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Baseline cytogenetics and disease status are key factors predicting the outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML). The importance of cytogenetic risk in patients with primary refractory or relapsed (R/R) AML undergoing haploidentical (Haplo) HCT is unknown. We studied the impact of cytogenetic risk in patients with R/R de novo AML with active disease who underwent non-T-cell–depleted Haplo-HCT with post-transplantation cyclophosphamide from 2010 to 2020. Four hundred forty patients with active disease at transplantation from the European Society for Blood and Marrow Transplantation database were analyzed (291 [66.1%] with intermediate-risk [AMLint] and 149 [44.1%] with adverse-risk cytogenetics [AMLadv]). Impact of baseline cytogenetic risk on various transplantation outcomes was evaluated. Pre-transplantation disease status was relapse in 48.1% and 26.8% and primary refractory in 51.9% and 73.2% of the patients with AMLint and AMLadv, respectively (P< .0001). Two-year leukemia-free survival (LFS, 35.5% versus 15.5%, P = .001) and overall survival (OS, 39.2% versus 20.1%, P = .001) were better in AMLint versus AMLadv. In multivariate analysis, the relapse rate was significantly higher (hazard ratio [HR] = 2.17 [95% confidence interval {CI} 1.57-3.0]) and LFS (HR = 1.71 [95% CI, 1.31-2.22]) and OS (HR = 1.69 [95% CI, 1.29-2.22]), significantly lower for patients with AMLadv compared to AMLint, conditioning intensity did not affect leukemia relapse rate. Non-relapse mortality (HR = 1.1 [95% CI, 0.7-1.74]) and graft-versus-host disease–free, relapse-free survival (HR = 1.37 [95% CI, 1.06-1.77]) did not differ significantly between the risk groups. Disease status before transplant (primary refractory versus relapsed) or conditioning intensity did not impact main transplant outcomes. Baseline cytogenetic risk remains a key prognostic factor for patients with R/R AML with persistent disease before non-T-cell–depleted Haplo-HCT.

There are no data indicating whether the number of induction courses needed to achieve first complete remission (CR1) is of prognostic significance in Haploidentical transplantation (HaploSCT). We compared transplantation outcomes of adults with AML that underwent HaploSCT in CR1, achieved following one or two induction courses. A total of 635 patients were included: 469 (74%) with 1 and 166 (26%) with two induction chemotherapy courses. A total of 429 (91.5%) and 151 (91%) patients had de novo AML and 40 (8.5%) and 15 (9%) had secondary AML (p= 0.84). Engraftment rates were 97.2 and 97.6%. Day 180 incidence of acute GVHD II-IV and III-IV was similar in both induction groups (31.1 and 34.8%, and 10 and 10.6 %), as was 2–4 year total and extensive chronic GVHD (33.7 and 36.5 %, and 12.2 and 12.1%), respectively. Two-year relapse incidence (RI) was higher while leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were inferior for patients achieving CR1 with 2 vs 1 course and were 29.1% vs 15.1%, 88 (p= 0.001), 56.2% vs 66.9% (p= 0.03), 58.8% vs 72.2% (p= 0.044) and 44% vs 55.6% (p= 0.013), respectively. Non-relapse mortality (NRM) did not differ, 18% vs 14.6% 90 (p= 0.25). These results were confirmed by multivariate analysis.

Introduction:Relapsed/Refractory (R/R) FLT3-mutated AML is a challenging clinical scenario with a dismal outcome. Gilteritinib, a selective and potent oral FLT3 tyrosine kinase inhibitor (TKI), is approved for treatment of FLT3 mutated R/R AML, and was shown to improve response rates and overall survival (OS) as compared to standard chemotherapy (Perl et al, NEJM 2019). However, remission rates and long-term survival with gilteritinib monotherapy are still unsatisfactory, highlighting the need for new therapies to improve patient outcomes.

