Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

BACKGROUND: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients. METHODS: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529. FINDINGS: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date. INTERPRETATION: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. FUNDING: Loxo Oncology.

Outpatient autologous stem cell transplantation in Royal Hobart Hospital, Tasmania: a single-centre, retrospective review in the Australian setting.

BACKGROUND: Several international centres have published their experiences with outpatient autologous stem cell transplantation (ASCT) as treatment of haematological malignancies. AIM: In this single-centre retrospective review, we aim to examine the outcomes of outpatient autograft and review healthcare resource utilisation in the pre-cytopenic period. METHODS: Patients undergoing ASCT in Royal Hobart Hospital, Tasmania between 2008 and 2018 had their records reviewed and key outcomes data collected based on whether they received inpatient/outpatient ASCT. An outpatient ASCT was defined as conditioning as an outpatient; patients could then be managed with an elective admission during the cytopenic period or admission only when clinically indicated. RESULTS: Of 231 ASCT performed, 135 (58%) were as outpatients: 59 used carmustine-etoposide-cytarabine-melphalan conditioning for lymphoma (BEAM-ASCT) and 76 used high-dose melphalan for myeloma and amyloidosis (MEL-ASCT). Approximately one-third of patients undergoing outpatient ASCT were admitted electively during nadir period; the majority of patients required minimal interventions prior to this time. The most common causes for unplanned hospitalisation (which occurred in 71 (80%) of the 89 planned outpatient transplants) were febrile neutropenia (39%) and mucositis (35%). Age was the only risk factor identified to increase risk of requiring unplanned hospitalisation. Use of oral antibiotic prophylaxis reduced febrile neutropenia rates among melphalan outpatient ASCT. Outpatient ASCT led to significantly reduced inpatient bed-days and overall cost (approximately A$13 000-A$16 000) compared with inpatient autografts, with no significant differences in engraftment, rates of febrile neutropenia, intensive care admissions or mortality. CONCLUSION: Outpatient autografts may save healthcare resources without compromising patient outcomes.

Variation in immunoglobulin use and impact on survival in myeloma.

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real-world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia-Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow-up time of 29.5 months (interquartile range 13.3-54.3 months) were included in the analysis - 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in-situ hybridisation status, receive first-line myeloma treatment with immunomodulatory drugs or anti-CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow-up (adjusted hazard ratio 0.72, 95% CI 0.46-1.14, p = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources.

The emerging roles of dual-specificity phosphatases and their specific characteristics in human cancer.

Reversible phosphorylation of proteins, controlled by kinases and phosphatases, is involved in various cellular processes. Dual-specificity phosphatases (DUSPs) can dephosphorylate phosphorylated serine, threonine and tyrosine residues. This family consists of 61 members, 44 of which have been identified in human, and these 44 members are classified into six subgroups, the phosphatase and tensin homolog (PTEN) protein phosphatases (PTENs), mitogen-activated protein kinase phosphatases (MKPs), atypical DUSPs, cell division cycle 14 (CDC14) phosphatases (CDC14s), slingshot protein phosphatases (SSHs), and phosphatases of the regenerating liver (PRLs). Growing evidence has revealed dysregulation of DUSPs as one of the common phenomenons and highlighted their key roles in human cancers. Furthermore, their differential expression may be a potential biomarker for tumor prognosis. Despite this, there are still many unstudied members of DUSPs need to further explore their precise roles and mechanism in cancers. Most importantly, the systematic review is very limited on the functional/mechanistic characteristics and clinical application of DUSPs at present. In this review, the structures, functions and underlying mechanisms of DUSPs are systematically reviewed, and the molecular and functional characteristics of DUSPs in different tumor types according to the current researches are summarized. In addition, the potential roles of the unstudied members and the possible different mechanisms of DUSPs in cancer are discussed and classified based on homology alignment and structural domain analyses. Moreover, the specific characteristics of their expression and prognosis are further determined in more than 30 types of human cancers by using the online databases. Finally, their potential application in precise diagnosis, prognosis and treatment of different types of cancers, and the main possible problems for the clinical application at present are prospected.

The role of WT1 in breast cancer: clinical implications, biological effects and molecular mechanism.

Although Wilms' tumor gene 1 (WT1) was first cloned and identified as a tumor suppressor gene in nephroblastoma, subsequent studies have demonstrated that it can also play an oncogenic role in leukemia and various solid tumors. WT1 exerts biological functions with high tissue- and cell-specificity. This article reviews the relationship between WT1 and breast cancer from two aspects: (1) clinical application of WT1, including the relationship between expression of WT1 and prognosis of breast cancer patients, and its effectiveness as a target for comprehensive therapy of breast cancer; (2) the biological effects and molecular mechanisms of WT1 in the development and progression of breast cancer, including proliferation, apoptosis, invasion, and metastasis of breast cancer cells.