Kooperativer Bibliotheksverbund

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 102, No. 3 ( 2023-03), p. 547-561

Abstract: A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA ( n  = 132) or to the study group arms ( n  = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-023-05087-8

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1458429-3

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1066-1066

Abstract: Despite recent advances, treatment of elderly patients with AML remains a challenge because of adverse disease biology, comorbidities and therapy related toxicities. The balance between effectivity and toxicity of treatment strategies play a key role. Since comparative studies are lacking, a prospective randomized trial was designed among German AML study groups with different treatment strategies to compare outcome. Patients ≥60 years with all AML subtypes except M3 were randomized up-front to a common standard arm (CSA) (10%) and to study specific arms (90%) of the AMLCG or the OSHO. The CSA consisted of one or two inductions of araC 100 mg/m2/d continuous IV (CI) d 1-7 d and daunorubicin (dauno) 60 mg/m2/d IV d 3, 4, 5 and two courses of araC 1 g/m2/d BID IV d 1, 3 and 5 as consolidation (Mayer RJ et al, NEJM 1994). The AMLCG study arm randomized TAD (araC 100 mg/m2/d CI d1-2 followed by BID d 3-8, dauno 60 mg/m2/d IV d 3-5 and 6-thioguanine 100 mg/m2/d po BID d 3-9) and HAM [araC 1 mg/m2/d IV BID d 1-3 and mitoxantrone (mito) 10 mg/m2/d IV d 3-5] versus two courses of HAM with any 2nd course only given if blasts persisted ± G-CSF. Two courses of TAD were given as consolidation followed by maintenance chemotherapy over three years. The OSHO study arm included araC 1 g/m²/d BID IV d 1 + 3 + 5 + 7 and mito 10 mg/m2/d IV d 1 - 3 for one or two induction courses and ara-C 500 mg/m² BID 1h IV d 1 + 3 + 5 in combination with mito10 mg/m2/d IV d 1 + 2 as consolidation. Pegfilgrastim 6 mg s.c. was applied on day 10 of induction and on d 8 of consolidation. The study was approved by the IRB and registered at clinicaltrials.gov (NCT01497002 and NCT00266136). Written informed consent was obtained from all patients prior to randomization. Between April 1st, 2005 and May 26th, 2015 1286 patients were assigned randomly to the CSA (n=132) or to the study groups arm (n=1154). After excluding 139 patients (10.8%), 1147 patients were eligible for analysis, 1120 with follow-up for overall survival (OS) and 1079 for complete remission (CR) analysis. Baseline characteristics of all eligible patients showed median ages of 68 (60-82) years for the CSA and 69 (60-87) and 70 (60-85) years in the study arms A and B, respectively (p=0.05). Proportions of patients with secondary AML differed significantly between study arms (A: 42%, B: 30%, CSA: 36%; p=0.003). The CSA had less flt3 wildtype/npm1 wildtype patients (31%) vs. arm A (51% p=0.040) and arm B (58%, p=0.0455). No differences were observed with respect to cytogenetic risk groups, white blood cell counts, LDH, and npm1 mutant/ flt3-wildtype or mutant. The primary endpoint event free survival (EFS) did not differ between the CSA and study group strategies. Three-year EFS was 12.4% (95% CI: 6.7 - 19.9%) in the CSA, 15.6% (95% CI: 13.1 - 18.3%) in group A and 11.4% (95% CI, 7.4% to 16.4%) in group B (n.s.;Fig.1). With a median follow-up of 67 months, OS did not differ significantly between CSA and study group regimens. The 3-year survival probability was 22.3% (95% CI: 14.7-30.9%) in the CSA, 24.7% (95% CI: 21.6-27.9%) in group A and 22.4% (95% CI, 16.7% - 18.3%) in group B (Fig.2). CR status after 90 days of therapy was evaluated as secondary endpoint. The proportion of patients in CR in the CSA [51% (95% CI: 42-61%)] was comparable to the 50% (95% CI: 47-54%) and 48% (95% CI: 41-55%) of the study group arms (p=n.s.). Persistent leukemia was seen in 16% (95% CI: 10-24%) in the CSA vs 17% (95% CI: 14-19%) and 12% (95% CI: 8-17%) in groups A and B, respectively (both p= n.s.). A total of 226 patients died within 90 days of treatment, 24% (95% CI: 17-33%) in CSA, 19% in group A (95% CI: 16-22%) and 27% (95% CI: 21-33%) in group B; CSA vs A p=0.1859, CSA vs B p=0.5902). Death without AML was 3% in CSA, 2% in group A and 3% in group B, death with AML was 9% in CSA, 6% in group A and 5% in group B and death from indeterminate cause was 12% in CSA, 11% in group A and 20% in group B. Three-year relapse free survival (RFS) was 21.3% (95% CI: 12.2 - 31.0) in the CSA, 28.9% (95% CI: 24.9 -33.0%) in group A and 24.0% (95% CI: 16.8 - 31.9) in group B (both p=n.s.; Fig.3). In multivariate analysis independent variables for EFS and OS were age, type of disease, cytogenetic group and WBC count, but not the allocation to one of the treatment arms. Age and cytogenetic group were determinants for RFS. Conclusion A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared to a common standard arm. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Niederwieser: Novartis Oncology Europe: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Hoffmann:Novartis Oncology Europe: Research Funding. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hegenbart:Pfizer: Other: Travel grant; Janssen: Honoraria, Other: Travel grant. Sayer:Riemser Pharma: Consultancy. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Fischer:Novartis: Consultancy, Honoraria. Dreger:Novartis: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Gilead: Speakers Bureau; Roche: Consultancy; Novartis: Speakers Bureau. Hiddemann:Roche: Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants; Roche: Other: Grants.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1066.1066

