Evaluation of voriconazole therapeutic drug monitoring in malignant hematology patients.

Introduction: Malignant hematology (MH) patients are susceptible to invasive fungal infections due to prolonged neutropenia and immunosuppressive therapies, which may require voriconazole therapy. Although voriconazole therapeutic drug monitoring (TDM) is common, evidence describing this practice is limited. The primary objective of this study was to describe the current practice of voriconazole TDM in MH patients at the Princess Margaret Cancer Centre (PM).

Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (m) acute myeloid leukemia (AML).

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with m AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase.

This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.

Biallelic disruption of DDX41 activity is associated with distinct genomic and immunophenotypic hallmarks in acute leukemia.

Introduction: Inherited mutations cause familial predisposition to hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with the majority of DDX41 mutated MDS/AMLs described to date harboring germline and co-occurring somatic variants. DDX41-AMLs were shown to share distinguishing clinical features such as a late AML onset and an indolent disease associated with a favorable outcome. However, genotype-phenotype correlation in DDX41-MDS/AMLs remain poorly understood.

3+7 Combined Chemotherapy for Acute Myeloid Leukemia: Is It Time to Say Goodbye?

Purpose Of Review: With the recent approval of multiple new drugs for the treatment of acute myeloid leukemia (AML), the relevance of conventional treatment approaches, such as daunorubicin and cytarabine ("3+7") induction chemotherapy, has been challenged. We review the AML risk stratification, the efficacy of the newly approved drugs, and the role of "3+7".

Recent Findings: Treatment of AML is becoming more niched with specific subtypes more appropriately treated with gemtuzumab, midostaurin, and CPX-351.

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free ALL Regimen.

Background: venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL), especially in patients treated with asparaginase (ASNase)-including regiments. However, VTE risk in adult Philadelphia-positive ALL (Ph+ve ALL) patients treated with non-hyperCVAD chemotherapy is unclear. In this study, we examined VTE incidence in adult Ph+ve ALL patients treated with imatinib plus a pediatric-inspired asparaginase (ASNase)-free regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol.

Quizartinib for the treatment of acute myeloid leukemia.

Introduction: . Up to 30% of patients with acute myeloid leukemia (AML) have a mutation in the FLT3 receptor. Molecular targets have acquired a significant interest in the treatment of AML and are changing patient outcomes, including improvement of overall survival (OS) and remission rates.

ITACA: A new validated international erythropoietic stimulating agent-response score that further refines the predictive power of previous scoring systems.

Background: In 'real-life', the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower-risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed.

Objectives: To validate existing ESA predictive scores and develop a new score that identifies non-responders.

A 17-gene stemness score for rapid determination of risk in acute leukaemia.

Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors.

A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells.

A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia.

ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase, as well as c-Kit, FLT3 and VEGFR2. A phase I study was conducted to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and toxicities of ENMD-2076 in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Patients received escalating doses of ENMD-2076 administered orally daily [225 mg (n = 7), 375 mg (n = 6), 325 mg (n = 9), or 275 mg (n = 5)].

Patient-related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS-CAN prospective study.

Unlabelled: Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi-centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS-related factors as predictors of OS in Cox proportional hazards models.

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10-Color flow cytometry diagnosis and HyperCVAD therapy.

Few studies describe the comprehensive immunophenotypic pattern of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the bone marrow and its treatment. This retrospective analysis evaluates the diagnostic flow cytometry (FCM) pattern and outcome of nine patients diagnosed with BPDCN. A four-tube 10-color FCM panel used for diagnosis of acute leukemia (AL), showed cells in the blast gate (CD45dim/low SSC) and were positive for CD4(bright), CD33(dim), CD56(heterogenous), CD123(bright), CD36, CD38, HLA-DR, CD71.

Tolerability of Vidaza (azacitidine) subcutaneous administration using a maximum volume of 3 ml per injection.

The azacitidine (Vidaza®) product monograph indicates that doses greater than 4 ml should be divided equally into two syringes and injected into different sites. Although 2 ml is a more commonly used maximum volume for subcutaneous injections, there is a lack of evidence to support the use of any given maximum volume with azacitidine. Applying the status quo of 2 ml to azacitidine results in patients receiving 3-4 injections per visit.

A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia.

This phase I trial evaluated two schedules of escalating vorinostat in combination with decitabine every 28 days: (i) sequential or (ii) concurrent. There were three dose-limiting toxicities: grade 3 fatigue and generalized muscle weakness on the sequential schedule (n = 1) and grade 3 fatigue on the concurrent schedule (n = 2). The maximum tolerated dose was not reached on both planned schedules.

A phase I and pharmacodynamic study of the histone deacetylase inhibitor belinostat plus azacitidine in advanced myeloid neoplasia.

Background We hypothesized that targeting two mechanisms of epigenetic silencing would be additive or synergistic with regard to expression of specific target genes. The primary objective of the study was to establish the maximum tolerated dose (MTD) of belinostat in combination with a fixed dose of azacitidine (AZA). Methods In Part A of the study, patients received a fixed dose of AZA, with escalating doses of belinostat given on the same days 1-5, in a 28 day cycle.

A retrospective observational study of leucoreductive strategies to manage patients with acute myeloid leukaemia presenting with hyperleucocytosis.

Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre-induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 × 10(9) /l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre-induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d).

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs.

Predictors of outcome in adults with BCR-ABL negative acute lymphoblastic leukemia treated with a pediatric-based regimen.

We retrospectively evaluated the outcome of 156 adults age 17-60 with BCR-ABL negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol. The CR rate was 93%; 5-year overall survival (OS) and disease-free survival were 66% and 70%, respectively. Age <34 years and low presenting WBC were independent predictors of favorable OS (p<0.

Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies.

The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m² oral ciclopirox olamine once daily for five days in 21-day treatment cycles.

Treatment of elderly patients with acute lymphoblastic leukaemia using a paediatric-based protocol.

All newly diagnosed patients aged 60-79 years with acute lymphoblastic leukaemia (ALL) receiving induction chemotherapy with a modified paediatric-based regimen over a 7-year period were retrospectively analysed (n = 51, median age 65 years). The treatment regimen consisted of induction, central nervous system prophylaxis, seven cycles of intensification and 24 cycles of maintenance. BCR-ABL1 negative patients received weekly asparaginase during intensification, while BCR-ABL1+ patients received daily imatinib.

Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms.

Leukemic transformation (LT) is a rare but fatal complication of Philadelphia-negative myeloproliferative neoplasms (MPNs) for which optimal treatment strategies are not known. At our center, we have adopted a treatment approach for LT where patients within the transplant age group who have a reasonable fitness level are treated with curative intent and offered induction chemotherapy. Subsequently, those who respond and have a suitable donor are considered for allogeneic hematopoietic cell transplantation (HCT).