Richard F. Schlenk

Individual Patient Data–Based Meta-Analysis of Patients Aged 16 to 60 Years With Core Binding Factor Acute Myeloid Leukemia: A Survey of the German Acute Myeloid Leukemia Intergroup

PURPOSEnTo evaluate prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in adult patients with core binding factor (CBF) acute myeloid leukemias (AML).nnnPATIENTS AND METHODSnIndividual patient data-based meta-analysis was performed on 392 adults (median age, 42 years; range, 16 to 60 years) with CBF AML (t(8;21), n = 191; inv(16), n = 201) treated between 1993 and 2002 in prospective German AML treatment trials.nnnRESULTSnRFS was 60% and 58% and OS was 65% and 74% in the t(8;21) and inv(16) groups after 3 years, respectively. For postremission therapy, intention-to-treat analysis revealed no difference between intensive chemotherapy and autologous transplantation in the t(8;21) group and between chemotherapy, autologous, and allogeneic transplantation in the inv(16) group. In the t(8;21) group, significant prognostic variables for longer RFS and OS were lower WBC and higher platelet counts; loss of the Y chromosome in male patients was prognostic for shorter OS. In the inv(16) group, trisomy 22 was a significant prognostic variable for longer RFS. For patients who experienced relapse, second complete remission rate was significantly lower in patients with t(8;21), resulting in a significantly inferior survival duration after relapse compared with patients with inv(16).nnnCONCLUSIONnWe provide novel prognostic factors for CBF AML and show that patients with t(8;21) who experience relapse have an inferior survival duration.

Quantification of CBFβ/MYH11 fusion transcript by Real Time RT-PCR in patients with INV(16) acute myeloid leukemia

Amplification of the CBFβ/MYH11 fusion transcript by a qualitative reverse transcription-polymerase chain reaction (RT-PCR) has been used to detect minimal residual disease (MRD) and assess the risk for disease relapse in inv(16)(p13q22) acute myeloid leukemia (AML). This strategy has, however, produced conflicting results and because of an uncertain predictive value, its use in the clinical setting cannot be recommended. The objective of the current study was to evaluate if quantification by Real Time RT-PCR could be useful to determine levels of CBFβ/MYH11 fusion transcripts predictive of clinical outcome in inv(16)(p13q22) AML at diagnosis or during remission. Bone marrow (BM) samples from 16 patients with inv(16) AML enrolled on a German multicenter trial (AML HD93) were analyzed for levels of CBFβ/MYH11 fusion transcripts by Real Time RT-PCR at diagnosis (nu2009=u200914), during remission (nu2009=u200910) and at relapse (nu2009=u20096). The CBFβ/MYH11 transcript copy number in each sample was normalized to copies of an internal control housekeeping transcript (ie 18S). The copy number measured at diagnosis or relapse were 3 to 4 log higher that those measured during remission, following completion of induction treatment. A high CBFβ/MYH11transcript copy number at diagnosis had a significant correlation with a high percentage of BM blasts (Spearmans coefficientu2009=u2009−0.66; Pu2009=u20090.03), and a borderline correlation with a short complete remission (CR) duration (Spearmans coefficientu2009=u2009−0.51; Pu2009=u20090.07). No difference in levels of CBFβ/MYH11 fusion transcripts measured during intensification therapy was found between patients destined to relapse and those who continued in CCR (Pu2009=u20090.75). Following completion of the entire chemotherapy program, patients that during CR showed a CBFβ/MYH11 fusion transcript copy number >10 had a significantly shorter CR duration (Pu2009=u20090.002) and higher risk for disease relapse (Pu2009=u20090.05) than patients with a CBFβ/MYH11fusion transcript copy number <10. The results of the current study, therefore, suggest that it is possible to determine in remission samples a threshold of CBFβ/MYH11 transcript copy number above which relapse occurs and below which continuous CR is likely.

Less intense conditioning with fludarabine, cyclophosphamide, idarubicin and etoposide (FCIE) followed by allogeneic unselected peripheral blood stem cell transplantation in elderly patients with leukemia

The objective of this study was to assess toxicity and feasibility of achieving engraftment of allogeneic blood progenitor cells following nonmyeloablative conditioning according to the FCIE protocol (fludarabine 25 mg/m2/day, days −7 to −3; cyclophosphamide 200 mg/m2/day, days −7 to −3; idarubicin 12 mg/m2/day, days −7 to −5; etoposide 250 mg/m2/day, days −4 to −3) in elderly patients with leukemia. Eleven patients were included in the study: six patients with acute myeloid leukemia (AML) in complete remission (CR); three patients with refractory or relapsed AML; one patient with chronic myeloid leukemia; one patient with acute lymphoblastic leukemia. The median age of the patients was 62 years. All patients received blood progenitor cells from an HLA-identical sibling with 8.8 × 106 CD34+ cells/kg (median; range 4.7 to 26.2 × 106/kg) and 5.5 × 108 CD3+cells/kg (median; range 4.5 to 7.9 × 108/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and three courses of methotrexate. The median duration of white blood cell counts <1 × 109/l was 17 days and of platelet counts <50 × 109/l 20 days. In two patients acute GVHD grade I occurred. Nine of 10 patients analyzed developed mixed chimerism. Of seven patients transplanted in CR, three remained in CR 19 to 31 months after transplantation. Three patients with refractory leukemia did not achieve CR, while the patient with relapsed AML achieved a 3rd CR. After a median follow-up time of 22 months, chronic GVHD was mild and limited. The data from this pilot study in elderly patients with leukemia show that the combination of primarily immunosuppressive (FC) and antileukemic (IE) drugs for nonmyeloablative conditioning has moderate nonhematological toxicity and allows engraftment of allogeneic blood progenitor cells.

Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis.

We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.

Deletion of the multidrug resistance-associated protein ( MRP1 ) gene in acute myeloid leukemia with inversion of chromosome 16 has no prognostic impact

Deletion of the multidrug resistance-associated protein ( MRP1 ) gene in acute myeloid leukemia with inversion of chromosome 16 has no prognostic impact

Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO)

We describe genetic and clinical characteristics of acute myeloid leukemia (AML) patients according to age from an academic population-based registry. Adult patients with newly diagnosed AML at 63 centers in Germany and Austria were followed within the AMLSG BiO registry (NCT01252485). Between January 1, 2012, and December 31, 2014, data of 3525 patients with AML (45% women) were collected. The median age was 65xa0years (range 18–94). The comparison of age-specific AML incidence rates with epidemiological cancer registries revealed excellent coverage in patients <xa070xa0years old and good coverage up to the age of 80. The distribution according to the European LeukemiaNet (ELN) risk categorization from 2010 was 20% favorable, 31% intermediate-1, 28% intermediate-2, and 21% adverse. With increasing age, the relative but not the absolute prevalence of patients with ELN favorable and intermediate-1 risk (pxa0<xa00.001), with activating FLT3 mutations (pxa0<xa00.001), with ECOG performance status <xa02 (pxa0<xa00.001), and with HCT-CI comorbidity index <xa03 (pxa0<xa00.001) decreased. Regarding treatment, obesity and favorable risk were associated with an intensive treatment, whereas adverse risk, higher age, and comorbidity index >xa00 were associated with non-intensive treatment or best supportive care. The AMLSG BiO registry provides reliable population-based distributions of genetic, clinical, and treatment characteristics according to age.