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Abstract Background Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood. Methods To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines. Results In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7—most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or −7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66–3.86]; P

Abstract Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000–2004) and last (2015–2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5–35%, LFS: 14.5–24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2.

Two new diagnostic classifications of acute myeloid leukemia (AML) were published in 2022 to update current knowledge on disease biology. In previous 2017-edition categories of AML with myelodysplasia-related changes, AML was not otherwise specified, but AML with mutated RUNX1 experienced profound changes. We performed whole exome sequencing on a cohort of 69 patients with cytogenetic intermediate-risk AML that belonged to these diagnostic categories to correlate their mutational pattern and copy-number alterations with their new diagnostic distribution. Our results show that 45% of patients changed their diagnostic category, being AML myelodysplasia-related the most enlarged, mainly due to a high frequency of myelodysplasia-related mutations (58% of patients). These showed a good correlation with multilineage dysplasia and/or myelodysplastic syndrome history, but at the same time, 21% of de novo patients without dysplasia also presented them. RUNX1 was the most frequently mutated gene, with a high co-occurrence rate with other myelodysplasia-related mutations. We found a high prevalence of copy-neutral loss of heterozygosity, frequently inducing a homozygous state in particular mutated genes. Mild differences in current classifications explain the diagnostic disparity in 10% of patients, claiming a forthcoming unified classification.

In recent years, major advances in the understanding of acute myeloid leukemia (AML) pathogenesis, together with technological progress, have led us into a new era in the diagnosis and follow-up of patients with AML. A combination of immunophenotyping, cytogenetic and molecular studies are required for AML diagnosis, including the use of next-generation sequencing (NGS) gene panels to screen all genetic alterations with diagnostic, prognostic and/or therapeutic value. Regarding AML monitoring, multiparametric flow cytometry and quantitative PCR/RT-PCR are currently the most implemented methodologies for measurable residual disease (MRD) evaluation. Given the limitations of these techniques, there is an urgent need to incorporate new tools for MRD monitoring, such as NGS and digital PCR. This review aims to provide an overview of the different technologies used for AML diagnosis and MRD monitoring and to highlight the limitations and challenges of current versus emerging tools.

Abstract Background Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still difficult to manage. Thus, new therapeutic approaches are needed. Based on in silico-generated preliminary data and the literature, the role of the prolactin (PRL)-mediated signaling was interrogated in AML. Methods Protein expression and cell viability were determined by flow cytometry. Repopulation capacity was studied in murine xenotransplantation assays. Gene expression was measured by qPCR and luciferase-reporters. SA-β-Gal staining was used as a senescence marker. Results The prolactin receptor (PRLR) was upregulated in AML cells, as compared to their healthy counterpart. The genetic and molecular inhibition of this receptor reduced the colony-forming potential. Disruption of the PRLR signaling, either using a mutant PRL or a dominant-negative isoform of PRLR, reduced the leukemia burden in vivo, in xenotransplantation assays. The expression levels of PRLR directly correlated with resistance to cytarabine. Indeed, acquired cytarabine resistance was accompanied with the induction of PRLR surface expression. The signaling associated to PRLR in AML was mainly mediated by Stat5, in contrast to the residual function of Stat3. In concordance, Stat5 mRNA was significantly overexpressed at mRNA levels in relapse AML samples. A senescence-like phenotype, measured by SA-β-gal staining, was induced upon enforced expression of PRLR in AML cells, partially dependent on ATR. Similar to the previously described chemoresistance-induced senescence in AML, no cell cycle arrest was observed. Additionally, the therapeutic potential of PRLR in AML was genetically validated. Conclusions These results support the role of PRLR as a therapeutic target for AML and the further development of drug discovery programs searching for specific PRLR inhibitors.

