Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044.

Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. METHODS: The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). FINDINGS: Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). INTERPRETATION: In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. FUNDING: Celgene and Acceleron Pharma.

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).

Baseline cluster of differentiation 22 fluorescent intensity correlates with patient outcome after Inotuzumab Ozogamicin treatment.

Antigen-directed target therapy for B-cell acute lymphoblastic leukemia (B-ALL) is now the standard of care for relapsed/refractory (R/R) disease. A comprehensive determination of the target itself is mandatory to aid physician's choice. We determined baseline Cluster of differentiation 22 (CD22) expression percentage and fluorescent intensity on lymphoblasts of 30 patients with R/R B-ALL treated with anti-CD22 immunoconjugate drug Inotuzumab Ozogamicin (INO) and analyzed the impact of both parameters on patient outcome. Most patients (24/30, 80%) had a high leukemic blast CD22-positivity defined as ≥90%. We did not observe a benefit in terms of complete remission, overall survival (OS) and duration of response (DoR) for patients with CD22 ≥ 90% versus CD22 < 90%. Concerning CD22-FI quartile analysis we appreciated a trend for superior response rates in higher quartiles (Q2 -Q4 ) compared to Q1 and a significant benefit in terms of OS and DoR for patients with higher CD22-FI. INO demonstrates to be effective also in patients with lower CD22 expression, but therapeutical benefits are more evident in patients with higher CD22-FI. The evaluation of both CD22 percentage and CD22-FI of the leukemic blast may help physicians in therapeutic choices for R/R B-ALL patients when multiple treatment options are available, although no CD22 expression threshold can currently be identified below which INO should be considered not effective.

Impact of infectious comorbidity and overall time of hospitalization in total outpatient management of acute myeloid leukemia patients following venetoclax and hypomethylating agents.

Venetoclax (VEN) and hypomethylating agent (HMAs) regimens are emerging as the standard of care for unfit for chemotherapy acute myeloid leukemia (AML) patients, but the safety and feasibility of a total outpatient management have not been fully investigated. Fifty-nine AML patients with active disease received VEN and HMAs. Nineteen out of 59 (32.2%) patients received the first cycle as inpatients, whereas 40/59 (67.8%) patients were treated in the outpatient setting. No significant differences were observed with regard to incidence of adverse events (AEs), including tumor lysis syndrome (TLS), and the 30-day and 60-day mortality was comparable. Notably, an infectious prophylaxis inspired to that adopted during intensive chemotherapy resulted in a low infection rate with a reduced bacterial infections incidence in out- versus hospitalized patients (p < .0001). The overall time of hospitalization was significantly shorter in patients who received a total outpatient treatment as compared to those who received the first cycle as inpatients (5.9 vs. 39.7 days, p < .0001). Despite the adopted differences in treatment management, the efficacy was similar. These data indicate that a total outpatient management of VEN and HMAs is feasible in AML patients without negatively impacting on treatment efficacy and may yield pharmacoeconomic and quality-of-life benefits.

Clinical Efficacy of Ponatinib in Philadelphia-Positive T-Cell Acute Lymphoblastic Leukemia with Extramedullary Involvement.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation.

MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.

INTRODUCTION: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen. METHODS AND PATIENTS: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification. RESULTS: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000). CONCLUSION: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery.

BACKGROUND: Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis. METHODS: To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E-AML) cases. RESULTS: A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A-AML, which was associated with a 3-gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A-AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E-AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression. CONCLUSIONS: These findings indicate that aneuploidy-related and leukemia-specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.

