Samah Nassereddine

The Role of Mutant IDH1 and IDH2 Inhibitors in the Treatment of Acute Myeloid Leukemia.

For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. Inhibition of various classes of αKG-dependent dioxygenases results in dramatic epigenetic changes in hematopoietic cells, which has been found to directly impair differentiation. In addition to a global dysregulation of gene expression, other mechanisms have been described through which R2-HG promotes leukemic transformation including the induction of B cell lymphoma 2 dependency and stimulation of the EglN family of prolyl 4-hydroxylases (EglN). Due to the fact that mutations in IDH1 and IDH2 are acquired early during AML clonal evolution as well as because these mutations tend to remain stable during AML progression, the pharmaceutical industry has prompted the development of specific mutant IDH enzyme inhibitors. More recently, the FDA approved the first mutant IDH2 inhibitor, enasidenib (AG-221), for patients with relapsed or refractory IDH2-mutated AML (RR-AML). This has brought a lot of excitement to researchers, clinicians, and patients, especially because the treatment of AML remains challenging and is still associated with a high mortality.

PD-1 signaling and inhibition in AML and MDS

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.

Disseminated intravascular coagulation-like reaction following rituximab infusion

Rituximab generally is a well-tolerated medication used in a variety of haematological and autoimmune conditions. The safety profile of the medication has been reviewed in the literature. Infusion reactions due to cytokine release are the most common side effects. With the increased use of rituximab, there is an increase incidence of cytopenias, most commonly thrombocytopenia and leucopenia. Coagulopathy is quite rare, reported previously in four cases in the literature. We highlighted the clinical course of a 39-year-old patient with precursor B-cell acute lymphoblastic leukaemia who was started on rituximab infusion. The patient developed a cytokine-release syndrome with haemodynamic instability, followed by rapid-onset cytopenias and disseminated intravascular coagulation abnormalities characterised by coagulopathy with fibrinolysis and mucocutaneous bleeding. The report is followed by a review of the literature. It is important to recognise rituximab-induced coagulopathy early as part of the differential diagnosis of thrombocytopenia and disseminated intravascular coagulation following rituximab administration.

A Rare Case of Lymphomatoid Granulomatosis Occurring with Ulcerative Colitis

Lymphomatoid granulomatosis (LyG) is a rare type of angiocentric and angiodestructive lymphoproliferative disorder. We report a rare presentation of lymphomatoid granulomatosis in a patient with ulcerative colitis who’s been maintained on 6-Mercaptopurine for prolonged period of time. Although it is not clear whether inflammatory bowel disease (IBD) by itself is associated with such disorder or whether the use of immunosuppressive agents for the treatment of IBD induces EBV related lymphoproliferative disorder, it is important that clinicians are aware of the possible occurrence to ensure appropriate diagnostic evaluation and intervention.

Post-Transfusion Purpura: A Case Report of an Underdiagnosed Phenomenon

Post-transfusion purpura is a rare transfusion-related complication that often goes undiagnosed. It is due to alloimmunization against platelet antigens which leads to acute profound thrombocytopenia following the transfusion of any platelet-containing product (red blood cells or platelets). It is commonly seen in multiparous women. Here, we report a case of post-transfusion purpura in a 56-year-old multiparous woman who developed acute thrombocytopenia seven days following a packed red blood cell transfusion. We will discuss the clinical presentation, diagnosis, workup and treatment of this rare disease. It is important to recognize this entity separately and to include it in the differential diagnosis of acute thrombocytopenia after a recent blood transfusion. Treatment for this condition consists of intravenous immunoglobulins, corticosteroids or plasmapheresis.

Integrating Genomics in Myelodysplastic Syndrome to Predict Outcomes After Allogeneic Hematopoietic Cell Transplantation

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic neoplastic disorders most commonly occurring in the elderly population; MDS has a tendency to progress to acute leukemia. Although epigenetic therapies have improved the outcomes of MDS patients, allogeneic hematopoietic cell transplantation remains the only curative option. Molecular characterization of MDS using next-generation sequencing has expanded not only the knowledge on MDS but also the depth of understanding of evolution and contribution of recurrent somatic mutations in precursor conditions. Rapidly evolving genomic information on MDS may provide clinicians with better risk stratification tools and may also aid in supplying useful information to allow comprehensive therapeutic decision making for MDS patients. In this concise review, we summarize the current knowledge and understanding of recurrent somatic mutations in MDS and discuss salient genomic information predicting response and influencing therapeutic outcomes in the context of allogeneic hematopoietic cell transplantation, as well as the potential application of these findings into future clinical practice.

P-093 Always Seen But Often Overlooked—Shortfalls in Skin Protective Practices Counseling for IBD Patients

Background:Patients with inflammatory bowel disease (IBD) have many unique health care needs. There is increasing evidence of an elevated baseline risk of skin cancer among individuals with IBD. This elevated risk may be related to the underlying disease, the use of certain immunomodulating medications, or the combination of the 2. It is recommended that individuals with IBD be counseled about preventative measures to reduce their risk of skin cancer. This study aims to examine physician counseling practices regarding skin cancer risk and prevention for IBD patients. Methods:A retrospective review was completed using an electronic medical record of consecutive IBD patients who presented for surveillance colonoscopy at an urban academic medical center during a 1-year period. Data regarding patient ethnicity, IBD type and extent, current treatment regimen, documentation of counseling regarding skin cancer and preventive practices, and colonoscopic findings were compiled in a database created with Microsoft Excel. Patient confidentiality was maintained. The study was approved by the university institutional review board. Statistical analysis was performed using Fishers exact test, with statistical significance set at P < 0.05. Results:There were 136 IBD patients included, 57 (41.9%) were male and 79 (58.1%) were female. Sixty-eight patients were Caucasian (50.0%), 34 (25.0%) African American, 8 (5.9%) Latino, 14 (10.3%) were of “other” ethnicity, and 12 (8.8%) were of unknown ethnicity. 78 had ulcerative colitis and 58 had Crohns disease. Of the 136 IBD patients, 46 (34%) were counseled on skin cancer preventative measures or referred to a dermatologist. Twenty-seven (39.7%) Caucasian and 8 (23.5%) African American patients were counseled. 28 (35.9%) ulcerative colitis patients and 18 (31.0%) Crohns patients were counseled. There was no statistically significant difference in the rate of skin protective counseling based on race/ethnicity (P = 0.2555) or disease type (P = 0.5869). Conclusions:Compared to the general population, IBD patients are at increased risk for the development of skin cancer. It is recommended that these patients receive counseling on skin protective practices. In this study only one-third of medical records showed documentation of counseling or dermatology referral. The shortfall in counseling or referral practices may be attributed to the complex nature of care required for IBD patients, decrease awareness or lack of clear documentation. While this study is limited due to size, the data should serve as a reminder to include counseling for skin protective in IBD patients. Efforts to increase awareness of health care providers and patients about skin cancer risks are important.

Sa1035 A High Stakes Learning Environment: Fellow-Performed Colonoscopies Are Associated With Lower ADRs

and presentation skills. Seventy-five percent of these fellows subsequently taught gastrointestinal pathophysiology. The majority of fellows organized teaching sessions locally, regionally and nationally in their current positions. One third perceived that the fellowship helped their academic promotions. On the basis of these data, we recommend that an optional, unfunded Gastrointestinal Pathophysiology Teaching Fellowship be incorporated into GI Fellowship Programs as a means of increasing academic teaching and leadership skill sets in interested fellows.

Su1101 Investigating the Smoking Gun: Should Tobacco Use Be Incorporated Into Colorectal Screening Guidelines?

Background: Inadequate bowel preparation before colonoscopy is common, resulting in clinical and economic harms. The US Multi-Society Taskforce advocates use of both written and oral instructions for patients before colonoscopy. However, little is known about the most effective method of patient education. This systematic review aims to assess the effectiveness of patient-oriented educational interventions in improving the quality of bowel preparation. Methods: Studies were identified from MEDLINE, EMBASE, Cochrane, CINAHL, and Web of Science. Two investigators evaluated each abstract for the following inclusion criteria: evaluation of a patient-oriented educational intervention, prospective design, and measurement of bowel preparation quality with a validated scale. Included studies underwent duplicate data extraction by 2 investigators using a standardized approach. Extracted data included the method of intervention, timing of intervention, staffing of intervention, purgative used, bowel preparation scale used, and bowel preparation quality. Methodological quality of studies was assessed using amodified Downs and Black instrument. Due to significant heterogeneity in assessment of outcomes, meta-analysis was not performed. Results: 1080 unique published studies were identified, and 7 of these studies met inclusion criteria. Five studies were randomized controlled trials, and 2 were quasi-experimental. The number of patients analyzed ranged from 99 to 969. 3 studies were performed in the US, 2 in Taiwan, 1 in China, and 1 in Korea. 3 interventions used paper-based tools (1 cartoon, 2 illustrated brochures), 2 interventions used videos, 1 intervention used face-to-face education, and 1 used telephone calls. In 6 of the 7 studies, the educational intervention was effective in improving bowel preparation quality, with an absolute increase in bowel preparation adequacy ranging from 2% to 32%. No study accounted for all significant confounders of bowel preparation quality (i.e. constipation, diabetes, opiates, socioeconomic status, literacy rate, age, gender, BMI). Validity scores ranged from 12-23, with a median value of 18, indicating fair methodological quality. Conclusions: Patient-oriented educational interventions significantly improve bowel preparation quality, but existing studies are of variable quality and may have limited generalizability. Gastroenterologists should work internally and with referring practices to ensure that patients receive evidence-based preparation education. Future studies should focus on comparative effectiveness and cost-effectiveness of educational interventions