Introduction:Sporadic cases of concomitant acute cytomegalovirus (CMV) infection and thrombosis have been reported several times in the past. However,the incidence of thrombosis among patients with acute CMV infection has never been studied. Moreover, since acute CMV infection is common, it might be diagnosed in patients suffering from thrombosis without actually triggering it.Aim: To study the incidence of thrombosis among patients with acute CMV infection hospitalized in a tertiary medical center. Among these patients, we compare the incidence of CMV-induced thrombosis with that of CMV-accompanied thrombosis.Methods: Medical charts and imaging study reports of all patients diagnosed with acute CMV infection during the years 2005-2006 were reviewed for the presence of thrombosis and for its acquired as well as inherited predisposition.Results: Overall 160 patients were diagnosed with acute CMV infection during the years 2005-2006. Six (3.8%) of these patients were diagnosed concomitantly with thrombosis. Of these patients, four were immunocompromised. Either the acute CMV infection or the thrombosis was diagnosed incidentally in all of these patients. Acquired predispositions for thrombosis, other than acute CMV infection, were present in four of them. Hence, the incidence of CMV-induced thrombosis and CMV-accompanied thrombosis was 1.3% and 2.5%, respectively. Conclusions: Though thrombosis among patients with acute CMV infection is not rare, it is unclear whether CMV actually triggered thrombosis in most of these cases. A case controlled study is needed to confirm the association between acute CMV infection and thrombosis. Keywords: Cytomegalovirus | Ganciclovir | Thrombosis, Introduction Concomitant acute cytomegalovirus (CMV) infection and thrombosis has been reported several times in medical literature. Though mainly seen in immunocompromised patients, it has been reported in immunocompetent patients as [...]

Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITDstatus has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITDstatus. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITDstatus was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITDto baseline cytogenetics in patients undergoing allo-HSCT.

Acute leukemia is an aggressive blood malignancy with low survival rates. A high expression of stem-like programs in leukemias predicts poor prognosis and is assumed to act in an aberrant fashion in the phenotypically heterogeneous leukemia stem cell (LSC) population. A lack of suitable genome engineering tools that can isolate LSCs based on their stemness precludes their comprehensive examination and full characterization. We hypothesized that tagging endogenous stemness-regulatory regions could generate a genome reporter for the putative leukemia stemness-state. Our analysis revealed that the ERG +85enhancer region can serve as a marker for stemness-state and a fluorescent lentiviral reporter was developed that can accurately recapitulate the endogenous activity. Using our novel reporter, we revealed cellular heterogeneity in several leukemia cell lines and patient-derived samples. Alterations in reporter activity were associated with transcriptomic and functional changes that were closely related to the hematopoietic stem cell (HSC) identity. Notably, the differentiation potential was skewed towards the erythro-megakaryocytic lineage. Moreover, an ERG +85Highfraction of AML cells could regenerate the original cellular heterogeneity and was enriched for LSCs. RNA-seq analysis coupled with in silico drug-screen analysis identified 4HPR as an effective inhibitor of ERG +85Highleukemia growth. We propose that further utilization of our novel molecular tool will identify crucial determinants of LSCs, thus providing a rationale for their therapeutic targeting.

FLAMSA followed by sequential reduced intensity conditioning and treosulfan/fludarabine are frequently used conditioning approaches used in centers of the European Society for Blood and Marrow Transplantation (EBMT) for older patients with acute myeloid leukemia (AML). It is currently unknown whether any of these regimens is superior to the others in terms of disease control and toxicity. Using the Acute Leukemia Working Party/EBMT multicenter registry we compared the outcomes of AML patients 45–65 of age transplanted between the years 2007 and 2016. A total of 629 patients were included in the analysis: 281 in the Treo/Flu group, 203 in the FLAMSA/TBI group, and 145 in the FLAMSA/Busulfan group. In multivariate analysis, FLAMSA/TBI conditioned patients had a decreased risk of relapse (hazard ratio (HR) = 0.43; 95% confidence interval (CI), 0.25–0.75; p= 0.002) and superior leukemia-free survival (HR = 0.67; 95% CI, 0.45–0.98; p= 0.042) compared to Treo/Flu conditioned patients. Rates of acute graft-versus-host disease (GVHD) were significantly higher in the FLAMSA/TBI group compared to the Treo/Flu group (HR = 2.004; 95% CI, 1.09–3.67; p= 0.024). Overall survival, non-relapse mortality, and chronic GVHD were not significantly impacted by the specific regimen used. The choice of either FLAMSA/TBI, FLAMSA/Bu, or Treo/Flu results in no major impact on survival of older AML patients.

Relapse has become the leading cause of treatment failure after stem cell transplantation. Besides cellular therapies and novel agents, immunotherapeutic strategies have entered clinical practice in order to reduce or prevent relapse. Here, we summarize the presentations on checkpoint inhibitors, vaccination strategies, and novel antibody therapies, which were presented and discussed at the third International Workshop on Biology, Prevention, and Treatment of Relapse after Stem Cell Transplantation.

Background:

Avigdor: Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding.

Canaani: Abbvie: Consultancy, Honoraria, Research Funding. Benjamini:Abbvie Inc: Consultancy, Research Funding. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.

Wolach: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy. Levi:Abbvie Inc: Consultancy, Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Tavor:Abbvie: Consultancy, Honoraria, Research Funding. Hellmann:Abbvie: Research Funding. Stemer:Abbvie: Research Funding. Cohen:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Afik:Abbvie Inc: Current equity holder in publicly-traded company. Ofek:Abbvie Inc: Current Employment. Banayan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Kan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Grunspan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Ofran:AbbVie: Membership on an entity's Board of Directors or advisory committees. Moshe:Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

Cytokine-induced expansion of hematopoietic stem and progenitor cells (HSPCs) is not fully understood. In the present study, we show that whereas steady-state hematopoiesis is normal in basic fibroblast growth factor (FGF-2)–knockout mice, parathyroid hormone stimulation and myeloablative treatments failed to induce normal HSPC proliferation and recovery. In vivo FGF-2 treatment expanded stromal cells, including perivascular Nestin+ supportive stromal cells, which may facilitate HSPC expansion by increasing SCF and reducing CXCL12 via mir-31 up-regulation. FGF-2 predominantly expanded a heterogeneous population of undifferentiated HSPCs, preserving and increasing durable short- and long-term repopulation potential. Mechanistically, these effects were mediated by c-Kit receptor activation, STAT5 phosphorylation, and reduction of reactive oxygen species levels. Mice harboring defective c-Kit signaling exhibited abrogated HSPC expansion in response to FGF-2 treatment, which was accompanied by elevated reactive oxygen species levels. The results of the present study reveal a novel mechanism underlying FGF-2–mediated in vivo expansion of both HSPCs and their supportive stromal cells, which may be used to improve stem cell engraftment after clinical transplantation.

To determine the role of bone marrow biopsy (BMBX), performed in association with comprehensive blood and imaging tests, in the evaluation of patients with fever of unknown origin (FUO).

Background. Early mortality remains a challenging therapeutic facet of the initial induction phase of intensive chemotherapy in patients with acute myeloid leukemia (AML). The impact of standard molecular evaluation and risk category of the European LeukemiaNet (ELN) 2017 classification model on early mortality have not been rigorously evaluated thus far.

Background:Achievement of initial remission remains the most important clinical factor predicting long term survival in acute myeloid leukemia (AML) patients treated with intensive chemotherapy. Yet, whether the patient subset in need of a second cycle of intensive induction chemotherapy to reach remission experiences inferior outcomes compared to patients reaching remission after a single cycle of therapy, remains uncertain with previous publication showing diverging outcomes with respect to patient survival and the risk for disease relapse (Rowe et al. Cancer2010; Othus et al. Leukemia2016). In this analysis we aimed to readdress this important clinical question in a uniform cohort of recently treated patients.

Background:

The recently introduced Bayer wide-range C-reactive protein (wr-CRP) assay might be relevant for the real-time low-cost and online determination of inflammatory bowel disease (IBD) activity. Our aim was to examine whether wr-CRP can substitute for the Dade Behring high sensitivity C-reactive protein (hs-CRP) assay in IBD patients.

•In matched sibling donor allogeneic hematopoietic cell transplantation, post-transplantation cyclophosphamide (PTCy) was associated with lower rates of acute and chronic graft-versus-host disease (GVHD) compared with cyclosporine A (CSA)/methotrexate (MTX).•GVHD-free relapse-free survival, leukemia-free survival, and overall survival were comparable in the PTCy and CSA/MTX arms.•In matched-pair analysis, PTCy was associated with a higher risk of relapse risk.

Savani: Jazz Pharmaceuticals: Speakers Bureau. Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty: Sanofi: Honoraria, Speakers Bureau.

Background

Introduction:A major mechanism of clinical response to FLT3tyrosine kinase inhibitors (TKIs) is the induction of terminal granulocytic differentiation of leukemic blasts (Sexauer, et al. Blood 2012). However, the clinical activity of many FLT3TKIs is limited by novel, treatment-emergent activating mutations in FLT3that confer in vitroresistance–particularly substitutions at D835 in the tyrosine kinase domain (TKD) activation loop and the so-called “gatekeeper” residue F691. Gilteritinib (ASP2215) is a highly potent and selective oral inhibitor of FLT3that is active against both FLT3-internal tandem duplication (ITD) and TKD mutations and is currently in phase 3 trials. As a single agent, gilteritinib shows significant clinical activity in relapsed/refractory (R/R) FLT3-mutated AML (Perl, et al. Lancet Oncol 2017), but mechanisms of therapeutic resistance have yet to be systematically described. We therefore analyzed the serial morphologic and genetic data of patients treated with gilteritinib to better characterize response and identify treatment-emergent genetic alterations associated with disease progression.

No relevant conflicts of interest to declare.

Loren: Merck: Research Funding. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Frey:Novartis: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding.

No relevant conflicts of interest to declare.