Challenges in Treating Older Patients with Acute Myeloid Leukemia

Whereas in younger patients diagnosed with acute myeloid leukemia (AML) treatment is straightforward and the goal is cure, the optimal treatment decision for older adults remains highly controversial. Physicians need to determine whether palliation, “something” beyond palliation, intensive therapy, or an investigational therapy is the most appropriate treatment option. This requires understanding of the biology and risk profile of the AML, clinical judgment in evaluating the functional status of the patient, communication skills in understanding the patient's wishes and social background, and medical expertise in available therapies. The physician has to accurately inform the patient about (a) the unique biological considerations of his leukemia and his prognosis; (b) the risks and benefits of all available treatment options; (c) novel therapeutic approaches and how the patient can get access to these treatments. Last but not least, he has to recommend a treatment. This paper tries to discuss each of these issues

Marrow versus Blood-Derived Stem Cell Grafts for Allogeneic Transplantation from Unrelated Donors in Patients with Active Myeloid Leukemia or Myelodysplasia

Peripheral blood stem cells (PBSCs) are increasingly used as the graft source in allogeneic hematopoietic cell transplantation. We compared long-term outcome after unrelated donor transplantation of 85 consecutive patients with acute myelogenous leukemia or myelodysplastic syndrome regarding disease status (early disease [CR1, refractory anemia); n = 25 and advanced/active disease [>CR1, >refractory anemia]; n = 60) who were treated with conventional conditioning regimens followed by bone marrow (BM) or PBSC grafts. Graft-versus-host disease prophylaxis consisted mainly of cyclosporine A, short-course methotrexate, and anti-T-lymphocyte globulin. After a median follow-up of 118 months (68-174), the 10-year event-free survival rate after peripheral blood stem cell transplantation (PBSCT) was 54.8% (95% confidence interval [CI], 39.7%-69.8%), and after bone marrow transplantation (BMT), it was 27.9% (14.5%-41.3%; P < .004). In the advanced/active disease group, the 10-year event-free survival rate after PBSCT was 50% (30.8%-69.2%), and after BMT, it was 23.5% (9.3%-37.8%; P < .007). Non relapse mortality was less after PBSCT than BMT (14.3% vs 30.2%), respectively. In multivariate Cox regression analysis, PBSCT showed a better overall survival (OS; hazard ratio [HR], 0.43; 95% CI, 0.23-0.79; P = .007) compared to BMT; unfavorable/unknown prognostic impact cytogenetic abnormalities were an adverse factor for all patients (HR, 2.202; 95% CI, 1.19-4.06; P = .011). In patients with advanced disease, the use of PBSCs showed a significant favorable outcome via multivariate analysis (HR, 0.49; 95% CI, 0.24-0.99; P = .046). Outcome of acute myelogenous leukemia/myelodysplastic syndrome after unrelated hematopoietic cell transplantation is adversely affected by cytogenetic abnormalities and state of remission at hematopoietic cell transplantation. PBSC as a graft source has a significant favorable influence on survival

Fatty acid-related modulations of membrane fluidity in cells: detection and implications

Metabolic homeostasis of fatty acids is complex and well-regulated in all organisms. The biosynthesis of saturated fatty acids (SFA) in mammals provides substrates for ?-oxidation and ATP production. Monounsaturated fatty acids (MUFA) are products of desaturases that introduce a methylene group in cis geometry in SFA. Polyunsaturated fatty acids (n-6 and n-3 PUFA) are products of elongation and desaturation of the essential linoleic acid and ?-linolenic acid, respectively. The liver processes dietary fatty acids and exports them in lipoproteins for distribution and storage in peripheral tissues. The three types of fatty acids are integrated in membrane phospholipids and determine their biophysical properties and functions. This study was aimed at investigating effects of fatty acids on membrane biophysical properties under varying nutritional and pathological conditions, by integrating lipidomic analysis of membrane phospholipids with functional two-photon microscopy (fTPM) of cellular membranes. This approach was applied to two case studies: first, pancreatic beta-cells, to investigate hormetic and detrimental effects of lipids. Second, red blood cells extracted from a genetic mouse model defective in lipoproteins, to understand the role of lipids in hepatic diseases and metabolic syndrome and their effect on circulating cells

Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years — a registry-based study by the Acute Leukemia Working Party of the EBMT

Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens based on ≥12 Gray total body irradiation (TBI) represent the current standard in patients ≤45 years, whereas elderly patients frequently receive intermediate intensity conditioning (IIC) to reduce toxicity. To evaluate the role of TBI as a backbone of IIC in ALL, a retrospective, registry-based study included patients >45 years transplanted from matched donors in first complete remission, who had received either fludarabine/TBI 8 Gy (FluTBI8, n = 262), or the most popular, irradiation-free alternative fludarabine/busulfan, comprising busulfan 6.4 mg/kg (FluBu6.4, n = 188) or 9.6 mg/kg (FluBu9.6, n = 51). At two years, overall survival (OS) was 68.5%, 57%, and 62.2%, leukemia-free survival (LFS) was 58%, 42.7%, and 45%, relapse incidence (RI) was 27.2%, 40%, and 30.9%, and non-relapse-mortality (NRM) was 23.1%, 20.7%, and 26.8% for patients receiving FluTBI8Gy, FluBu6.4, and FluBu9.6, respectively. In multivariate analysis, the risk of NRM, acute and chronic graft-versus-host disease was not influenced by conditioning. However, RI was higher after FluBu6.4 (hazard ratio [HR] [95% CI]: 1.85 [1.16–2.95]), and LFS was lower after both FluBu6.4 (HR: 1.56 [1.09–2.23]) and FluBu9.6 (HR: 1.63 [1.02–2.58]) as compared to FluTBI8. Although only resulting in a non-significant advantage in OS, this observation indicates a stronger anti-leukemic efficacy of TBI-based intermediate intensity conditioning

Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m(2) (FluMel) and fludarabine/treosulfan 42 g/m(2) (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.Peer reviewe

Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donors

Background Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD. Methods Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis Results No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis. Conclusion These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.Peer reviewe

Plasma and Serum Metabolite Association Networks: Comparability within and between Studies Using NMR and MS Profiling

Blood is one of the most used biofluids in metabolomics studies, and the serum and plasma fractions are routinely used as a proxy for blood itself. Here we investigated the association networks of an array of 29 metabolites identified and quantified via NMR in the plasma and serum samples of two cohorts of ∼1000 healthy blood donors each. A second study of 377 individuals was used to extract plasma and serum samples from the same individual on which a set of 122 metabolites were detected and quantified using FIA–MS/MS. Four different inference algorithms (ARANCE, CLR, CORR, and PCLRC) were used to obtain consensus networks. The plasma and serum networks obtained from different studies showed different topological properties with the serum network being more connected than the plasma network. On a global level, metabolite association networks from plasma and serum fractions obtained from the same blood sample of healthy people show similar topologies, and at a local level, some differences arise like in the case of amino acids

Reduced 8-Gray compared to standard 12-Gray Total Body Irradiation for allogeneic transplantation in first remission acute lymphoblastic leukemia: a study of the Acute Leukemia Working Party of the EBMT

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray

Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3 internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in 25-30% of patients with acute myeloid leukemia . Because of the poor prognosis associated with FMS-like tyrosine kinase 3 internal tandem duplication mutated Acute myeloid leukemia, allogeneic-hematopoietic stem-cell transplantation was commonly performed in first complete remission. Remarkable progress has been made in frontline treatments with the incorporation of FLT3 inhibitors and the development of highly sensitive minimal/measurable residual disease assays. Similarly, recent progress in allogeneic-hematopoietic stem-cell transplantation includes improvement of transplant techniques, the use of haplo-identical donors in patients lacking an HLA matched donor, and the introduction of FLT3 inhibitors as posttransplant maintenance therapy. Nevertheless, current transplant strategies vary between centers and differ in terms of transplant indications based on the internal tandem duplication allelic ratio and concomitant nucleophosmin-1 mutation, as well as in terms of post-transplant maintenance/consolidation. This review generated by international leukemia or transplant experts, mostly from the European Society for Blood and Marrow Transplantation, attempts to develop a position statement on best approaches for allogeneic-hematopoietic stem-cell transplantation for acute myeloid leukemia with FMS-like tyrosine kinase internal tandem duplication including indications and modalities of allogeneic-hematopoietic stem-cell transplantation and on potential optimization of post-transplant maintenance with FMS-like tyrosine kinase inhibitors