Real-world efficacy and safety outcomes of imatinib treatment in patients with chronic myeloid leukemia: an Australian experience

Background: Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of chronic myeloid leukaemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. Aims: To investigate real-world use and outcomes of imatinib in patients with CML in Australia. Methods: A retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, survival and molecular response were evaluated. Results: 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32–53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥ 3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92–100%) and 81% (95% CI, 72–92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50–73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. Conclusion: Imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.

Detection of Lethal Dose 50 of Biofilm-producing Methicillin-resistant Staphylococcus aureus Local Isolate From Mastitis

It is very important, before starting the manufacture of any vaccine from any microorganism estimation of LD₅₀ of that microorganism to determine their pathogenicity and virulence. Estimated LD₅₀ was very important to be used in challenge tests later to estimate the protection level of the manufactured vaccine in experimental animals. So, this study was aimed to estimate LD₅₀ of local methicillin-resistant Staphylococcus aureus (MRSA) bacterial isolate. A pilot study has been done to determine approximately LD₅₀ of used MRSA in the study by using different bacterial concentrations of MRSA to determine approximate LD₅₀ that can be able to kill half numbers of animals used in the study to be used later in the estimation of exact LD₅₀ by using of Up-and-Down method. Ninety Wistar albino rats have been used for this purpose, eighty-four animals which divided into fourteen groups by six animals for each group (for pilot study) and remained six animals for (Up-and-Down method). The results showed that 9 X 10¹⁰ CFU/ml was led to killing half number of animals used in the study, this dose has been used as starting dose in the Up-and-Down method to the estimation of the exact LD₅₀ dose. The results showed that 5.526 X 10¹⁰ CFU/ml was the exact LD₅₀ of local MRSA isolate, which will be used later in the challenge test to estimate the protection level of a locally prepared vaccine against MRSA isolate.

Low dose meloxicam is safe and tolerable when combined with toceranib phosphate in cancer-bearing cats

Objectives Non-steroidal anti-inflammatory drugs (NSAIDs) are infrequently utilized in cats due to concern for renal compromise; however, recent studies demonstrate tolerability of low dose meloxicam. Toceranib phosphate is used to treat several feline cancers and is well tolerated. This study aimed to determine the tolerability and adverse event profile of combined toceranib and low dose meloxicam in cancer-bearing cats. Secondary goals involved assessing anticancer tumor efficacy and impact upon quality of life and analgesia. Methods Cats with any cancer not involving the kidneys were eligible. The study adopted a conventional 3 + 3 dose escalation design. Toceranib was administered every other day at a standard dose with meloxicam administered in an escalating fashion in subsequent cohorts, at a starting dose of 0.01 mg/kg on opposite days to toceranib, up to a maximum of 0.02 mg/kg daily, based upon previous safety studies. Laboratory work, blood pressure, tumor measurements, pain score and client-completed quality-of-life surveys were recorded every 2–4 weeks during the 12-week study period. Results Twenty-one cats were enrolled. When combined with toceranib, a meloxicam dose of 0.02 mg/kg q24h was safe and well tolerated, with no cats being withdrawn due to adverse events from the drug combination. The majority of cats demonstrated clinical benefit with stable to mildly improved tumor measurements, quality of life and pain scores. Conclusions and relevance Low dose meloxicam combined with toceranib is safe and well tolerated in cancer-bearing cats. Continued patient recruitment and data collection are needed to determine the maximum tolerated dose of meloxicam. The results of our study will guide further phase II/III trials.

An international survey on the use of intrapleural tPA/DNase therapy for pleural infection

IntroductionIntrapleural tissue plasminogen activator (tPA) combined with human recombinant DNase (DNase) could be an effective alternative to surgery in managing pleural infection as demonstrated in the Multi-centre Intrapleural Sepsis Trial (MIST)-2. However, the optimal delivery regime is still unknown. The aim of this survey is to identify the current practice of tPA/DNase use by physicians with published interests in pleural infection, and their opinions on dose de-escalation of tPA/DNase therapy.MethodsPotential participants were identified using four search strategies. Only practicing physicians who are managing patients with pleural infections and are either actively involved in pleural research and publications, or members of relevant pleural disease guideline panels at the time of survey were included.ResultsAn invitation email with the questionnaire was sent to 102 participants of which 49 (48%) responded. Most respondents (90%, n=44) have used tPA/DNase to manage pleural infection but the dosing and delivery regimens employed varied. Many (86%, n=38/44) respondents have used 10 mg tPA, while 73% (n=32), 16%, (n=7) and 9% (n=4) have used 5 mg, 2.5 mg and 1 mg doses respectively. Most respondents instilled tPA/DNase concurrently (61%, n=27) and routinely administered 6 doses of tPA/DNase (52%, n=23) twice daily (82%, n=36). Respondents would consider using a lower starting dose of tPA (with the possibility of escalation if clinically needed) if 80% [IQR 50–80] of patients could be successfully treated at that dose.ConclusionThis survey observed a large variation in the current treatment protocol of intrapleural tPA/DNase therapy worldwide and the need for more data on this subject.

