CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting.

Chronic myelomonocytic leukemia (CMML) is a rare blood cancer of older adults (3 in every 1,000,000 persons) characterized by poor survival and lacking effective mutation-specific therapy. Mutations in the ubiquitin ligase Cbl occur frequently in CMML and share biological and molecular features with a clonal disease occurring in children, juvenile myelomonocytic leukemia (JMML). Here we analyzed the clinical presentations, molecular features and immunophenotype of CMML patients with CBL mutations enrolled in a prospective Phase II clinical trial stratified according to molecular markers.

Identifying disease-modifying potential in myelofibrosis clinical trials.

The ultimate goal of bringing most new drugs to the clinic in hematologic malignancy is to improve overall survival. However, the use of surrogate end points for overall survival is increasingly considered standard practice, because a well validated surrogate end point can accelerate the outcome assessment and facilitate better clinical trial design. Established examples include monitoring minimal residual disease in chronic myeloid leukemia and acute leukemia, and metabolic response assessment in lymphoma.

Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a highly aggressive and devastating malignancy of the bone marrow and blood. For decades, intensive chemotherapy has been the frontline treatment for AML but has yielded only poor patient outcomes as exemplified by a 5-year survival rate of < 30%, even in younger adults. As knowledge of the molecular underpinnings of AML has advanced, so too has the development new strategies with potential to improve the treatment of AML patients.

Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax.

MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AML's heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines.

Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies.

Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders.

Variability of bone marrow biopsy reporting affects accuracy of diagnosis of myeloproliferative neoplasms: data from the ALLG MPN01 registry.

The Philadelphia-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of overlapping bone marrow disorders defined by characteristic peripheral blood counts and bone marrow morphological findings in conjunction with recurrent somatic mutations. The accurate diagnosis and subclassification of MPN relies upon careful reporting of bone marrow morphology combined with ancillary information in an integrated pathology report. This co-operative trial group study ALLG MPN01 (ANZCTR:12613000138785), led by the Australasian Leukaemia & Lymphoma Group (ALLG), aimed to describe the current approach to diagnosis of MPN in routine practice.

Lineage-specific detection of residual disease predicts relapse in patients with chronic myeloid leukemia stopping therapy.

Patients with chronic myeloid leukemia who are eligible for treatment-free remission (TFR) may still relapse after tyrosine kinase inhibitor (TKI) cessation. There is a need for accurate predictors of outcome to enable patients with a favorable profile to proceed while avoiding futile attempts. Sensitive detection of residual disease in total leukocytes at treatment cessation is associated with relapse but is not highly discriminatory, likely because it is a composite measure of residual leukemia derived from different cell lineages, whereas only some lineages are relevant for relapse.

Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.

Unlabelled: Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN); however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621).

Immune modulation in chronic myeloid leukaemia patients treated with nilotinib and interferon-alpha.

The addition of interferon to tyrosine kinase inhibitors (TKIs), to improve deep molecular response (DMR) and potentially treatment-free remission (TFR) rates in chronic-phase chronic myeloid leukaemia (CP-CML) patients is under active investigation. However, the immunobiology of this combination is poorly understood. We performed a comprehensive longitudinal assessment of immunological changes in CML patients treated with nilotinib and interferon-alpha (IFN-α) within the ALLG CML11 trial (n = 12) or nilotinib alone (n = 17).

Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes.

Acute myeloid leukemia (AML) kills 75% of patients and represents a major clinical challenge with a need to improve on current treatment approaches. Targeting sphingosine kinase 1 with a novel ATP-competitive-inhibitor, MP-A08, induces cell death in AML. However, limitations in MP-A08's "drug-like properties" (solubility, biodistribution, and potency) hinder its pathway to the clinic.

Platelets from patients with myeloproliferative neoplasms have increased numbers of mitochondria that are hypersensitive to depolarization by thrombin.

Thrombosis is one of the cardinal manifestations of myeloproliferative neoplasms (MPN). The mechanisms leading to a prothrombotic state in MPN are complex and remain poorly understood. Platelet mitochondria play a role in platelet activation, but their number and function have not been extensively explored in MPN to date.

Impact of additional genetic abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated patients receiving proactive treatment intervention.

The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGA) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGA at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy.

Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia.

Dysregulation of immune-checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), however, their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed programmed cell death-1 (PD-1), T-cell immunoglobulin, and mucin-domain containing protein-3 (TIM-3), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), lymphocyte-activation gene-3 (LAG-3), and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 patients sustained treatment-free remission [TFR] and 22 experienced molecular relapse [MolR]). We confirmed our previous finding that absolute numbers of T-regs are increased in patients who experienced MolR compared with those who sustained TFR.