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 280-280

Abstract: Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML. The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients 〈 75 years receiving either CT or HCT. Probabilities for overall survival (OS) and leukemia free survival (LFS) were estimated according to the Kaplan-Meier method and differences tested by the log-rank test. Relapse incidence (RI) and non relapse mortality (NRM) were described by estimating the cumulative incidence and testing the differences using the Gray's test. Multivariate Cox regression models and competing risks regression models were used to identify independent prognostic variables for outcomes. The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p 〈 0.0005), respectively. There were no differences between CT and HCT regarding gender, AML type (de novo, secondary or therapy related) and FLT3 mutation status. However more patients with mutated NPM1 were observed in the CT as compared to the HCT group (39% vs 28%; p=0.07) and more patients entered into remission after one induction in the CT as compared to the HCT group (89% vs. 81%; p=0.05). Low risk cytogenetics and normal karyotype were present more frequently in the CT than in the HCT arm (p 〈 0.0005). The interval from CR to CT was 50 days and from CR to HCT 72 days (p 〈 0.0005). Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p 〈 0.0005). The difference was more distinct when only those patients with matched related or unrelated donors were compared to those receiving CT (36±6% vs. 13±4% at 8 years; p 〈 0.0005). Similar figures were obtained for overall survival [OS, 35±5% matched/mismatched HCT vs. 24±4% for CT (p=0.18) and 41±6% for matched HCT patients vs. 24±4% for CT (p=0.09)]. RI was lower after HCT (40±5%) than after CT (79±5%; p 〈 0.0001). In contrast, NRM was higher in HCT patients (28±7%) than in CT patients (9±11%; p 〈 0.0001). Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp. Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p 〈 0.01) with a trend for lower age (p=0.07) and HCT (p=0.14). Prognostic factors for RI were cytogenetics (p 〈 0.0006), FLT3 mutation status (p 〈 0.03) and HCT (p 〈 0.0005). NRM was influenced by HCT (p=0.002). Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.280.280

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 100, No. 9 ( 2021-09), p. 2387-2398

Abstract: Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17–85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of  〉  60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4–16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8–48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5–31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem.

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-021-04565-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 1458429-3