Prognostic implications of additional genomic lesions in adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

To shed light onto the molecular basis of Philadelphia chromosome-positive acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia carry an average of 7.8 lesions/case, with deletions outnumbering gains (88% versus 12%). The most common deletions were those targeting IKZF1, PAX5 and CDKN2A/B, which were detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of IKZF1 plus CDKN2A/B and/or PAX5 had a significantly lower disease-free survival rate (24.9% versus 43.3%; P=0.026). The only IKZF1 isoform affecting prognosis was the dominant negative one (P=0.003). Analysis of copy number aberrations showed that 18% of patients harbored MEF2C deletions, which were of two types, differing in size: the longer deletions were associated with the achievement of a complete molecular remission (P=0.05) and had a favorable impact on disease-free survival (64.3% versus 32.1% at 36 months; P=0.031). These findings retained statistical significance also in multivariate analysis (P=0.057). KRAS deletions, detected in 6% of cases, were associated with the achievement of a complete molecular remission (P=0.009). These results indicate that in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia a detailed evaluation of additional deletions - including CDKN2A/B, PAX5, IKZF1, MEF2C and KRAS - has prognostic implications and should be incorporated in the design of more personalized treatment strategies.

Bad Is Stronger Than Good for Stigmatized, but Not Admired Outgroups: Meta-Analytical Tests of Intergroup Valence Asymmetry in Individual-to-Group Generalization Experiments.

Theories of risk aversion, epistemic defense, and ingroup enhancement converge in predicting greater impact of negative (vs. positive) experiences with outgroup members on generalized evaluations of stigmatized outgroups. However, they diverge in predictions for admired outgroups. Past tests have focused on negative outgroups using correlational designs without a control group. Consequently, they have not distinguished between alternative explanations or ascertained the direction of causality/generalization, and they have suffered from self-selection biases. These limitations were redressed by a meta-analysis of experimental research on individual-to-group generalization with positive and negative outgroups (59 tests; 3,012 participants). Controlling for modest confounds, the meta-analysis found a generalization advantage of negative experiences for stigmatized outgroups and a generalization advantage of positive experiences for admired outgroups. These results highlight the centrality of valenced expectations about outgroups, consistent with epistemic defense and ingroup enhancement and inconsistent with risk aversion. Implications for positive changes in intergroup dynamics are discussed.

Saprochaete clavata infections in patients undergoing treatment for haematological malignancies: A report of a monocentric outbreak and review of the literature.

Saprochaete clavata is a rare cause of fungaemia with deep organ involvement in patients with haematological malignancies with reported mortality rates of 60%-80%. We describe four cases of S clavata infection in a haematology unit over several months that were treated with voriconazole-based regimens. We also review the literature on factors that could contribute to earlier recognition and effective treatment of S clavata. We included all cases of culture-positive S clavata from sterile sites with associated signs of infection in patients undergoing treatment for a haematological malignancy. Isolates were identified by MALDI-TOF MS, and spectrum profiles were used to prepare clustering analysis of isolates. Susceptibility testing was performed using a commercial microtitre methods. Saprochaete clavata was isolated from the bloodstream in three cases and bronchial alveolar lavage (BAL) fluid in one case. Clustering analysis suggested strains of S clavata were clonal without evidence of divergence although a common source was not identified. Susceptibility testing yielded elevated MICs to fluconazole (8 mg/L) and echinocandins (>1-8 mg/L). All patients were treated with voriconazole-based regimens resulting in survival of 3/4 patients, who continued chemotherapy for their underlying malignancy without evidence of relapse. Saprochaete clavata is a rare but aggressive cause of breakthrough yeast infection in patients undergoing treatment for haematological malignancies, particularly patients with a prior history of echinocandin treatment. Timely initiation of appropriate treatment, aided by more rapid identification in microbiology laboratory, can reduce the risk of deep organ dissemination and patient death.

Mediating Effects of the 'eCoFit' Physical Activity Intervention for Adults at Risk of, or Diagnosed with, Type 2 Diabetes.

BACKGROUND: The study aim was to examine the mechanisms of physical activity behaviour change in the multi-component eCoFit randomised controlled trial (RCT) among adults diagnosed with, or at risk of, T2D. METHOD: The RCT included two phases: phase 1 (weeks 1-10) integrated group sessions (outdoor physical activity and cognitive mentoring) and the use of the eCoFit smartphone application (app), and phase 2 (weeks 11-20), which included the use of the eCoFit smartphone application only. Participants (n = 84) were assessed at baseline and 10 and 20 weeks from baseline. Physical activity was assessed using pedometers, and the following mediators were tested: action self-efficacy, barrier self-efficacy, recovery self-efficacy, implementation intentions, intention to have regular physical activity, outcome expectations, risk perception and implicit associations related to physical activity. The PROCESS INDIRECT Macro was used to perform mediation analyses. RESULTS: Significant mediation pathways were found for implementation intention measured at 10 weeks, AB (95% CI = 486.04 [128.19, 1073.42]). No significant pathways were found for the other social-cognitive and implicit attitudinal mediators. CONCLUSION: Increased daily steps among the intervention participants were explained by increased implementation intentions. The eCoFit study successfully operationalised implementation intentions in the smartphone app designed to promote outdoor physical activity. TRIAL REGISTRATION: The trial was approved by a University Human Research Committee and is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12615000990527).

Acute Myeloid Leukemia Mutations: Therapeutic Implications.

Acute Myeloid Leukemia (AML) is an extremely heterogeneous group of hematological neoplasms, for which allogeneic stem cell transplantation (HSCT) still represents the only potentially curative option in the majority of cases. However, elderly age and clinically severe comorbidities may often exclude a wide amount of patients from this therapeutic approach, underlying the urgent need for alternative strategies. Thanks to the introduction of advanced high-throughput techniques, light is being shed on the pathogenesis of AML, identifying molecular recurrent mutations as responsible for the onset, as well as progression, of disease. As a consequence, and in parallel, many new compounds, including targeted therapies (FMS-like tyrosine kinase 3 (FLT3) and Isocitrate dehydrogenase 1-2 (IDH1-2) inhibitors), have found a wide room of application in this setting, and are now available in daily practice, or in late phases of clinical development. Moreover, several further innovative molecules are currently under investigation, and promising results for many of them have already been reported. In this review, we will present an update on the most relevant molecular alterations of AML, focusing on the most frequent genomic mutations of the disease, for which compounds have been approved or are still currently under investigation.

Inotuzumab ozogamicin is effective in relapsed/refractory extramedullary B acute lymphoblastic leukemia.

BACKGROUND: Extramedullary involvement of B-cell Acute Lymphoblastic Leukemia (EM-ALL) is a rare occurrence, characterized by dismal outcome and the absence of a defined and shared therapeutic approach. In the landscape of innovative compounds, inotuzumab ozogamicin (IO) is a promising drug, whose mechanism of action relies on the killing of CD22 positive leukemic cells, through the delivery, after cell binding, of a molecule of calicheamicin. CASE PRESENTATION: We report two cases of CD22 positive relapsed EM-ALL treated with IO, obtained as compassionate use. Case 1, a 66 years old woman, affected by Philadelphia (Ph) negative B-ALL, relapsed with extramedullary involvement after 6 standard chemotherapy courses, who reached a complete metabolic response with IO treatment. Case 2, a 67 years old man with Ph positive B-ALL, initially treated with ponatinib, a third generation tyrosine-kinase inhibitor (TKI), obtaining a prolonged deep molecular remission. Nevertheless, for skin relapse during TKI treatment, the patient received local radiotherapy and, shortly after, standard chemotherapy, as multiple abdominal sites of relapse were detected too, with no response. The patient then received IO, obtained as compassionate use, with a good metabolic response. CONCLUSIONS: These two cases suggest a possible key role of IO in the setting of advanced CD22 positive ALL, and underline its potential activity also in patients with EM involvement, relapsed after or refractory to conventional chemotherapy. Despite the well known hepatotoxic effect of the compound (Sinusoid Occlusive Syndrome), neither of them had such adverse event, moreover the second patient safely underwent allogeneic bone marrow transplantation.

Increased angiogenesis seems to correlate with inferior overall survival in myeloid sarcoma patients.

Myeloid sarcomas (MS) are tumors composed by myeloid elements and developing outside bone marrow. The prognosis is overall poor, only stem cell transplantation being consistently reposted as a potentially curative approach. In this study we explored whether microvessel density, a biomarker of angiogenesis, might be relevant in MS. We studied 60 MS, 24 acute myeloid leukemia, 5 normal bone marrow samples and 2 cases of extramedullary hemopoiesis in patients without evidence of hematological malignancy. We used immunohistochemistry (anti-CD34) to identify and quantify micro-vessel density (MVD) and micro-vessel grading (MVG). We found that MS had significantly higher MVD and MVG than normal bone marrow (p = 0.0002 and p < 0.001, respectively). We then found that cases with monocytic morphology had significantly higher MVD than myelo-monocytic and blastic ones (p = 0.005), while no differences were recorded based on extramedullary site. Finally, we found that higher MVD and higher MVG were associated with inferior outcome in terms of overall survival in multivariate analysis (p = 0.05 and p = 0.02, respectively), when censoring for stem cell transplantation was undertaken. In conclusion, we documented for the first time that increased angiogenesis is characteristic of MS and correlates with survival, suggesting that anti-angiogenic approaches might deserve a clinical evaluation in this setting.

The clonal evolution of two distinct T315I-positive BCR-ABL1 subclones in a Philadelphia-positive acute lymphoblastic leukemia failing multiple lines of therapy: a case report.

BACKGROUND: The treatment of Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients who harbor the T315I BCR-ABL1 mutation or who have two or more mutations in the same BCR-ABL1 molecule is particularly challenging since first and second-generation Tyrosine Kinase Inhibitors (TKIs) are ineffective. Ponatinib, blinatumomab, chemotherapy and transplant are the currently available options in these cases. CASE PRESENTATION: We here report the case of a young Ph+ ALL patient who relapsed on front-line dasatinib therapy because of two independent T315I-positive subclones, resulting from different nucleotide substitutions -one of whom never reported previously- and where additional mutant clones outgrew and persisted despite ponatinib, transplant, blinatumomab and conventional chemotherapy. Deep Sequencing (DS) was used to dissect the complexity of BCR-ABL1 kinase domain (KD) mutation status and follow the kinetics of different mutant clones across the sequential therapeutic approaches. CONCLUSIONS: This case presents several peculiar and remarkable aspects: i) distinct clones may acquire the same amino acid substitution via different nucleotide changes; ii) the T315I mutation may arise also from an 'act' to 'atc' codon change; iii) the strategy of temporarily replacing TKI therapy with chemo or immunotherapy, in order to remove the selective pressure and deselect aggressive mutant clones, cannot always be expected to be effective; iv) BCR-ABL1-mutated sub-clones may persist at very low levels (undetectable even by Deep Sequencing) for long time and then outcompete BCR-ABL1-unmutated ones becoming dominant even in the absence of any TKI selective pressure.

Complex karyotype, older age, and reduced first-line dose intensity determine poor survival in core binding factor acute myeloid leukemia patients with long-term follow-up.

Approximately 40% of patients affected by core binding factor (CBF) acute myeloid leukemia (AML) ultimately die from the disease. Few prognostic markers have been identified. We reviewed 192 patients with CBF AML, treated with curative intent (age, 15-79 years) in 11 Italian institutions. Overall, 10-year overall survival (OS), disease-free survival (DFS), and event-free survival were 63.9%, 54.8%, and 49.9%, respectively; patients with the t(8;21) and inv(16) chromosomal rearrangements exhibited significant differences at diagnosis. Despite similar high complete remission (CR) rate, patients with inv(16) experienced superior DFS and a high chance of achieving a second CR, often leading to prolonged OS also after relapse. We found that a complex karyotype (i.e., ≥4 cytogenetic anomalies) affected survival, even if only in univariate analysis; the KIT D816 mutation predicted worse prognosis, but only in patients with the t(8;21) rearrangement, whereas FLT3 mutations had no prognostic impact. We then observed increasingly better survival with more intense first-line therapy, in some high-risk patients including autologous or allogeneic hematopoietic stem cell transplantation. In multivariate analysis, age, severe thrombocytopenia, elevated lactate dehydrogenase levels, and failure to achieve CR after induction independently predicted longer OS, whereas complex karyotype predicted shorter OS only in univariate analysis. The achievement of minimal residual disease negativity predicted better OS and DFS. Long-term survival was observed also in a minority of elderly patients who received intensive consolidation. All considered, we identified among CBF AML patients a subgroup with poorer prognosis who might benefit from more intense first-line treatment.