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•Little data is available on Quality of Life (QoL) of patients with AML treated with decitabine.•Current QoL findings support the use of lower intensity decitabine, compared to the current standard of care in fit older patients with AML.

•More older patients with AML remain MRD positive after decitabine treatment compared to intensive chemotherapy.•Survival after transplantation is comparable in older patients with AML who were treated with chemotherapy or decitabine.•Pre-transplant MRD is not predictive for survival in older patients with AML treated with decitabine, in contrast to those treated with intensive chemotherapy.

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)–adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.

Interleukin-1α (IL-1α) and IL-1β are potent inflammatory cytokines that activate local and systemic inflammatory processes and are involved in protective immune responses against infections. However, their dysregulated production and signaling can aggravate tissue damage during infection, inflammatory diseases, and chemotherapy-induced intestinal mucositis. Additionally, cytokines of the IL-1 family play an important role in homeostatic as well as “emergency” hematopoiesis and are involved in the pathogenesis of several myeloid and lymphoid hematological malignancies. In the pathogenesis of intestinal mucositis and graft-versus-host disease (GVHD), these cytokines are considered pivotal during the initiation as well as propagation phase, and insights from animal studies suggest that targeting the IL-1 pathway can significantly ameliorate mucositis and GVHD. Moreover, IL-1α and IL-1β might prove to be valuable targets for both prevention and treatment of cancer and cancer therapy–related complications, and the first clinical studies have already been performed in the setting of hematological malignancies. In this review, we will discuss the role of cytokines of the IL-1 family in hematological malignancies, chemotherapy-induced intestinal mucositis, and GVHD, and speculate on possibilities of therapeutically targeting the IL-1 pathway in hematological patients.

Host-pathogen interactions at epithelial barriers play an important role in health and disease. This also applies to the clinical setting of stem cell transplantation (SCT) in which deregulated sensing of microbes and their cell wall components by pattern recognition receptors (PRRs) can contribute to inflammatory and infectious complications. The role of Candida species herein has recently been rediscovered since a 'loss-of-function' Y238X polymorphism in dectin-1, a C-type lectin receptor recognizing the β-1,3-glucan motif of Candida,resulted in diminished membrane expression and lower cytokine responses upon β-1,3-glucan recognition, and was associated with increased Candida colonization of SCT recipients, rendering them at risk for candidaemia. In addition, Candida colonization was associated with an increased incidence of acute graft-versus-host disease (GvHD), but only in those individuals with the wild-type dectin-1 allele. The Th17 mediated immune responses might provide a common link in these processes, as they have recently been implicated in anti-Candidaimmunity as well as the pathogenesis of GvHD. These new insights suggest that immunogenetics could contribute to a more individualized risk-based strategy for managing SCT recipients, for example concerning antifungal prophylaxis. In addition, modulating host-pathogen interactions by selectively modulating PRR activity could be exploited in SCT to achieve better outcomes.

Clofarabine (CLO) is a nucleoside analogue with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase III study aimed to evaluate whether CLO added to induction and consolidation would improve outcome in adults with newly diagnosed ALL.Treatment for younger (18-40 years) patients consisted of a pediatric inspired protocol and for older patients (41-70 years) of a semi-intensive protocol was used. 340 patients were randomized. After a median follow up of 70 months,5-year EFS was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, while in patients >40 years EFS was 43% in both arms. CR rate was 89% in both arms and similar in younger and older patients.Minimal residual disease (MRD) was assessedin 200 patients (60%).Fifty-fourof 76evaluable patients(71%) were MRD negative after consolidation 1 in arm A vs 75/81 (93%) in arm B (p=0.001). Seventy (42%) patients proceeded to allogeneic hematopoietic stemcell transplantation in both arms. Five years OS was similar in both arms, 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and non-relapse mortality was 16% vs 17% after CR. CLO treated patients experienced more serious adverse events, moreinfections, and more often went off-protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD-negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity.The trial is registered at www.trialregister.nl as NTR2004.

Meyer: Stanford University: Patents & Royalties. Marks:Pfizer: Honoraria. Lübbert:Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding. Scheid:Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work. Kobbe:Celgene: Honoraria, Other: travel support, Research Funding; Jansen: Honoraria, Other: travel support. Negrin:Stanford University: Patents & Royalties. Brune:Meda Pharma: Consultancy. Mielke:JAZZ Pharma: Speakers Bureau; Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Gilead: Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau. Kuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Peschel:MophoSys: Honoraria. von Bubnoff:BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding.

Efficace: TEVA: Consultancy, Research Funding; Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; Lundbeck: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; Roche: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau.

*The 2 first authors contributed equally to the work.

We have previously reported on the efficacy of the JAK1/2 inhibitor ruxolitinib in corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) in 95 patients (pts) (Leukemia 2015;29(10):2062-8). To assess long-term follow-up results, we collected data from the same pts treated in 19 centers in Europe and the US. Pts were classified as SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). Median numbers of pre-ruxolitinib GVHD treatment lines were 3 (1-7) and 3 (1-10) for SR-aGVHD and SR-cGvHD, respectively. The median follow-up was 19 and 24 months for aGVHD and cGVHD, respectively.

Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematological malignancies due to graft-versus-tumor (GVT) responses. This, however, is often accompanied by graft-versus-host disease (GVHD). Both the GVT effect and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. Here, we evaluated whether MiHA mismatches are associated with clinical outcome after partial T cell depleted allo-SCT.We retrospectively analyzed the impact of MiHA mismatches in a cohort of 327 patients who received a partially T cell-depleted allo-SCT because of a hematological malignancy. MiHA allele genotyping was performed by fluorescence-based competitive allele-specific PCR. Subsequently, a multivariable statistical analysis of immunogenic MiHA disparity rates and association with clinical outcome was performed. In addition, development of MiHA-specific T cell responses was assessed by dual-color tetramer staining.Statistical analysis revealed that an autosomal MiHA disparity on DNA level associates with increased relapse-free survival in sibling transplants, especially in patients transplanted for multiple myeloma. In addition, mismatches for the ubiquitous Y chromosome-encoded MiHA resulted in more acute GVHD (grade 3–4), while other MiHA mismatches, either ubiquitous or restricted to hematopoietic cells, were not associated with GVHD. Finally, we demonstrated considerable differences between MiHA in the capability to induce in vivo T cell responses post-transplantation.These data support that autosomal MiHA contribute to the induction of GVT immunity providing a rationale for MiHA-based post-transplantation immunotherapy to prevent and treat persistent and recurrent cancer following allo-SCT.No relevant conflicts of interest to declare.

Abstract 4136

No relevant conflicts of interest to declare.

Abstract 4498