52±3% in those with intermediate risk cytogenetics, and 37 ± 10% in those with poor risk cytogenetics (P=0.01); patients ≤50 years old had better overall survival (77±2% versus 56±3%; P<0.001), leukemia-free survival (61±3% versus 45±3%; P<0.001), relapse incidence (35±2% versus 45±3%; P<0.005), and non-relapse mortality (4±1% versus 10±2%; P<0.001) than older patients. The combination of intravenous busulfan and high-dose melphalan was associated with the best overall survival (75±4%). Our results suggest that the use of intravenous busulfan simplifies the autograft procedure and confirm the usefulness of autologous stem cell transplantation in acute myeloid leukemia. As in allogeneic transplantation, veno-occlusive disease is an uncommon complication after an autograft using intravenous busulfan

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Section: Introductionmentioning

confidence: 99%

“…1 Autologous hematopoietic stem cell transplantation (ASCT) offers an alternative possibility of delivering high-dose myeloablative treatment in AML. Several historical randomized trials have reported significantly lower relapse incidences after ASCT than after conventional chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

et al. 2014

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“…Efforts aimed at improving long-term survival of these patients thus have involved the fine-tuning of dosing within this framework, leading to adoption of 317 variants in recent years as attempts to intensify induction chemotherapy. Although escalation of ARA-C dosing is one of the most extensively explored avenues in clinical trials [10][11][12][13][14]27], results overall remain inconclusive [10][11][12][13][14]27]. One plausible explanation for conflicting evidence is that the efficacy of a given regimen, as reflected by survival estimates, may be influenced by the nature of post-consolidation strategies.…”

Section: Discussionmentioning

confidence: 99%

Minimal residual disease as biomarker for optimal biologic dosing of ARA‐C in patients with acute myeloid leukemia

et al. 2014

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We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard-dose (SDAC) and high-dose ARA-C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18-59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n 5 78) or HDAC (n 5 52) plus etoposide and daunorubicin. Consolidation consisted of intermediate-dose ARA-C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs. 15%, P 5 0.007) and consolidation (44% vs. 18%, P 5 0.002).Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 3 10 23 and 4 3 10 23 (P 5 0.033) after induction and 5.7 3 10 24 and 2.9 3 10 23 (P 5 0.008) after consolidation. Based on ARA-C schedule and post-consolidation MRD status, the four patient groups (SDAC-MRD 2 , HDAC-MRD 2 , SDAC-MRD 1 , and HDAC-MRD 1 ) displayed 5-year overall survival rates of 60%, 33%, 24%, and 42% (P 5 0.007), respectively, with 24%, 35%, 74%, and 48% (P < 0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA-C, and SDAC regimen appears to yield more frequent MRD negativity.

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“…Two patients withdrew their consent before initiation of treatment; thus, a total of 93 patients are reported. Prior treatments of the patients were as follows: 29 patients received standard induction therapy with idarubicin, cytarabine, and etoposide (ICE), 26 patients ICE in combination with ATRA (A-ICE), 17 patients with valproic acid (V-ICE), and 12 patients with both ATRA and valproic acid (VA-ICE), according to the initial randomization of the AMLSG 07-04 protocol (clinicaltrials.gov identifier: 00151242); 28 9 patients were treated in the German AML Intergroup trial 29 and received standard induction therapy with daunorubicin and cytarabine (DA). Median age was 48 years (range 22-62 years); further demographics and baseline characteristics of the 93 patients are shown in Table 1.…”

Section: Patients' Characteristicsmentioning

confidence: 99%

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

et al. 2016

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O utcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m² intravenously on day 1), all-trans retinoic acid (45 mg/m² orally on days 4-6 and 15 mg/m² orally on days 7-28), high-dose cytarabine (3 g/m²/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m² intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975) Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

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Acute Myeloid Leukemia (AML): Different Treatment Strategies Versus a Common Standard Arm—Combined Prospective Analysis by the German AML Intergroup

Abstract: A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared through a common standard treatment arm. The results provide a representative basis for further therapeutic approaches.

Cited by 122 publications

References 21 publications

Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Minimal residual disease as biomarker for optimal biologic dosing of ARA‐C in patients with acute myeloid leukemia

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

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