The Ketogenic Effect of Medium-Chain Triacylglycerides

Medium-chain triacylglycerides (MCTs) are dietary supplements that can induce ketosis without the need for a traditional ketogenic diet or prolonged fasting. They have the potential to marginally delay the progression of neurodegenerative diseases, such as Alzheimer's disease. However, there have been inconsistencies in reports of the MCT dose–response relationship, which may be due to differences in MCT composition, participant characteristics, and other factors that can influence ketone generation. To resolve these discrepancies, we reviewed studies that investigated the ketogenic effect of MCTs in healthy adults. Aside from the treatment dose, other factors that can influence the ketogenic response, such as accompanying meals, fasting duration, and caffeine intake, were assessed. Based on the available literature, four practical recommendations are made to optimize the ketogenic effect of MCTs and reduce unwanted side effects (primarily gastrointestinal discomfort and diarrhea). First, the starting dose should be either 5 g of octanoic acid [caprylic acid (C8); a component of MCTs] or 5 g of a combination of C8 and decanoic or capric acid (C10; another component of MCTs), and the dose should be progressively increased to 15–20 g of C8. Second, MCTs should be consumed after an overnight fast, without an accompanying meal if tolerable, or with a low-carbohydrate meal. Third, the addition of caffeine may slightly increase the ketogenic response. Fourth, emulsifying the MCTs might increase their ketogenic effect and alleviate side effects.

Personalized therapy with lenvatinib for progressive radioiodine refractory differentiated thyroid cancer in routine clinical practice

Among the differentiated forms of thyroid cancer, the least favorable clinical prognosis is observed in radioiodine-refractory differentiated thyroid cancer. The next step in the treatment of such patients is effective and potential toxicity multi-kinase inhibitors. Often, patients with refractory radioiodine thyroid cancer have a high tumor burden, various symptoms and comorbidity; therefore, clinicians may decide to initiate therapy at a reduced starting dose. In a randomized clinical multicenter study 211 higher objective response rate at 24th weeks were observed in the group of patients receiving lenvatinib at a dose of 24 mg per day compared with patients receiving Lenvatinib at a dose of 18 mg per day, while the difference in the incidence of serious adverse events grade 3–4 (SAE) at the 24th week of treatment were insignificant. Real clinical practice differs from randomized clinical trials regarding to the population of patients, their selection for treatment, adherence to drug dosage regimens, follow-ups, etc. In this paper, we analyzed the world and domestic clinical practice of the treatment of radioiod-refractory thyroid cancer and assessed the effect of the starting dose of lenvatinib and the duration of breaks in its administration on the effectiveness and safety of therapy.

Octogenarians with AML Can Have Durable Remissions with Venetoclax and Hypomethylating Agent Therapy Despite Significant Dose Reductions

Introduction Venetoclax in combination with a hypomethylating agent (VEN-HMA) has become a standard of care for older or unfit patients with newly diagnosed AML. Although primarily administered in the outpatient setting, VEN-HMA is associated with significant cytopenias and infectious complications, requiring careful monitoring and dose adjustments. Patients treated with VEN-HMA on clinical trials had a median age of ~75 years. The optimal dose and schedule, safety, and efficacy of VEN-HMA in octo- and nonagenarians is not clearly defined. Methods We performed a retrospective analysis of AML patients ≥80-years-old who received at least 1 day of VEN-HMA at our institution from 11/2018 to 7/2021. Patients with de novo or secondary AML with or without prior HMA or chemotherapy were included. Venetoclax starting dose was 200-400 mg for 14-28 days. Dose adjustments for drug interactions with azole anti-fungals were implemented. HMA was started at 50-75 mg/m2 for 5-7 days of azacitidine or 20mg/m2 for 5 days of decitabine. Dose reduction was defined as any decrease from the starting dose and schedule. Patients who did not complete cycle 1 were included in the overall survival and safety analysis but excluded from response assessment. Results Among 21 patients ≥80-years-old treated with VEN-HMA (20 newly diagnosed, 1 relapsed/refractory), median age was 82 years (range: 80-89) (Table 1), 57% had antecedent MDS, and 38% received HMAs previously. Most patients (81%) were ELN adverse risk, 38% had a complex karyotype, 24% had a TP53 mutation, and 43% had ECOG PS of 2-3. Median overall survival for all patients was 8.0 months (0.5-31.4 months). At time of analysis, 12 patients (57%) were still alive and in remission on VEN-HMA with a median follow-up of 11.5 months (range 2.3-31.4 months). Five patients (24%) died during cycle 1 from sepsis. Of these 5 patients, 4 had a TP53 mutation, 3 had prior MDS, and 3 had received prior therapy for lymphoma. In the remaining 16 patients, median overall survival was 9.9 months (2.3-31.4 months) and the CR/CRh rate was 81% (13/16 patients). Median duration of response was 8.9 months (range 1.0-30.0). Consistent with previous reports, all patients who achieved CR/CRh did so by the end of cycle 2 (median 2 cycles). Most patients also received the standard dose and schedule of VEN (75%) and HMA (57%) during the first cycle. All patients (100%) required venetoclax dose and schedule reduction, with a median final venetoclax dose of 200 mg and duration of 14 days. Average final cycle length was 35 days. Most patients (69%) also required dose reduction of HMA. Median duration of treatment was 7.5 months (range 0.5-31.4). Treatment emergent grade 3-4 anemia occurred in 67% of patients, thrombocytopenia in 81%, and neutropenia in 86%; 17 patients (81%) had treatment emergent febrile neutropenia. There were no infectious deaths in patients who survived cycle 1. The median number of neutropenic fever episodes per patient was 1 (0 to 2). The 4 deaths after cycle 1 were due to progressive disease (n=3) or relapse (n=1). Conclusion VEN-HMA can be safely and effectively given to octogenarians with careful monitoring and dose adjustments. All patients required dose reduction of venetoclax after CR/CRh was achieved, and most also required adjustment of HMA. Despite this, over half of patients achieved durable remissions. The greatest risk of infectious death was in the first cycle, in patients who were heavily pre-treated and enriched for TP53 mutations. When compared to historical controls, outcomes in octogenarians who survive the first cycle appear similar to younger age groups. This work highlights the need for a prospective multi-center effort to optimize the dose and schedule of VEN-HMA in older patient populations. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

Heterozygous NUDT15 Gene Polymorphism Would Not Associate with the Severity of 6-Mercaptopurine Side Effects in Early Intensification Therapy for Childhood Acute Lymphoblastic Leukemia

Background In the treatment of childhood acute lymphoblastic leukemia (ALL), 6-mercaptopurine (6-MP) is essential for early intensification and maintenance therapy. Recently, it has been reported that a gene polymorphism of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) rs116855232 is associated with the 6-MP induced severe myelotoxicity. Since the NUDT15 rs116855232 polymorphism is relatively common in East Asian and Hispanic populations, it is important to evaluate the association between the polymorphism and 6-MP for determining the dose of effective therapy and avoiding the side effect in Japan. However, there are few reports on the association between NUDT15 polymorphisms and the therapeutic efficacy or side effects of 6-MP in the early intensification; most previous reports focused on the maintenance therapy so far. The purpose of this study is to clarify the association between NUDT15 polymorphism and the actual treatment status with 6-MP or its side effects, therefore to contribute to the effective and safe treatment of childhood ALL in Japan. Methods Twenty-four patients with ALL who received early intensification therapy according to the JPLSG ALL-B12 or JPLSG ALL-T11 protocol at the Department of Pediatrics, Hokkaido University Hospital, between April 2013 and May 2021 were included in the study. We retrospectively collected the clinical and laboratory data from the clinical records. And we also performed the sequence analysis of the exon 1 and 3 in NUDT15 gene Results Genetic analysis of NUDT15 showed no nucleotide changes other than rs116855232. Twenty patients were CC (wild-type), 4 patients were CT (heterozygous-variant), and 0 patients were TT (homozygous-variant). Of the 4 patients with heterozygous-variant, one patient received a reduced dose of 6-MP because of early onset myelotoxicity during early intensification therapy. In this patient, the total dose of 6-MP was 70% of the standard dose. All the 24 patients showed myelotoxicity and hepatotoxicity during early intensification therapy. Correlations between NUDT15 haplotype and side effects as myelotoxicity and hepatotoxicity were not significant. Discussion In the heterozygous-variant of NUDT15 rs116855232, the incidence and degree of myelotoxicity and hepatotoxicity during early intensification therapy did not differ from the wild-type. The international consortium (Clinical Pharmacogenetics Implementation Consortium Guideline, 2018) recommends that the dose of 6-MP should be reduced to 10mg/m2/day in patients with homozygous variant of NUDT15, however, the reduction of the starting dose of 6-MP in those with heterozygous variant is not recommended. Of note, these recommendations were made based on the data in the maintenance therapy. Our study suggests that the reduction of the starting dose may not be necessary in children with heterozygous variant. The NUDT15 rs116855232 polymorphism is common in Japan, with 10% of heterozygotes and 1.1% of homozygotes. In future study, a larger study on the association between NUDT15 polymorphism and treatment outcome including side effects in the early intensification is needed in East Asia to confirm the results of our study. Disclosures No relevant conflicts of interest to declare.

CTNI-42. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA

BACKGROUND Ruxolitinib is a novel, potent, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. METHODS Newly diagnosed patients with MGMT not hypermethylated, Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily. Patients with MGMT hypermethylated glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks. RESULTS 45 patients had survival data, 25 patients were in Arm I and 20 arm in II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p=0.01 and p= 0.002), respectively. 9 patients had partial response, 16 patients were stable, and 28 patients had progression. CONCLUSION Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone..