Q12 Hours Research Articles

VR-CAP Alternating with Rituximab and High-Dose Cytarabine: An Effective First-Line Mantle Cell Lymphoma Regimen Prior to Autologous Stem Cell Transplant

Background: Mantle Cell Lymphoma (MCL) remains incurable, though induction regimens including high-dose cytarabine followed by autologous stem cell transplant (ASCT) provide prolonged disease control. VR-CAP affords superior complete response (CR) rates and survival compared to R-CHOP in older adults with mantle cell lymphoma, but causes significant thrombocytopenia. To improve pretransplant CR rates and outcomes, we administered an alternating regimen of modified VR-CAP and rituximab with high-dose cytarabine (VR-CAP/R+ara-C) on a standard-of-care basis to newly diagnosed MCL patients in need of treatment. Herein we describe our results with this regimen administered at our center, and at referring sites, employing these FDA-approved drugs in a novel sequence prior to ASCT.Methods: We retrospectively reviewed features of a uniformly treated cohort of patients with newly diagnosed MCL and indications for therapy. VR-CAP was modified to include 2 bortezomib doses (1.3 mg/m2 subcutaneously D1 and D8) and given for 3 cycles, alternating with 3 cycles of rituximab and cytarabine (3 gm/m2 for patients under 60, or 2 gm/m2 for patients 60 or over, 4 doses q12 hours). Other doses were standard, with adjustments left to treating physician discretion.Cycles were given every 21 days, followed by stem cell collection on recovery from nadir of cycle 6. Growth factor support, biweekly laboratory evaluations, and transfusional support were performed as part of institutional standard-of-care. Events for Kaplan-Meier analysis included disease relapse, refractory disease, start of second line/other therapy, or death. EFS and OS were measured from diagnosis.Results: 19 patients have been treated to date. Median age is 57 (range 37-67) and 30% are female. MIPI-combined risk group is low: 8, int:6, high: 5.Patients started VR-CAP/R+ara-C at a median of 28 days from diagnosis (range, 11-106 days). Median number of platelets transfused during VR-CAP/R+ara-C was 4 (range, 0-16), and these occurred exclusively during high-dose cytarabine cycles. Dose reduction of cytarabine was required (clinician discretion) for 6/8 pts starting at 3 gm/m2 and 0/6 pts starting at 2 mg/m2. (For 5 pts. cytarabine dose modifications are unknown).Complete response to induction (PET, marrow, and endoscopy when indicated) were observed in 14/19 patients, or 14/17 (82%) when considering only the 17 who completed all 6 cycles.Stem cell collection on recovery from cycle 6 was achieved in 1 day of apheresis for 10 patients; 5 required 2 days. Two patients required plerixafor but others were mobilized with GCSF 10mcg/kg alone. To date, fourteen pts have proceeded to ASCT. Reasons for the 5 others not receiving ASCT include: 2 change of regimen (after bowel perforation complicated the first cycle for one, and due to psychiatric comorbidity for another); 1 required allogeneic transplantation for refractory disease; 1 declined autologous transplant (censored); and 1 has collected but not yet undergone ASCT. Median CD34+ cell dose was 9.5 x 10^6/kg. Median time to platelet engraftment >50k is 13.5 days, and 15 days for neutrophil engraftment >500/uL.With a median follow-up of 13 months, there have been no deaths among the 19 pts. Rituximab maintenance was given in 6/14 pts who underwent ASCT. EFS is shown in Figure 1. The three observed events include 2 patients who changed therapy as noted and the pt. who had refractory disease and underwent additional salvage and allogeneic SCT.Conclusions: Alternating induction therapy with VR-CAP/R+ara-C, 3 cycles each, produces a promising CR rate and permits adequate stem cells. Reduction of starting cytarabine dose from 3 gm/m2 among younger MCL patients may reduce platelet transfusion requirements while preserving efficacy of this regimen. Prospective comparative trials of VR-CAP/R+ara-C, and analogous regimens incorporating novel agents, are warranted. [Display omitted] DisclosuresSmith:Sharp: Research Funding; Janssen: Research Funding; Merck: Research Funding; Portola Pharmaceuticals: Research Funding; Dohme Corp: Research Funding; Seattle Genetics: Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Genentech: Research Funding. Shadman:Genentech: Consultancy, Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; PLEXXIKON: Research Funding; Emergent: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Other: advisory board, Research Funding; Gilead: Research Funding; Celgene: Research Funding; AbbVie: Other: advisory board.

Continuous Platelet Transfusion As a Potential Desensitization Regimen in HLA Class I Alloimmune-Mediated Platelet Refractoriness

Background: The development of HLA antibodies is responsible for 4-8% of platelet transfusion refractoriness (PTR). The presence of HLA antibodies is a clinical complication that is generally managed by the selection of products that are negative for the antigens cognate to the patient's antibodies. Often, this selection is facilitated by targeted recruitment of donors with known HLA types. However, for very broadly HLA-alloimmunized patients, compatible products may be exceedingly scarce or completely unavailable, precluding the ability to consistently provide products the patient will likely increment to and benefit from. Here we describe a case of a patient with severe aplastic anemia (platelet count chronically <1 K/uL) and platelet transfusion refractoriness secondary to broad HLA-alloimmunization (98% PRA). HLA compatible products were unavailable due to the patient's rare HLA type and breadth of antibodies, and attempts at procuring compatible products via multiple national agency searches were unsuccessful. Thus, the patient could only be supplied with HLA incompatible products, which yielded insufficient post-transfusion platelet corrected-count increments (CCI). Her course was eventually complicated by multifocal intracranial hemorrhages, necessitating ICU admission with aggressive platelet transfusion support, immune-targeting therapy consisting of IVIg, and aminocaproic acid and recombinant activated factor VIIa.Methods: A continuous platelet infusion, or “platelet drip,” was employed in order to provide platelet transfusion support in the face of her severe thrombocytopenia with profound refractoriness. This consisted of consecutive transfusions of 4-6 equivalent unit apheresis platelet products (“doses”) transfused over 4 hours with a 15 minute post-transfusion CBC obtained from Q8 to Q12 hours to assess platelet increments. This ultimately resulted in 24-30 equivalent unit platelet product infusions/day.Results: Two days into the continuous platelet infusion, the patient began incrementing appropriately to occasional platelet products (CCI>>5) and, consequently, the infusions were able to sustain a platelet count >10K/uL, with a range of 20-70 K/uL, over the subsequent week. The improved counts, along with the patient's improved clinical condition and stable imaging findings showing resolving intracranial hemorrhages, allowed the transfusion support to be goal-directed targeting a prophylactic platelet threshhold of 10K/uL. Continued monitoring of the patient's CCIs enabled the identification of permissive antigens (i.e., allogeneic platelets with HLA antigens predicted to be incompatible with the patient's serum by solid-phase testing but were found to result in satisfactory increments); this knowledge allowed progressive widening of her permissive donor pool and enabled continued prophylactic support as needed. After three weeks the patient was able to be discharged from the ICU.Subsequent HLA class I antibody screens using flow-cytometry based single antigen bead (SAB) technology revealed progressive decrease in the patient's mean fluorescence intensity for most of her antibody specificities, with the majority of her class I A antibodies falling to undetectable or near-undetectable levels (while previously >5000 MFI). Simple regression analysis (RStudio 1.0.153, R version 3.4.1) was used to test to how level of exposure to individual HLA platelet antigens (as measured by the number of doses with a given antigen) affected subsequent MFI levels. The results of the regression indicate that pre MFI and exposure explain 70.6% of the variance (R2=0.706, F(2,78)=93.7, p=<2.2e-16). It was found that exposure is a significant predictor of decreased MFI (b=-107.20, p=0.01422). High initial MFI was strongly associated with high subsequent MFI (b=0.75, p= <2.2e-16).Conclusions: This data raises the possibility that large bolus platelet infusions could not only be of immediate therapeutic benefit in patients with HLA-alloimmune-mediated platelet refractoriness, but may also accelerate the evanescence of the responsible antibodies. Further research is warranted to explore this possibility, and to ascertain the potential magnitude of this effect in comparison to competing factors such as natural evanescence and/or B-cell immunosuppressive or immunomodulatory therapies. DisclosuresNo relevant conflicts of interest to declare.

Unusual Presentation of Myxedema Coma in Type 1 Diabetes Mellitus With Hyperglycemia and Polysubstance Abuse

Background: Myxedema coma is a severe manifestation of hypothyroidism that typicallypresents with altered mental status and requires close monitoring in the intensive care unit dueto 30-60% mortality rate. Clinical Case: A 56 year old white male with type 1 diabetes with recurrent DKA, polysubstanceabuse, Bipolar disorder on lithium and post surgical hypothyroidism presented due to change inmental status after being brought in by sister. Patient was found to be lethargic with confusionthat worsened over the last week. The patient was admitted several times in the past monthsecondary to pneumonia, sepsis, and recurrent DKA. On physical examination, he found to have lethargy, macroglossia, hyporeflexia, and periorbitaledema. Patient had acute respiratory failure with metabolic encephalopathy, bradycardia,tachypnea, severe hyperglycemia, hypotension of 77/51, tachypnea of 31 breaths per minuteand hyponatremia. Laboratory findings showed T4 levels 2.87(n=5.28-9.87ug/dL) withundetectable FT4 and elevated TSH (>50, n=0.300-4.500uIU/mL). Electrolyte panel showedhyponatremia (133, n=136-145mmol/L), hyperglycemia up to 532mg/dL and lithium levels werewithin normal limits (n=0.5-1.5 mmol/L). Urine drug screen was positive for cocaine. A CT scanof the head was negative. His myxedema score was diagnostic (>60). The patient wasdiagnosed with myxedema coma and admitted to the ICU. Patient was treated with IV LT4 400mcg, LT3 10mcg and hydrocortisone 100mg and started onIV LT4 100mcg daily, LT3 2.5mcg daily and hydrocortisone 100mg Q8 hours. There was wideglycemic variation from 46-532 mg/dL on POCT. The patient improved clinically, with resolutionof lethargy, confusion, fatigue, improved appetite, and improved lab work of FT3 2.30 (n=2.28-3.96pg/mL), FT4 at 0.76 (n=0.50-1.26ng/dL) and was downgraded from the ICU. On hospitalday four, he was transitioned to oral levothyroxine and discharged home. Conclusion: It is important to diagnose early and promptly manage decompensatedhypothyroidism in the setting of other comorbidities such as hyperglycemia in diabetes andpolysubstance abuse. The cocaine in the system may cause tachypnea and tachycardia. Manyconditions may have altered mental status, but with a history of hypothyroidism, Myxedemacoma should be on the differential due to its high mortality rate.

POS-692 Euglycemic Diabetic Ketoacidosis Related to SGLT2 Inhibitor Use in Kidney Transplant Patient with Squamous Cell Carcinoma