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3666-3666

Abstract: Purpose: To define prognostic factors for overall survival in adult patients (pts) with relapsed acute myeloid leukemia (AML). Introduction: Prognostic factors for overall survival after AML relapse are poorly defined. Here, we investigate patient and disease related factors in terms of their impact on prognosis after AML relapse in a cohort of 495 adult AML relapse patients treated in two prospective AML trials of the East German Society of Hematology and Oncology (OSHO). Patients and methods: We retrospectively evaluated all consecutive relapsed AML pts treated in two OSHO trials (OSHO #61 (pts 〈 60 years) and OSHO #69 (pts 〉 60 years)). Age, cytogenetic risk at initial diagnosis, FLT3/NPM1 mutational status, type of AML (de novo versus secondary to myelodysplastic syndrome or myeloproliferative neoplasia (MDS/MPN) versus therapy related), time interval from first complete remission (CR1) to relapse and allogeneic stem cell transplantation (alloSCT) as consolidation in CR1 were evaluated in univariate and multivariate analysis. Results: Between March 2002 and July 2014, a total of 862 and 968 patients (pts) were enrolled in the OSHO #61 and #69 trial, respectively. Five hundred and thirty two of 690 (77%) documented pts achieved first complete remission in the #61 and 501 of 813 (62%) pts in the #69 trial. Of these, 495 pts (252 male, 243 female) experienced AML relapse, 207(39%) pts in #61 and 288(57%) pts in #69. Median age at relapse was 63 years (range 18 to 86 years). Initial diagnoses were de novo AML, secondary AML to MDS/MPN and therapy related AML in 332(67%) pts, 129 (25.9%) pts and 30 (6%) pts, respectively. Time from CR1 to relapse was 〈 = 6 months in 198 (40%) pts, 7 to 18 months in 226 (45.7%) pts and 〉 18 months in 71 (14.3%) pts. Initial karyotpe was available for 449 pts (90.7 %). It was favorable, intermediate and poor in 20 (4.5%) pts, 301(67%) pts and 128(28.5%) pts, respectively. Sixty two (13.9%) relapsed pts had a monosomal karyotype at initial diagnosis. NPM1/FLT3 mutational status at initial diagnosis was available in 354 (78.8%) pts, 378 (71%) pts in #61 and 370 (74%) pts in #69. One hundred and three (20.8%) had allogeneic stem cell transplantation as consolidation in CR1 (56 pts) in #61 and (47 pts) in #69. Relapse therapy was documented in 450 (91%) pts. Six pts that had immunosuppression withdrawn as the only therapy and nine pts that had received a tyrosine kinase inhibitor as monotherapy were excluded from further analysis due to small numbers. All other treatments were as follows: intensive chemotherapy (INT) n=225, alloSCT with or without prior INT n=50, donor lymphocyte infusions (DLi) with or without prior chemotherapy n=22, palliative mild cytoreductive chemotherapy (mCT) n=66, azacitidine (Aza) n=52, best supportive care (BSC) n=20. With these, CR was achieved in 78 (36%), 34 (68%), 8 (36%), 6 (9%), 1 (2%), 0 (0%), respectively. Median overall survival probability (OS) for all 495 relapsed patients was 6 months. It was 11.3 months, 5.7 months, 4.5 months and 4.6 months for patients aged 18 to 50 years, 51 to 60 years, 61 to 70 years and 71 to 86 years, respectively (p 〈 0.0005). Initial cytogenetics also influenced OS, it was 10.4 months, 7.5 months and 3.8 months for patients with a favorable, intermediate and poor karyotype, respectively (p 〈 0.0005). Having a monosomal karyotype at initial diagnosis was associated with a median OS of only 2.3 months (p 〈 0.001). Initial FLT3/NPM1 mutational status had no impact on OS after relapse. OS was 4 months, 7.1 months and 16.9 months for pts with a time interval from CR1 to relapse of 〈 = 6 months, 7 to 18 months and 〉 18 months, respectively (p 〈 0.0005). In univariate analysis age (p 〈 0.0005), initial cytogenetic risk (p 〈 0.0005), type of AML (p=0.01), interval from CR1 to relapse (p 〈 0.0005), alloSCT in CR1 (p=0.03) and type of relapse therapy (p 〈 0.0005) had a significant impact on OS. In multivariate analysis favorable prognostic factors for OS were lower age (p 〈 0.0005), favorable initial cytogenetics (p=0.01), longer interval from CR1 to relapse (p 〈 0.0005) and not having undergone alloSCT in CR1. Conclusions: Our study shows that outcome of relapsed AML pts is poor. Younger age, favorable cytogenetics at initial diagnosis, a longer interval from CR1 to relapse and not having undergone alloSCT as consolidation in CR1 are positive prognostic factors, whereas type of AML and FLT3/NPM1 mutational status have no significant impact on survival after relapse. Disclosures Off Label Use: Azacitidine is licensed in Germany for the treatment of adult patients with the following conditions, who are not eligible for haematopoietic stem cell transplantation: intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder, acute myeloid leukaemia (AML) with 20-30% blasts and multi-lineage dysplasia,according to World Health Organisation (WHO) classification.. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Sayer:Takeda: Other; Medac: Other. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3666.3666

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 264-264

Abstract: Cytogenetic high risk AML (abn 3q26, abn 11q23, −5/5q-, −7/7q- and complex) has a dismal prognosis with a two year overall survival (OS) below 20% even in young patients. Attempts to improve survival by intensifying consolidation chemotherapy have so far failed. In the two OSHO protocols AML 96 and AML 2002, we investigated the role of allogeneic HCT in these patients. A total of 708 patients have been entered into the two studies between 1997 and the present. The first protocol (AML 96) compared two different schedules employing identical total dosages of intermediate AraC and Idarubicin. The second protocol (AML 2002) studied the role of two different induction therapies in patients failing to reach CR after the first induction therapy. In patients with cytogenetic high risk AML, the search for a donor (either familial or, if none available, then unrelated) was initiated as soon as possible. Allogeneic HCT was scheduled either after induction or after first consolidation therapy. HCT was performed after conditioning with cytoxan and 1200 cGy total body irradiation followed by GvH-D prophylaxis with cyclosporine and methotrexate. Of the 708 patients, 138 (19,5%) had high risk cytogenetics and 77 (55,8%) of these went into remission after one or two cycles of induction chemotherapy. Of these 77 patients, 54 were alive and in CR after the first consolidation therapy and were allocated to either related (n=12) or unrelated (n=21) HCT or, if no compatible donor was available, to a two courses of chemotherapy (n=21). Median age of the patients was 36 (range 17–51) years, 46 years (range 23–59) years and 49 (range 16–60) years for patients receiving related HCT, unrelated HCT and chemotherapy respectively. Data were analysed as intention to treat.LFS at 3 years was 67 ± 14% after related and 44 ± 14 % after unrelated HCT, but decreased to 11 ± 7% in patients receiving chemotherapy. Allogeneic HCT results were significantly better than the results of chemotherapy with p-values of 0.005 and 0.002 for related vs. chemotherapy and unrelated vs. chemotherapy respectively. Major differences in relapse incidences were seen between the three groups, with the lowest RI at 3 years after related HCT 26±0.13%, followed by unrelated HCT 48±15% and by chemotherapy 89±8% (p=0.003 and p=0,0006 for chemotherapy vs. related or unrelated HCT). Transplant related mortality at 3 years was 10±9%, 14±10% and 6±6% for patients receiving HCT from related donors, from unrelated donors and chemotherapy, respectively. Conclusions: From the results observed in the two prospective, multicenter studies we conclude that consolidation with allogeneic HCT is superior to chemotherapy in younger patients with high risk cytogenetics. While no differences in TRM were seen between the three treatment arms, a lower relapse incidence after related and unrelated HCT contributed to the improved OS.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.264.264

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. e18501-e18501

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2016.34.15_suppl.e18501

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2016

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3664-3664

Abstract: The incidence of acute myeloid leukemia (AML) is age-dependent with the majority of patients (pts) being older than 60 years at diagnosis. Treatment of these pts needs to be well balanced between sufficient efficacy and tolerable toxicity. Here, we report long term follow-up of the OSHO AML97 study. Pts with AML older than 60 years were registered after informed consent and received age-adapted intensive chemotherapy treatment (curative arm; induction therapy with AraC 2 g/m2 iv day 1, 3, 5, 7 and mitoxantrone 10 mg/m2 iv day 1 to 3 to induce complete remission (CR), followed by 2 consolidation courses with AraC 240 mg/m2 iv day 1 to 5 and mitoxantrone 10 mg/m2 iv day 1 to 2), low dose chemotherapy (palliative arm; idarubicin 10 mg po day 1 and either thioguanine 40 mg po day 1-5, or AraC 80 mg sc day 1-5 or etoposide 100mg po day 1-5) or supportive therapy (best supportive care including transfusions). A total of 618 pts were enrolled (curative arm n=471, palliative treatment n=115 and supportive therapy n=32 pts). In the curative arm, CR was obtained in 66.8% of pts. Treatment related mortality (TRM) was 11.2% after induction and 4.5% after consolidation I, respectively. Median overall survival for all pts in the curative arm was 12 months, event free survival (EFS) at 12 years was 0.11±0.02%. In multivariate analysis, cytogenetics at diagnosis was the most important prognostic factor for CR (p=0.001). With a median follow up of 10 years (range 0.1 - 11.8) probability of overall survival (OS) at 5 years was 0.48±0.11; 0.13±0.03; 0.10±0.04 and 0.08±0.03 for pts with favorable, normal, other and unfavorable cytogenetics. Median survival for pts treated with palliative chemotherapy was 54 days. In conclusion treatment of older AML pts with an intense dose of AraC in the induction therapy is feasible and able to induce high rates of CR. Nevertheless, despite the high CR rate in this setting OS and EFS are still low. However, importantly, this does not apply for patients with favorable cytogenetics. This result also confirms the need for cytogenetic analysis to be performed in all pts older than 60 years potentially eligible for intensive induction therapy. The treatment results with palliative chemotherapy are disappointing. These results reported here need to be set in relation with the new therapeutic modalities for AML including epigenetic and molecular therapies. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3664.3664

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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

URL: Article

DOI: 10.1182/blood.V108.11.1921.1921

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2645-2645

Abstract: The optimal consolidation chemotherapy in AML patients 〉 60 years has yet to be defined in detail. Although age-adjusted induction chemotherapy results in CR rates comparable to those in younger patients, relapse remains the major hurdle to successful treatment. While the role of stem cell transplantation (HSCT) in elderly patients is currently being evaluated in randomized studies, we focus here on the intensity of consolidation chemotherapy. Patients data from the elderly AML trials OSHO 1997 (n=410) and OSHO 2004 (n=733) were pooled and analyzed. These protocols have identical inclusion/exclusion criteria and induction chemotherapy, but differ in the intensity of consolidation therapy. In the OSHO 1997 trial, Ara-C 120 mg/m2 bid was given from day 1-5 and mitoxantrone 10 mg/m2 from day 1-2 as consolidation. In the OSHO 2004 an intensified consolidation using Ara-C 500 mg/m2 bid on day 1/3/5 was applied together with mitoxantrone as used in the OSHO 1997 study. Of the 1143 patients, 689 entered CR (60% in the OSHO 1997 and 61% in the OSHO 2004) and 536 (OSHO 1997, n=242, OSHO 2004, n=294) did not receive HSCT as consolidation. The analysis concentrated on the dose of AraC used in the consolidation for this elderly population and on the cycles of consolidation applied. Patient characteristics were compared using chi-square test for categorical data and Wilcoxon rank sum test for continuous data. OS was analyzed using the Kaplan-Meier method, and univariate comparisons were made by means of the log-rank test. Cox regression was used to find any association between consolidation chemotherapy considered as a time-dependent covariate on Overall Survival (OS) or Relapse Incidence (RI). RI and Non Relapse Mortality (NRM) were calculated using the competing risk method, and the Gray test was applied to compare differences. Multivariate modeling was performed by Cox regression analyses with a forward selection method. Median ages in the AML studies were 66 (60-81) years and 69 (60-85) years for the OSHO 1997 and OSHO 2004, respectively. Patients characteristics were balanced except for age and Karnofsky score (p 〈 .0005) and a trend towards more intermediate and high risk karyotypes, more female and less WBC in the OSHO 2004 compared to the OSHO 1997 study (p=0.06). OS at 15 years was 14±2% in all patients with no difference between the two consolidations, but strong dependence on cytogenetic risk factors. In multivariate analyses risk factors for survival were high/intermediate risk karyotypes, male gender, non de-novo AML and less than two consolidations. Patients with two consolidations had better OS than patients with one or no consolidations in the pooled group and in each of the two protocols with no difference between OSHO 1997 and OSHO 2004. Relapse incidence amounted to 79±2% and NRM 10±04% at 15 years with no difference between the two protocols. Relapse incidence was dependent upon cytogenetic risk and the number of consolidations applied in a multivariate model. There were no risk factors predicting TRM in multivariate analysis. Our analysis of patient characteristics according to the number of consolidations showed the distribution of consolidation therapies to be 15.2%, 28.0%, 56.6% and 14.2%, 32.3% and 53.4% for 0, 1 and 2 consolidations in the OSHO 1997 and OSHO 2004 respectively (n.s.). Higher age, higher risk cytogenetics, non-de novo AML type, less CR after one induction cycle and lower WBC count at diagnosis were characteristic of patients receiving none or one as compared to two consolidation therapies. The multivariate analysis revealed cytogenetics and gender as independent risk factors, but not the application of one as opposed to two consolidation treatments. The increase of AraC dose in the OSHO 2004 was unable to either increase survival or improve relapse incidence in the cohort of elderly patients. TRM was not different between the OSHO 1997 and 2004 studies. However, the application of one or two consolidation cycles had a significant impact on survival that was not due to decreased relapse incidence after normalization for risk factors. Interestingly, just above 50% of patients received 2 consolidations as proposed in the protocol with no statistically significant difference between OSHO 1997 and OSHO 2004. Patients receiving fewer consolidation therapy cycles are older, have more non-de novo AML and lower WBC count. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2645.2645

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7