Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients

Röllig, Christoph; Kramer, Michael; Gabrecht, Maria; Hänel, Mathias; Herbst, Regina; Kaiser, Ulrich; Schmitz, Norbert; Kullmer, Johannes; Fetscher, Sebastian; Link, Hartmut; Mantovani-Löffler, Luisa; Krümpelmann, Ulrich; Neuhaus, Thomas J.; Heits, Frank; Einsele, Hermann; Ritter, Barbara; Bornhäuser, Martin; Schetelig, Johannes; Thiede, Christian; Mohr, Brigitte; Schaich, Markus; Platzbecker, Uwe; Schäfer‐Eckart, Kerstin; Krämer, Alwin; Berdel, Wolfgang E.; Serve, Hubert; Ehninger, Gerhard; Schuler, Ulrich S.

doi:10.1093/annonc/mdy030

Cited by 28 publications

(22 citation statements)

References 13 publications

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“…The protocols were registered for prospective trials of the Study Alliance Leukemia (SAL) with NCT numbers 00180115 (AML96), 00180102 (AML2003), 00180167 (AML601), and 00893373 (SORAML). Detailed descriptions of the treatment protocols have been published previously; [31][32][33][34] all protocols included intensive induction chemotherapy and consolidation treatment. AML was defined as de novo when no previous malignancy and no previous treatment were reported.…”

Section: Patientsmentioning

confidence: 99%

Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

et al. 2021

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The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11 mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11 mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11 mutations were associated with concomitant mutations in NPM1 (63%), DNMT3A (37%), and NRAS (21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P < .001) and higher white blood cell counts (P = .007) compared with PTPN11 wild-type patients. In a multivariable analysis, PTPN11 mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P < .001), relapse-free survival (HR: 1.52; P = .013), and a lower rate of complete remission (odds ratio: 0.46; P = .008). Importantly, the deleterious effect of PTPN11 mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11 mutations (HR: 2.28; P < .001) but not found with dominant PTPN11 mutations (HR: 1.07; P = .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11 mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur.

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Section: Patientsmentioning

confidence: 99%

Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

et al. 2021

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“…High dose daunorubicin improved the 3‐year OS for NPM1 , DNMT3A and MLL rearranged AML patients (44.2% of the study cohort) from 25% to 44% . The CR rates with induction chemotherapy in newly diagnosed elderly AML patients have been discouraging, with numbers ranging from 40% to 50% in different studies . Our study results are superior with >75% of patients achieving a CR with one cycle of induction in both younger and elderly populations.…”

Section: Discussionmentioning

confidence: 64%

“…In younger age group, dose intensifications of “7 + 3” have achieved CR rates approaching 60‐80% in different studies with increased 5‐year OS rates ranging from 40 to 50% . However, in the elderly, despite the improvements in CR rates with dose intensifications, the OS rates have been dismal due to increased treatment‐related mortality (TRM) . In 2010, Kantarjian et al reported on more than 400 elderly (>70 years) AML patients treated with various induction regimens at their center.…”

Section: Introductionmentioning

confidence: 99%

Elderly do benefit from induction chemotherapy: High dose mitoxantrone‐based (“5 + 1”) induction chemotherapy regimen in newly diagnosed acute myeloid leukemia

et al. 2018

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An intensive "5 + 1" regimen, which included bolus high dose cytarabine (HiDAC) at 3 g/m 2 once daily over 3 hours on days 1-5 and high dose mitoxantrone (HDM) 80 mg/m 2 on day 2, was evaluated in 101 consecutively treated newly diagnosed acute myeloid leukemia (AML) patients at a single center since 2009. The median age was 65 (range 18-90) years. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%), respectively. The overall response (complete remission [CR] + CRi) was 76.2% (77/101). The median overall survival (OS) stratified by age group <60, 60-69 and ≥70 years were 56, 31 and 9 months respectively (log-rank, P = 0.02). 51.7% (45/84) of patients with intermediate/adverse risk category proceeded to allogeneic stem cell transplants. Among these 84 patients, the percentage of patients able to proceed to transplant in age groups <60, 60-69, and ≥ 70 years were 75% (18/24), 60.7% (17/28), and 31.2% (10/32), respectively. In conclusion, HDM-based chemotherapy regimen produces high CR rates, is well tolerated and more patients can undergo curative postremission therapy including stem cell transplant.in treating AML in the elderly age group and during the local shortage of daunorubicin in 2011, we substituted mitoxantrone for daunorubicin for all newly diagnosed AML patients. The induction regimen consisted of a once-daily dose of HiDAC 3 g/m2 given for 5 days combined with a single HDM 80 mg/m 2 on the second day ("5 + 1"). In a phase I study of this combination, reversible hyperbilirubinemia was the dose-limiting toxicity observed in 25% of all patients. 9 In 2006, Seiter et al. 10 published a 12-year follow-up of HDM-based induction for newly diagnosed AML patients from their institution.A total of 165 patients received HDM with high dose Ara-C over a period from 1991 to 2003. In a subset of patients, who would be eligible for most US trials, the CR rate was 84% in younger patients and 60% in older patients. The median OS was 19.4 and 7.6 months in younger and older patients, respectively.Here, we describe our experience with long-term follow-up of the first 101 patients treated with HDM-based induction regimen at our institution with a particular emphasis on elderly patients. | PATIENTS AND METHODS | Study groupA total of 101 patients who changed our institutional protocol to treat all newly diagnosed AML patients with "5 + 1" HDM and HiDAC induction chemotherapy. All patients were confirmed to have AML based on a bone marrow or peripheral blood myeloblasts count of ≥20%. Patients with a diagnosis of acute promyelocytic leukemia were excluded. The study was approved by the Institutional Review Board

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“…Eligibility criteria were newly diagnosed AML according to WHO definitions [ 29 ], age ≥ 18 years, and available biomaterial at diagnosis. All patients were treated with intensive regimens in the following clinical trials: AML96 [ 30 ], AML2003 [ 31 ], AML60+ [ 32 ], and SORAML [ 33 ] or were enrolled in the German Study Alliance Leukemia (SAL)’s AML registry (NCT03188874). Detailed information on treatment regimens is given in the respective references.…”

Section: Methodsmentioning

confidence: 99%

Loss-of-Function Mutations of BCOR Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia

Stasik

Kramer

Röllig

et al. 2021

Cancers

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Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.

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Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients

Cited by 28 publications

References 13 publications

Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

Elderly do benefit from induction chemotherapy: High dose mitoxantrone‐based (“5 + 1”) induction chemotherapy regimen in newly diagnosed acute myeloid leukemia

Loss-of-Function Mutations of BCOR Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia

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