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have renal protective effect in diabetic and non-diabetic patients with significant reduction of cardiovascular events. The data is emerging for the short-term efficacy and safety of SGLT2 inhibitor in diabetic kidney transplant patients. Diabetic ketoacidosis is a well recognized side effect of SGLT2i with variable predisposing factors. There is limited data regarding the use of SGLT2i in oncology patients. We described a case of diabetic kidney transplant patient on dapagliflozin who developed DKA during active therapy for squamous cell carcinoma. A 65 years old female, known to have hypertension and diabetes mellitus type 2 leading to end stage renal disease. She underwent living unrelated kidney transplantation in 2018. Her home medications included insulin glargine, dapagliflozin 10 mg, pantoprazole 40mg, prednisolone 7.5 mg daily, cyclosporine 125 mg q12 hours and atorvastatin 20mg. She was diagnosed with right inner cheek moderately differentiated keratinizing squamous cell carcinoma with submandibular lymphadenopathy (Stage: cT4aN2M0). She was initiated on concurrent chemotherapy (Cetuximab) and radiotherapy. Cycle 4 of therapy was complicated with poor oral intake and severe mucositis for 3 days prior to admission. She had evidence of acute kidney injury stage 1 in transplanted kidney (serum creatinine increased from baseline of 58 to 110 micromole/l). Other laboratory investigations revealed hyperkalemia 5.7mmol/l, metabolic acidosis 6mmol/l, high anion gap metabolic acidosis, normal lactate level, arterial PH of 7.1, ketones were positive in urine and blood glucose level of 12mmol/l. She was diagnosed with severe euglycemic diabetic ketoacidosis DKA, due to SGLT2i (dapagliflozin 10 mg) and starvation. She required critical care admission with rigorous IV hydration, insulin infusion per DKA protocol, IV sodium bicarbonate, IV hydrocortisone and IV cyclosporine. Her clinical condition improved by fifth day of critical care. Urinary tract infection and re-feeding syndrome post nasogastric enteral feeding complicated her hospital course. Dapagliflozin was held and next cycle of chemo-radiotherapy was delayed. Some of the potential risk factors for euglycemic DKA induced by SGLT2 inhibitors are infections, withdrawal of insulin, starvation, dehydration and acute kidney injury. The underlying pathophysiologic process of ketoacidosis induced by SGLT2 inhibitors is not well established. There are few case reports describing this complication in diabetic oncology patients, leading to discontinuation of the drug. The use of SGLT2 inhibitor is limited in diabetic kidney transplant patients and about 100 cases reported in literature without evidence of DKA in short-term follow up. To the best of our knowledge, this is the first case describing a successful management of dapagliflozin-induced euglycemic DKA in kidney transplant patient with squamous cell carcinoma. SGLT2 inhibitor associated eDKA is very rare in oncology patients and this is the first case reported in kidney transplant patient who was on active chemotherapy and radiotherapy for squamous cell carcinoma. We suggest to hold SGLT2i therapy during active oncology treatment especially in the setting on severe mucositis.

Anaplastic features (AnaF) and DNA-damage repair pathway (DDR) mutations in metastatic castration-resistant prostate cancer (mCRPC).

92 Background: Anaplastic prostate cancer displays features of small-cell carcinoma, a type of neuroendocrine tumor. Treatments for anaplastic prostate cancer are based on small cell lung cancer regimens. Both AnaF and mutations in DDR pathways, including BRCA2 confer an aggressive phenotype. For patients (pts) with certain DDR mutations, olaparib (O) was recently FDA approved, and an ongoing study is evaluating whether the addition of durvalumab (D) confers additional benefit in mCRPC (NCT02484404). We evaluate a potential preliminary relationship between DDR mutations, treatment with D and O, and AnaF. Methods: This is a phase II study of O plus D in pts with mCRPC with disease that is amenable to biopsy. On-study core biopsies undergo mutational analysis. Prior treatment with enzalutamide (enza) and/or abiraterone (abi) is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Pts were categorized into those with and without AnaF as defined by Aparicio et al. (2013). AnaF include small-cell histology; exclusively visceral metastases; predominantly lytic bone metastases; bulky lymphadenopathy (≥5 cm) or high-grade (Gleason ≥8) mass in prostate/pelvis; low PSA (≤10 ng/mL) at initial presentation with high volume (≥20) bone metastases; neuroendocrine markers in histology or serum plus elevated LDH, malignant hypercalcemia, or elevated serum CEA; or short interval (≤6 months) to androgen-independent progression. Results: Of 55 pts accrued, 24 had prior abi and enza; 19 pts had prior taxane. Common adverse events include anemia, fatigue, and nausea. Also, 11 pts (20.0%) displayed clear AnaF (Table) and 43 pts lacked AnaF, including 8 (14.5%) with partial AnaF that did not meet the full criteria, 4 (7.3%) who likely did not have AnaF due to difficulty in quantifying disease burden, 29 (52.7%) who did not have AnaF, and 2 (3.6%) had unknown status. Four pts (36.4%) with clear AnaF had DDR aberrations, including 3 (27.3%) with BRCA2, 1 (9.1%) with both BRCA2 and CHEK2, and 1 (9.1%) with ATM. Conclusions: Pts with mCRPC with DDR mutations can also have AnaF. This preliminary data demonstrates that pts with anaplastic prostate cancer and pts with DDR mutations are two distinct populations with some degree of overlap. O+D is well-tolerated, and future studies should focus on finding optimal treatments for pts with AnaF without and without DDR mutations. Clinical trial information: NCT02484404. [Table: see text]

Impact of a multimodal analgesic protocol modification on opioid consumption after cesarean delivery: a retrospective cohort study

Introduction Adequate pain control is a mainstay in enhanced recovery after surgery (ERAS) protocols. ERAS protocols are widely accepted in colorectal and gynecologic surgeries and are increasingly implemented in the obstetric setting. Multimodal analgesia incorporating non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen is a mainstay of ERAS protocols for cesarean delivery, but little research has focused on the choice of NSAIDs or timing of initiation in women undergoing cesarean delivery. At our institution, patients undergoing cesarean delivery receive a standardized multimodal analgesic regimen consisting of neuraxial morphine with NSAIDs and acetaminophen. Our initial protocol involved starting the oral analgesics in the recovery room. There was variability in whether these medications were given in a timely manner or withheld in the setting of postoperative nausea and vomiting. We modified this protocol and performed a retrospective analysis to assess the impact of this change on postoperative opioid rescue requirements in women undergoing cesarean delivery under neuraxial anesthesia. Methods This retrospective analysis included patients who underwent cesarean deliveries from 1 July 2014 to 22 August 2017. With the initial analgesic protocol, patients received neuraxial morphine, followed by naproxen 500 mg PO Q12 hours and acetaminophen 650–975 mg PO Q6 hours initiated in the recovery room. After protocol revision in January 2016, the same neuraxial morphine dose was used in addition to acetaminophen 975 mg PR at the start of the case and ketorolac 15–30 mg IV at the end of the case. Postoperatively, patients received acetaminophen PO 975 mg Q6 hours, ketorolac IV 15 mg Q6 hours for 3 doses, transitioning to ibuprofen 600 mg Q6 hours. Fentanyl, oxycodone, and intravenous hydromorphone were given for breakthrough pain with both protocols. The primary outcome of the study is the need for rescue opioid analgesia. Secondary outcomes are total opioid usage, time to first rescue opioid, maximum reported pain scores, and need for rescue antiemetics. Univariate and multivariate analyses were performed controlling for variables significantly different between the two cohorts. Results 3250 patients were included in our analysis (1574 in the old protocol and 1676 in the new protocol). There was no significant difference in patient demographics or intraoperative characteristics between the two cohorts except for more primiparous women (25% vs. 17%), more Pfannenstiel incision (98% vs. 96%), and less repeat cesarean deliveries (40% vs. 44%) in the new protocol cohort. Need for rescue opioids was reduced with the new protocol at 2, 24, and 48 h [(36.46% vs. 75.73%, p < .0001), (74.28% vs 91.99%, p < .0001), (87.53% vs 95.49% p < .0001), respectively]. Among those who received opioids, opioid consumption over 48 h was reduced (median [IQR]: 55 [30, 95] vs. 40 [20, 70] mg oxycodone equivalents) after protocol revision (GMR 0.75, 95% CI 0.7, 0.80, p < .0001). The time to first rescue opioid medication was significantly longer in the new protocol compared to the old protocol (175 [79, 1057] min vs 51 [28, 104] min, p < .001). Conclusion There was a significant decrease in the need for and the dose of rescue opioid medications with the new protocol. This highlights the importance of optimizing the choice of agents, as well as route and timing of administration of the components of the postoperative multimodal analgesic regimen.

A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Frontline Selinexor and Chemotherapy Is Highly Active in Older Adults with Acute Myeloid Leukemia (AML)

Background: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by resistance to treatment and dismal outcomes, especially in the elderly. Novel approaches are desperately needed. Exportin 1 (XPO1) is involved in the selective nuclear export of certain proteins and RNA species. It is overexpressed in a subset of AML, conferring an adverse prognosis. Selinexor is a small-molecule inhibitor of XPO1 with activity in AML. Selinexor sensitizes AML cells to anthracyclines by retaining topoisomerase II in the nucleus resulting in increased DNA strand breaks. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in AML. This abstract reports the ongoing results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML, 60 years of age or older and preclinical studies to assess the mechanisms of chemo-sensitization. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized 3:1 between 7+3+selinexor or 7+3. Responding patients could go on to high dose cytarabine consolidation with or without selinexor as per initial randomization. Patients in the selinexor arm who completed all consolidation could then move to maintenance therapy with selinexor alone. Induction consisted of cytarabine 100 mg/m2/d by continuous infusion for 7 days and daunorubicin 60 mg/m2 on days 1-3. Consolidation consisted of cytarabine at 1.5 gm/m2 given Q12 hours days 1-3 with G-CSF given 24 hours following the last dose of cytarabine. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days during maintenance. Preclinical studies were conducted with murine AML cell lines. Results: Twenty-seven of a planned twenty-eight patients were enrolled to date. Of the 27 evaluable patients, 20 were randomized to the selinexor arm and 7 to the control arm. Baseline demographics are listed in Table 1. In the standard arm, both 30- and 60-day mortality were 14% (1/7). In the selinexor arm, both 30- and 60-day mortality were 10% (2/20). In the standard arm, 43% (3/7) of patients achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi). Of the 3 responders 1 has gone on to transplant. In the selinexor arm, 85% (17/20) of patients achieved a CR or CRi. Of the 17 responders, 4 have gone on to transplant. Progression free and overall survival both favor the selinexor arm with trends towards significance despite the small size of the trial (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. Selinexor induces retention of topoisomerase II in the nucleus increasing sensitivity to anthracyclines. To determine if selinexor sensitized to cytarabine viability assays using murine AML cell lines were done (Figure 2A). Selinexor significantly sensitized both cell lines to cytarabine. AML cells increase mitochondrial oxygen consumption in response to cytarabine leading to resistance. The ability of selinexor to interfere with this response was assessed using Seahorse flux analysis. AML cells treated with cytarabine for 16 hours showed a diminished mitochondrial oxygen response when co-treated with selinexor (Figure 2B). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older patients with de novo AML. Selinexor may increase response to cytarabine by interfering with nuclear-mitochondrial communication. Enrollment is ongoing. Disclosures Pardee: Rafael Pharmaceuticals: Consultancy; AbbVie: Consultancy; Genentech, Inc.: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Research Funding; Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau. Ellis:Rafael Pharmaceuticals: Consultancy. Howard:Jazz Pharmaceuticals: Consultancy. Powell:Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Genentech: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding. OffLabel Disclosure: Selinexor for the treatment of AML

Preliminary Results of a Phase II Study to Determine the Safety of Defibrotide in Children and Adolescents with Sickle Cell Disease-Associated Acute Chest Syndrome (IND 127812)

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.

A Prospective Phase II Clinical Trial of CD26/Dipeptidyl Peptidase (DPP)-IV Inhibition for Prevention of Acute Graft Versus Host Disease (aGVHD) Following Myeloablative Allogeneic Peripheral Blood Stem Cell (PBSC) Transplantation.

<h3>Introduction</h3> DPP-IV is a homodimeric type II transmembrane receptor identical to the leucocyte surface antigen CD26. The interaction of CD26/DPP-IV on T cells with its ligand caveolin-1 on antigen-presenting cells (APC) enhances T cell activation, proliferation, and cytokine production. It also upregulates CD86 on APC resulting in co-stimulation. In a xenograft mouse model, reducing CD26 expression by a monoclonal antibody prevented aGVHD and preserved graft-versus-tumor effects (Hatano et al. <i>BJH</i> 2013). In a pilot trial testing sitagliptin for enhancement of cord blood engraftment, we observed a lower than expected rate of aGVHD (Farag et al. <i>Stem Cell Dev</i> 2013) and hypothesized that CD26/DPP-IV inhibition with sitagliptin may prevent aGVHD following allogeneic PBSC transplants. <h3>Objective</h3> Conduct a prospective phase II trial to test if sitagliptin can reduce the rate of grade II-IV aGVHD by day +100 following myeloablative allogeneic PBSC transplants (ClinicalTrials.gov, NCT02683525). The primary endpoint was grade II-IV aGVHD by day +100. <h3>Methods</h3> Patients received thiotepa (15 mg/kg) and cyclophosphamide (120 mg/kg), followed by G-CSF mobilized PBSC from matched related (6/6 HLA match) or unrelated (10/10 HLA match) donors. Sitagliptin (600 mg q12 hours) was given on days -1 to day +14, together with tacrolimus and sirolimus through day +100, then tapering until day +180. In a Simon two-stage design, <8 of a total of 36 patients developing grade II-IV aGVHD by day +100 would demonstrate a reduction of aGVHD from a historical rate of 30% to <15% with 80% power and type 1 error = 0.1. <h3>Results</h3> Thirty-six (17 M; 19 F) patients of median age 46 (20-59) years were enrolled. Patients had AML (n=19), ALL (n=9), MDS (n=4), and CML (n=4). Transplants were from matched related (13 patients) or unrelated (23 patients) donors. Acute GVHD occurred in 2 of 36 patients by day +100 (1 grade II; 1 grade IV), for cumulative incidences of 5.6% (95% confidence interval [CI], 0% - 13.2%) and 2.8% (95% CI, 0% - 8.2%) for grade II-IV aGVHD and grade III-IV aGVHD at day +100, respectively (Fig 1). An additional patient developed late-onset grade II aGVHD at day +140 following abrupt stopping of immunosuppression on day +100 for low donor chimerism in absence of relapse. Significant toxicities though day +30 included grades III-IV mucositis (n=15), acute kidney injury (4 with high tacrolimus levels, 1 sepsis), viral reactivation/infection (4 CMV, 2 BK, 1 EBV, 1 HHV6), and passenger lymphocyte syndrome (n=2). Non-relapse mortality was 0% at 12 months. With median follow-up of 699 (118-1312) days, the relapse-free survival was 77.2% (95% CI, 63.2% - 91.1%) and overall survival was 94.3% (95% CI, 86.7% - 100%) at 12 months (Fig 2a-b). <h3>Conclusion</h3> CD26/DPP-IV inhibition with sitagliptin is well-tolerated and significantly reduced the rate of aGVHD by day +100 in patients undergoing myeloablative allogeneic PBSCT transplantation.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Younger Patients with Newly Diagnosed FLT3-Mutant AML Treated with Crenolanib Plus Chemotherapy Achieve Adequate Free Crenolanib Levels and Durable Remissions

Younger Patients with Newly Diagnosed FLT3-Mutant AML Treated with Crenolanib Plus Chemotherapy Achieve Adequate Free Crenolanib Levels and Durable Remissions

Selinexor in Combination with Induction and Consolidation Therapy in Older Adults with AML Is Highly Active

Background: Acute myeloid leukemia (AML) is an aggressive myeloid cancer of the hematopoietic system that primarily affects older adults and is characterized by therapy resistance and dismal outcomes. Novel approaches to treat AML are desperately needed. Selinexor is a small-molecule inhibitor of the nuclear export protein XPO1. Treatment of AML cells with selinexor was shown to sensitize them to chemotherapy in part by blocking the nuclear export of topoisomerase II, resulting in increased DNA strand breaks when an anthracycline is present. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in the relapsed setting. This abstract reports on the initial results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML 60 years of age or older. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized between 7+3 or 7+3+selinexor induction. Responding patients could then go on to high dose cytarabine consolidation with or without selinexor as per their initial treatment assignment. Patients in the selinexor arm who completed all planned consolidation could then move to maintenance therapy with selinexor alone. During induction cytarabine was dosed at 100 mg/m2 by continuous infusion for 7 days and daunorubicin was dosed at 60 mg/m2 on days 1-3. In consolidation cytarabine was dosed at 1.5 gm/m2 given Q12 hours on days 1, 3 and 5. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days in maintenance. Optional blood samples were collected just prior to and at several time points after selinexor during induction. Mononuclear cells were isolated from these samples, lysed and lysates evaluated for protein pathway drug target activation mapping by reverse phase phosphoprotein array (RPPA). Results: Thirteen patients have been enrolled to date with 12 available for evaluation. Of the 12 evaluable patients 6 were randomized to each arm. