Steve Gore

Methods of gene inactivation include genetic events such as mutations or deletions. Epigenetic changes, heritable traits that are mediated by changes in DNA other than nucleotide sequences, play an important role in gene expression. Two epigenetic events that have been associated with transcriptional silencing include methylation of CpG islands located in gene promoter regions of cancer cells and changes in chromatin conformation involving histone acetylation. Recent evidence demonstrates that these processes form layers of epigenetic silencing. Reversal of these epigenetic processes and up-regulation of genes important to prevent or reverse the malignant phenotype has therefore become a new therapeutic target in cancer treatment.

PURPOSE: This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. EXPERIMENTAL DESIGN: Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. RESULTS: The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. CONCLUSION: The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit.

BACKGROUND: Irritable bowel syndrome (IBS) costs the National Health Service almost £12 million per annum. Despite national guidelines advising primary care management, these have failed to stem secondary care referrals of patients with likely IBS for unnecessary and costly assessment and investigation without necessarily achieving resolution of their symptoms. METHODS: In 2011, an integrated team from primary and secondary care developed a business case using baseline data to create a Somerset-wide IBS pathway using Clinical Commissioning Group funding. This provided face-to-face general practitioners (GP) education, developed a diagnostic pathway and funded faecal calprotectin (FC) testing to exclude inflammatory pathology for patients aged 16-45 years with likely IBS and no alarm symptoms. For those with FC≤50 μg/g, we provided a management algorithm and community-based dietetic treatment. Audit results measured usage and outcomes from FC testing, changes in patterns and costs of new patients reviewed in gastroenterology outpatients and dietetic IBS treatment outcomes. RESULTS: The proportion of new patient slots used reduced from 14.3% to 8.7% over 10 months while overall costs reduced by 25% for patients with no alarm symptoms and likely IBS aged 16-45 years. FC results confirmed research findings with no inflammatory pathology, if FC≤50 μg/g over 2 years. 63% of patients had satisfactory control of their IBS after specialist dietetic input with 74% reporting improved quality of life. CONCLUSIONS: The combination of GP education, providing diagnosis and management pathways, using FC to exclude inflammatory pathology and providing an effective treatment for patients with likely IBS appeared successful in our pilot. This proved cost-effective, reduced secondary care involvement and improved patient care.

The Joint International Conference on Acute Promyelocytic Leukemia and Differentiation Therapy held from October 4-7, 2001 in Rome, Italy was part of a series of biannual conferences, which had its beginnings in Sardinia in 1985, with the goal of establishing differentiation induction and programmed cell death as cancer cell-selective therapies. As in the past, the organizers of this meeting joined basic and clinical investigators in workshops to establish collaboration and information exchange. Because only a portion of the conference is summarized, additional information can be obtained from the abstracts published in Journal of Biological Regulators and Homeostatic Agents, Volume 15, 2001. The next International Conference on Differentiation Therapy will be held in Shanghai from October 24-27, 2003.

Background: Patients (pts) with newly diagnosed acute lymphoblastic leukemia (ALL) often relapse even with achieving complete remission (CR) and minimal residual disease (MRD) negative (MRD-) status after chemotherapy (chemo). Blinatumomab (blin) is a bi-specific T cell engager molecule approved for relapsed/refractory ALL pts and pts MRD positive (MRD+) (>0.1%) in 1st or 2nd CR. E1910 was a phase III trial randomizing pts age 30-70 yrs to chemo +/-blin to test whether blin improves outcomes in BCR:ABL-negative B-ALL. The study showed that in pts who were MRD- after induction, there was a significant improvement in overall survival (OS) in favor of the blin arm. These subgroup analyses describe outcomes in pts based on age (< or > 55 yr) and depth of MRD (undetectable vs between undetectable-0.01%). Aims: Primary objective compared OS in MRD- pts who received chemo +/- blin. Subgroup analyses look at outcomes based on age <55 or >=55 yrs, which was a pre-specified stratification factor. Additional subgroup analyses look at depth of MRD below 0.01%, which was not a pre-specified stratification factor. Methods: Pts received 2.5 mo of combination chemo using a BFM-like regimen adapted from the E2993/UKALLXII clinical trial with extended remission induction, addition of pegaspargase for pts <55 yr of age and addition of rituximab for CD20+ pts. Details regarding remission induction (step 1), high dose methotrexate with pegaspargase for CNS prophylaxis (step 2), blin randomization (step 3), and maintenance (step 4) or hematopoietic cell transplant (HCT) were presented previously at ASH 2022. MRD status was determined centrally by 6-color flow cytometry with level of sensitivity of 0.01%. MRD- was defined as <0.01%. With a minimum of 190 MRD- pts, the study had an 80% power to detect a 45% reduction in hazard rate in the blin arm relative to the control chemo arm, using one-sided log rank test at significance level of 0.025 and assuming 2 yrs of follow-up. Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms was conducted using age, CD20 status, rituximab use, and whether pts were intended to receive HCT or not as stratification factors. Results: 772 pts were screened and 488 were enrolled. Median age was 51 yr. 224 MRD- pts were randomized, 112 pts to each arm. 22 pts in each arm proceeded to allogeneic HCT. The CR/CRi rate after induction was 81%. Among MRD- pts, OS significantly favored the blin arm (median OS: not reached vs. 71.4 mo; Hazard ratio (HR) 0.42, 95% CI: 0.24 - 0.75; two-sided p=0.003). The RFS in MRD- pts (n=224) favored the blin arm (median RFS: not reached vs. 71.4 mo; HR 0.46, 95% CI:.027-0.78; p=0.004). In MRD+ pts (N=62), the OS for blin vs control arm was (median OS: not reached vs 22.4 months; HR 0.39, 95% CI: 0.14-1.10; p=0.066). In MRD- pts < 55 yr (n=132), OS favored the blin arm (median OS not reached vs not reached; HR 0.18, 95% CI: 0.06-0.52; p <0.001). In MRD- pts >55 yr (n=92), the OS for blin vs control arm was (median OS not reached vs. 71.4 mo; HR 0.77, 95% CI: 0.37-1.58; p=0.47). In pts with undetectable MRD (n=187) at randomization, OS favored the blin arm (median OS not reached vs. not reached; HR 0.51, 95% CI: 0.27-0.97; p=0.038). In pts with MRD between undetectable and 0.01% (n=37), the OS for blin vs control arm was (median OS not reached vs. 38.0 mo; HR 0.35, 95% CI 0.06-1.94; p=0.16). Summary/Conclusion: Adding blin to chemo improves OS and RFS in pts MRD- at randomization. The effect of blin was particularly evident in pts < 55 yr and in patients with undetectable MRD. Keywords: B cell acute lymphoblastic leukemia, Acute lymphoblastic leukemia, Immunotherapy