Abstract Midostaurin added to intensive chemotherapy is the standard of care for acute myeloid leukemia (AML) with FLT3 mutations (FLT3mut). We analyzed the impact of midostaurin in 227 FLT3mut-AML patients included in the AML-12 prospective trial for fit patients ≤70 years (#NCT04687098). Patients were divided into an early (2012–2015) and late (2016–2020) cohorts. They were uniformly treated except for the addition of midostaurin in 71% of late group patients. No differences were observed in response rates or the number of allotransplants between groups. Outcome was improved in the late period: 2-year relapse incidence decreased from 42% vs 29% in early vs late group (p = 0.024) and 2-year overall survival (OS) improved from 47% vs 61% (p = 0.042), respectively. The effect of midostaurin was evident in NPM1mut patients (n = 151), with 2-yr OS of 72% (exposed) vs 50% (naive) patients (p = 0.011) and mitigated FLT3-ITD allelic ratio prognostic value: 2-yr OS with midostaurin was 85% and 58% in low and high ratio patients (p = 0.049) vs 67% and 39% in naive patients (p = 0.005). In the wild-type NPM1 subset (n = 75), we did not observe significant differences between both study periods. In conclusion, this study highlights the improved outcome of FLT3mut AML fit patients with the incorporation of midostaurin.

Chimeric antigen receptor (CAR) T therapies are being developed for acute myeloid leukemia (AML) on the basis of the results obtained for other haematological malignancies and the need of new treatments for relapsed and refractory AML. The biggest challenge of CART therapy for AML is to identify a specific target antigen, since antigens expressed in AML cells are usually shared with healthy haematopoietic stem cells (HSC). The concomitant expression of the target antigen on both tumour and HSC may lead to on-target/off-tumour toxicity. In this review, we guide researchers to design, develop, and translate to the clinic CART therapies for the treatment of AML. Specifically, we describe what issues have to be considered to design these therapies; what in vitro and in vivo assays can be used to prove their efficacy and safety; and what expertise and facilities are needed to treat and manage patients at the hospital.

Abstract Background The ZBTB16‐RARA fusion gene, resulting from the reciprocal translocation between ZBTB16 on chromosome 11 and RARA genes on chromosome 17 [t(11;17)(q23;q21)], is rarely observed in acute myeloid leukemia (AML), and accounts for about 1% of retinoic acid receptor‐α (RARA) rearrangements. AML with this rare translocation shows unusual bone marrow (BM) morphology, with intermediate aspects between acute promyelocytic leukemia (APL) and AML with maturation. Patients may have a high incidence of disseminated intravascular coagulation at diagnosis, are poorly responsive to all‐trans retinoic acid (ATRA) and arsenic tryoxyde, and are reported to have an overall poor prognosis. Aims The mutational profile of ZBTB16‐RARA rearranged AML has not been described so far. Materials and methods We performed targeted next‐generation sequencing of 24 myeloid genes in BM diagnostic samples from seven ZBTB16‐RARA+AML, 103 non‐RARA rearranged AML, and 46 APL. The seven ZBTB16‐RARA‐positive patients were then screened for additional mutations using whole exome sequencing (n = 3) or an extended cancer panel including 409 genes (n = 4). Results ZBTB16‐RARA+AML showed an intermediate number of mutations per patient and involvement of different genes, as compared to APL and other AMLs. In particular, we found a high incidence of ARID1A mutations in ZBTB16‐RARA+AML (five of seven cases, 71%). Mutations in ARID2 and SMARCA4, other tumor suppressor genes also belonging to SWI/SNF chromatin remodeling complexes, were also identified in one case (14%). Discussion and conclusion Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16‐RARA+AMLs, where they may support the peculiar disease phenotype.

CART19 cells are emerging as an alternative therapy for patients with chronic lymphocytic leukemia (CLL). Here we report the outcome of nine consecutive patients with CLL treated with ARI-0001 CART19 cells, six of them with Richter’s transformation (RT). One patient with RT never received therapy. The cytokine release syndrome rate was 87.5% (12.5% grade ≥3). Neurotoxicity was not observed in any patient. All patients experienced absolute B-cell aplasia, and seven (87.5%) responded to therapy. With a median follow-up of 5.6 months, two patients with RT experienced a CD19-negative relapse. In conclusion, ARI-0001 cell therapy was feasible, safe, and effective in patients with high-risk CLL or RT.

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1–10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95–2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8–1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.

Background: Despite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies. Methods: An in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene signature. Hit compounds were validated in AML cell lines. Cytotoxic effects were assessed both in primary AML patient samples and healthy donor blood cells. Xenotransplantation assays were undertaken to determine the effect on engraftment of hit compounds. The mechanism of action responsible for the antileukaemic effect was studied focussing on lysosomes and mitochondria. Findings: We identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukaemic cells. ANHAs behaved as antileukaemic agents against primary AML samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired the in vivo leukaemia regeneration capacity. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition. Interpretation: Dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for leukaemia treatment, supporting the further clinical development. Fund: This work was funded by the Fundación Mutua Madrileña (RMR), CaixaImpulse (RMR), the Spanish Ministry of Economy (RMR), the Josep Carreras International Leukaemia Foundation (RMR), l'Obra Social “La Caixa” (RMR), and Generalitat de Catalunya (IJC). Keywords: Leukaemia, Antihistamines, Ebastine, Lysosomes, Mitochondria

Core binding factor acute myeloid leukemia (AML) comprises two subtypes with distinct cytogenetic abnormalities of either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22). Since long-term response to chemotherapy in these leukemias is relatively good, allogeneic hematopoietic stem cell transplantation is considered in patients who relapse and achieve second complete remission. To evaluate the outcomes of allogeneic transplantation in this indication, we studied 631 patients reported to the European Society for Blood and Marrow Transplantation Registry between the years 2000 and 2014. Leukemia-free survival probabilities at two and five years were 59.1% and 54.1%, while overall survival probabilities were 65% and 58.2%, respectively. The incidence of relapse and risk of non-relapse mortality at the same time points were 19.8% and 22.5% for relapse and 20.9% and 23.3% for non-relapse mortality, respectively. The most important adverse factors influencing leukemia-free and overall survival were: leukemia with t(8;21), presence of three or more additional chromosomal abnormalities, and Karnofsky performance score

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in 25-30% of patients with acute myeloid leukemia (AML). Because of the poor prognosis associated with FLT3-internal tandem duplication mutated AML, allogeneic hematopoietic stem-cell transplantation (SCT) 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 SCT includes improvement of transplant techniques, the use of haploidentical donors in patients lacking an HLA matched donor, and the introduction of FLT3 inhibitors as post-transplant 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 nucleophos-min-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 SCT for AML with FLT3-internal tandem duplication including indications for and modalities of such transplants and on the potential optimization of post-transplant maintenance with FLT inhibitors.

Background Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.Methods We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs.Results Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs.Conclusions This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.

Deletion 5q or monosomy 5 (-5/5q-) in acute myeloid leukemia (AML) is a common high-risk feature that is referred to allogeneic stem cell transplantation. However, -5/5q- is frequently associated with other high-risk cytogenetic aberrations such as complex karyotype, monosomal karyotype, monosomy 7 (-7), or 17p abnormalities (abn (17p)), the significance of which is unknown. In order to address this question, we studied adult patients with AML harboring -5/5q- having their first allogeneic transplantation between 2000 and 2015. Five hundred and one patients with -5/5q- have been analyzed. Three hundred and thirty-eight patients (67%) were in first remission and 142 (28%) had an active disease at time of allogeneic transplantation. The 2-year probabilities of overall survival and leukemia-free survival were 27% and 20%, respectively. The 2-year probability of treatment-related mortality was 20%. We identified four different cytogenetic groups according to additional abnormalities with prognostic impact: -5/5q- without complex karyotype, monosomal karyotype or abn(17p), -5/5q- within a complex karyotype, -5/5q- within a monosomal karyotype and the combination of -5/5q- with abn(17p). In multivariate analysis, factors associated with worse overall survival and leukemia-free survival across the four groups were active disease, age, monosomal karyotype, and abn(17p). The presence of -5/5q- without monosomal karyotype or abn(17p) was associated with a significantly better survival rate while -5/5q- in conjunction with monosomal karyotype or abn(17p) translated into a worse outcome. The patients harboring the combination of -5/5q- with abn(17p) showed very limited benefit from allogeneic transplantation.

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.

Abstract: Patients with secondary AML (sAML) with antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs) tend to have high-risk disease based on the older age of patients, high-risk cytogenetics, and higher number of prior treatments. Allogeneic hematopoietic cell transplant (HCT) is the only potentially curative therapy available. Eight hundred and two adults with sAML and prior MDS/MPN who received a first HCT between 2000 and 2016 were included in the European Society for Blood and Marrow Transplant (EBMT) Acute Leukemia Working Party (ALWP) study. Median age of the cohort was 59.6 years (range, 18.6-78.6 years). Myeloablative conditioning (MAC) was given to 40% of patients, and 60% received reduced-intensity conditioning (RIC). Overall, the 2-year cumulative incidence of relapse (RI) was 37%, leukemia-free survival (LFS) was 40%, overall survival (OS) was 46%, nonrelapse mortality (NRM) was 23%, and chronic graft-versus-host disease (cGVHD) was 39%. In univariate analysis, a statistical difference between conditioning regimens 6 months after HCT in favor of the MAC group was noted with regard to RI (hazard ratio [HR], 1.47; P = .03), LFS (HR, 1.43; P = .01), and OS (HR, 1.55; P < .05). There was no difference in the cumulative incidence of NRM (HR, 1.38; P = .15). This effect was similarly seen in multivariate analysis (MVA): cumulative incidence of relapse (HR, 1.79; P < .05), LFS (HR, 1.43; P = .02), and OS (HR, 1.53; P = .005) with no difference in NRM (HR, 1; P = .98). This EBMT ALWP analysis suggests that long-term survival can be achieved in patients with sAML with antecedent MDS/MPN and that MAC is a suitable conditioning regimen in patients with sAML.

Acute lymphoblastic leukaemia (ALL) in adults has a survival rate of 40–50% at 5 years, with a high relapse rate after first-line chemotherapy. After relapse, results with salvage therapy are currently unsatisfactory. Therefore, both the optimisation of front-line therapy to reduce relapse incidence and the search for effective salvage therapies for relapsed/refractory (r/r) ALL have been of great interest to the medical community in recent years. The well-characterised expression of well-defined cell-surface antigens in B cell ALL (B)-ALL and T cell (T)-ALL, such as CD19, CD20, CD22, and CD52, has led to the development of several immunotherapy strategies, comprising ‘nude’ monoclonal antibodies (moAbs), conjugated moAbs, bispeciphic, or highly sophisticated chimeric antigen receptor (CAR)-T cell therapy. Recently, both the bispecific moAb blinatumomab (anti-CD19 coupled with a CD3 recognition subunit) and the conjugated anti-CD22 moAb inotuzumab-ozogamicin have resulted in higher remission rates (44% versus 25%, and 80.7% versus 29.4%, respectively) and survival advantages (median overall survival [OS]: 7.7 months versus 4 months, and 7.7 months versus 6.7 months, respectively) in patients with r/r B-ALL when compared to standard salvage chemotherapy-based regimens. On the other hand, preliminary reports show feasibility and unprecedented response rates of ≤90% in highly refractory children and adults treated with CAR-modified T cells targeting the B cell specific CD19 antigen, which seem to be durable in a significant proportion of patients. Furthermore, the addition of anti-CD20 moAb rituximab to front-line standard chemotherapy in patients with CD20+ B-ALL has resulted in a clinical benefit, with prolongation of response duration and survival (3-year leukaemia-free survival and OS: 70% versus 38%; p

Abstract Background Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. Methods The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors (n = 660) versus unrelated donors (n = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. Conclusions HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients’ outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated.

Abstract Background Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option. Methods To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. Results One hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54 years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients’ age. Conclusions In contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1.

Acute myeloid leukemia (AML) with FLT3-mutation carries a poor prognosis, and allogeneic stem cell transplantation (allo-SCT) is recommended at first complete remission (CR1). We assessed 462 adults (median age 50 years) with FLT3-mutated AML allografted between 2010 and 2015 from a matched related (40%), unrelated (49%), or haploidentical donor (11%). The median follow-up of alive patients was 39 months. Day-100 acute graft versus host disease (GVHD) grades II–IV and III–IV were encountered in 26% and 9%, whereas the 2-year incidence of chronic and extensive chronic GVHD were 34% and 16%, respectively. The 2-year incidences of relapse and nonrelapse mortality were 34% and 15%, respectively. The 2-year leukemia-free survival, overall survival (OS), and GVHD relapse-free survival (GRFS) were 51%, 59%, and 38%, respectively. In multivariate analysis, NPM1-mutation, transplantation in CR1, in vivo T-cell depletion, and posttransplant sorafenib improved OS, whereas more than one induction (late CR1) negatively affected OS. Similarly, NPM1-mutation, a haploidentical donor, T-cell depletion, and sorafenib maintenance improved GRFS, whereas late CR1 or persistent disease negatively affected it. In conclusion, FLT3-mutated AML remains a challenge even following allo-SCT. In vivo T-cell depletion and posttransplant sorafenib significantly improve OS and GRFS, and may be considered as standard of care.

Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P

OBJECTIVES:We assess the epidemiology and risk factors for mortality of bloodstream infection (BSI) in patients with acute leukemia (AL). METHODS:Prospectively collected data of a cohort study from July 2004 to February 2016. Multivariate analyses were performed. RESULTS:589 episodes of BSI were documented in 357 AL patients, 55% caused by gram-positive bacteria (coagulase-negative staphylococci 35.7%, Enterococcus spp 10.8%) and 43.5% by gram-negative bacteria (E. coli 21%, PA 12%). We identified 110 (18.7%) multidrug-resistant (MDR) microorganisms, especially MDR-Pseudomonas aeruginosa (7%) and extended-spectrum beta-lactamase producing Enterobacteriaceae (7%). The 30-day mortality was 14.8%. Age (OR 3.1; 95% CI 1.7-5.7); chronic lung disease (4.8; 1.1-21.8); fatal prognosis according to McCabe index (13.9; 6.4-30.3); shock (3.8; 1.9-7.7); pulmonary infection (3.6; 1.3-9.9); and MDR-PA infections with inappropriate treatment (12.8; 4.1-40.5) were related to mortality. MDR-PA BSI was associated to prior antipseudomonal cephalosporin use (9.31; 4.38-19.79); current use of betalactams (2.01; 1.01-4.3); shock (2.63; 1.03-6.7) and pulmonary source of infection (9.6; 3.4-27.21). CONCLUSIONS:MDR organisms were commonly isolated in BSI in AL. Inappropriate empiric antibiotic treatment for MDR-PA is the primary factor related to mortality that can be changed. New treatment strategies to improve the coverage of MDR-PA BSI should be considered in those patients with risk factors for this infection.

Mixed phenotype acute leukemias are infrequent and considered high risk. The optimal treatment approach and the role of allogeneic hematopoietic stem cell transplantation are not entirely clear. In this study, we investigated 519 patients with mixed phenotype acute leukemia in first complete remission who underwent allogeneic hematopoietic stem cell transplantation between 2000 and 2014, and who were reported to the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Median age was 38.1 years (range 18–75). Cytogenetics classified 49.3% as poor risk. At three years, relapse incidence was 31.4% (26.9–35.9), non-relapse mortality was 22.1% (18.4–26.1), the leukemia-free survival was 46.5% (41.7–51.4), and the overall survival was 56.3% (51.5–61.2). At six months, 32.5% had developed acute graft-versus-host disease, while at three years, 37.5% had developed chronic graft-versus-host disease (32.6–42.3). In a multivariate analysis, age and year of transplant had a strong impact on outcome. Myeloablative conditioning using total body irradiation correlated with a better leukemia-free survival. Our study suggests that mixed phenotype acute leukemia is potentially sensitive to graft-versus-leukemia and thus can benefit from allogeneic hematopoietic stem cell transplantation with a potential for cure.

Allogeneic blood or marrow hematopoietic cell transplantation continues to be the most potent anti-leukemic treatment for adult patients with standard, high-risk, or chemo-refractory acute myeloid leukemia. Until recently, this procedure was generally limited to those recipients who had an available matched-sibling donor or matched-unrelated donor. Technical advances in graft cell processing and manipulation, control of bidirectional T cell alloreactivity, graft-versus-host disease prophylaxis, and other supportive measures in haploidentical transplantation now enable nearly all patients with acute myeloid leukemia to benefit from the graft-versus-leukemia effect with substantial reduction in procedure-related mortality. Over recent years, haploidentical donors have been increasingly adopted as a valid donor source in allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the absence of an HLA-matched donor. Among centers of the European Society for Blood and Marrow Transplantation, the use of haploidentical related donor transplantation has increased by 250% since 2010, and 291% since 2005. On behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize recent utilization trends in haploidentical transplantation for acute myeloid leukemia and describe the transformative changes in haploidentical hematopoietic cell transplantation techniques over the past decade, which have led to the current widespread use of this procedure. Furthermore, we review the efficacy of haploidentical hematopoietic cell transplantation for acute myeloid leukemia from available studies, including preliminary comparative studies, and bring attention to remaining unanswered questions and directions for future research. We conclude this report with our recommendations for the role of haploidentical hematopoietic cell transplantation in acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation is increasingly used as treatment for patients with life-threatening blood diseases. Its curative potential is largely based on immune-mediated graft-versus-leukemia effects caused by donor T cells contained in the graft. Unfortunately, donor T cells are also the cause of graft-versus-host disease. The vast majority of human leukocyte antigen-matched allogeneic hematopoietic stem cell transplants are nowadays carried out with peripheral blood stem cells as the stem cell source. In comparison with bone marrows, peripheral blood stem cells contain more hematopoietic stem/progenitor cells but also one log more T cells. Consequently, the use of peripheral blood stem cells instead of bone marrow has been associated with faster hematologic recovery and a lower risk of relapse in patients with advanced disease, but also with a higher incidence of chronic graft-versus-host disease. These observations have been the basis for several studies aimed at assessing the impact of immunoregulation with anti-thymocyte globulin on transplantation outcomes in patients given human leukocyte antigen-matched peripheral blood stem cells from related or unrelated donors. After a brief introduction on anti-thymocyte globulin, this article reviews recent studies assessing the impact of anti-thymocyte globulin on transplantation outcomes in patients given peripheral blood stem cells from human leukocyte antigen-matched related or unrelated donors as well as in recipients of grafts from human leukocyte antigen haploidentical donors.

The outcome of patients undergoing HLA-matched unrelated donor allogeneic hematopoietic cell transplantation following reduced-intensity conditioning or myeloablative regimens is reported to be equivalent; however, it is not known if the intensity of the conditioning impacts outcomes after mismatched unrelated donor transplantation for acute myeloid leukemia. Eight hundred and eighty three patients receiving reduced-intensity conditioning were compared with 1041 myeloablative conditioning regimen recipients in the setting of mismatched unrelated donor transplantation. The donor graft was HLA-matched at 9/10 in 872 (83.8%) and at 8/10 in 169 (16.2%) myeloablative conditioning recipients, while in the reduced-intensity conditioning cohort, 754 (85.4%) and 129 (14.6%) were matched at 9/10 and 8/10 loci, respectively. Myeloablative conditioning regimen recipients were younger, 70% being

Increasing numbers of patients are receiving reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation. We hypothesized that the use of bone marrow graft might decrease the risk of graft-versus-host disease compared to peripheral blood after reduced intensity conditioning regimens without compromising graft-versus-leukemia effects. Patients who underwent reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation from 2000 to 2012 for acute leukemia, and who were reported to the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation were included in the study. Eight hundred and thirty-seven patients receiving bone marrow grafts were compared with 9011 peripheral blood transplant recipients after reduced intensity conditioning regimen. Median follow up of surviving patients was 27 months. Cumulative incidence of engraftment (neutrophil ≥0.5×109/L at day 60) was lower in bone marrow recipients: 88% versus 95% (P

Despite the overall benefit from allogeneic hematopoietic stem cell transplantation observed in patients with poor cytogenetic risk acute myeloid leukemia in first complete remission, the precise effect of this procedure for different poor-risk subtypes has not been fully analyzed. This retrospective analysis was performed to investigate whether allogeneic hematopoietic stem cell transplantation performed in first complete remission in patients with monosomal karyotype can overcome the adverse prognosis associated with these patients. Of the 4635 patients included in the study, 189 (4%) harbored a monosomal karyotype. The presence of a monosomal karyotype was associated with a worse outcome, with an inferior leukemia-free survival and overall survival (5-year leukemia-free survival and overall survival: 24±3% and 26±3% vs. 53±1% and 57±1% in monosomal-karyotype and non-monosomal-karyotype, respectively; P

Models for prediction of allogeneic hematopoietic stem transplantation (HSCT) related mortality partially account for transplant risk. Improving predictive accuracy requires understating of prediction limiting factors, such as the statistical methodology used, number and quality of features collected, or simply the population size. Using an in-silico approach (i.e., iterative computerized simulations), based on machine learning (ML) algorithms, we set out to analyze these factors. A cohort of 25,923 adult acute leukemia patients from the European Society for Blood and Marrow Transplantation (EBMT) registry was analyzed. Predictive objective was non-relapse mortality (NRM) 100 days following HSCT. Thousands of prediction models were developed under varying conditions: increasing sample size, specific subpopulations and an increasing number of variables, which were selected and ranked by separate feature selection algorithms. Depending on the algorithm, predictive performance plateaued on a population size of 6,611-8,814 patients, reaching a maximal area under the receiver operator characteristic curve (AUC) of 0.67. AUCs' of models developed on specific subpopulation ranged from 0.59 to 0.67 for patients in second complete remission and receiving reduced intensity conditioning, respectively. Only 3-5 variables were necessary to achieve near maximal AUCs. The top 3 ranking variables, shared by all algorithms were disease stage, donor type, and conditioning regimen. Our findings empirically demonstrate that with regards to NRM prediction, few variables "carry the weight" and that traditional HSCT data has been "worn out". "Breaking through" the predictive boundaries will likely require additional types of inputs.

This study aimed to determine the impact of tyrosine kinase inhibitors given pre- and post-allogeneic stem cell transplantation on long-term outcome of patients allografted for Philadelphia chromosome-positive acute lymphoblastic leukemia. This retrospective analysis from the EBMT Acute Leukemia Working Party included 473 de novo Philadelphia chromosome-positive acute lymphoblastic leukemia patients in first complete remission who underwent an allogeneic stem cell transplantation using a human leukocyte antigen-identical sibling or human leukocyte antigen-matched unrelated donor between 2000 and 2010. Three hundred and ninety patients received tyrosine kinase inhibitors before transplant, 329 at induction and 274 at consolidation. Kaplan-Meier estimates of leukemia-free survival, overall survival, cumulative incidences of relapse incidence, and non-relapse mortality at five years were 38%, 46%, 36% and 26%, respectively. In multivariate analysis, tyrosine-kinase inhibitors given before allogeneic stem cell transplantation was associated with a better overall survival (HR=0.68; P=0.04) and was associated with lower relapse incidence (HR=0.5; P=0.01). In the post-transplant period, multivariate analysis identified prophylactic tyrosine-kinase inhibitor administration to be a significant factor for improved leukemia-free survival (HR=0.44; P=0.002) and overall survival (HR=0.42; P=0.004), and a lower relapse incidence (HR=0.40; P=0.01). Over the past decade, administration of tyrosine kinase inhibitors before allogeneic stem cell transplantation has significantly improved the long-term allogeneic stem cell transplantation outcome of adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Prospective studies will be of great interest to further confirm the potential benefit of the prophylactic use of tyrosine kinase inhibitors in the post-transplant setting.

We report the clinical features and treatment outcome of 33 patients with multiple sclerosis who developed acute promyelocytic leukemia. Thirty patients were previously exposed to mitoxantrone. The median latency period between treatment initiation and acute promyelocytic leukemia diagnosis was 32 months. The PML-RARA bcr1 iso-form was identified in 87% of cases. Twenty-nine (90%) patients achieved hematologic remission after all-trans retinoic acid and chemotherapy (n=31) or arsenic trioxide and all-trans retinoic acid. Consolidation included modified chemotherapy or arsenic trioxide. At a median follow up of 26 months, 23 patients are in complete remission, 4 relapsed and one developed secondary leukemia. The 5-year cumulative incidence of relapse and overall survival were 23% and 68%, respectively. Although treatment heterogeneity and suboptimal post-remission therapy must be taken into account, overall results and development of secondary leukemia in one patient suggest that effective and less toxic agents like arsenic trioxide warrants further investigation in this context.

Background The concept of “accelerated” chronic lymphocytic leukemia is frequently used by both pathologists and clinicians. However, neither histological criteria to define this form of chronic lymphocytic leukemia nor its clinical correlates and prognostic impact have been formally defined in large series of patients.Design and Methods Tissue biopsies from 100 patients with chronic lymphocytic leukemia were analyzed for the size of proliferation centers and their proliferation rate as assessed by mitosis count and Ki-67 immunostaining. Histological patterns were correlated with main clinico-biological features and outcome.Results A suspicion of disease transformation was the main reason for carrying out tissue biopsy, which was performed at a median time of 14 months (range, 0 to 204 months) after the diagnosis of chronic lymphocytic leukemia. The biopsy showed histological transformation to diffuse large B-cell lymphoma in 22 cases. In the remaining 78 patients, the presence of expanded proliferation centers (broader than a 20x field) and high proliferation rate (either >2.4 mitoses/proliferation center or Ki-67 >40%/proliferation center) predicted a poor outcome and were selected to define a highly proliferative group. Thus, 23 patients with either expanded proliferation centers or high proliferation rate were considered as having “accelerated” chronic lymphocytic leukemia. These patients displayed particular features, including higher serum lactate dehydrogenase levels and more frequently elevated ZAP-70 than “non-accelerated” cases. The median survival from biopsy of patients with “non-accelerated” chronic lymphocytic leukemia, “accelerated” chronic lymphocytic leukemia and transformation to diffuse large B-cell leukemia was 76, 34, and 4.3 months, respectively (P

Background Imatinib, given concurrently or alternating with chemotherapy, has improved the response and survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but relapses are still frequent. The aim of this study was to evaluate the feasibility and results of giving imatinib concurrently with intensive chemotherapy, stem cell transplantation and post-transplant imatinib maintenance therapy in patients with newly diagnosed Ph+ ALL.Design and Methods This was a phase II study of patients with newly diagnosed Ph+ ALL given standard chemotherapy, together with imatinib (400 mg/day) until stem cell transplantation, followed by imatinib maintenance therapy for all patients regardless of the molecular status of the disease.Results Of the 30 patients included, 27 (90%) achieved complete remission, one was resistant to treatment and two died during induction therapy. The percentages of major and complete molecular responses were 86% and 21% after induction, and 81% and 65% after consolidation, respectively. Similar results were observed assessing minimal residual disease by flow cytometry. Of the 27 patients who achieved complete remission, 21 underwent stem cell transplantation (16 allogeneic, 5 autologous). Imatinib (400 mg/day) could be administered after transplantation for a median of 3.9 months in 12 patients, although it was interrupted in 10 patients (in 2 cases because of side effects of the drug). Nine patients relapsed, four before and five after stem cell transplantation and eight patients died of transplant-related causes. With a median follow-up of 4.1 years, the probabilities (95% CI) of disease-free and overall survival were 30% (15% to 45%) and 30% (16% to 45%), respectively.Conclusions These results confirm that imatinib is an effective first-line treatment for adult Ph+ ALL when given concurrently with chemotherapy, making stem cell transplantation feasible in a high proportion of patients. However, post-transplantation imatinib administration was limited, mainly because of transplantation-derived complications rather than drug-specific toxicity.

Background The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter.Design and Methods Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given.Results Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse.Conclusions This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors.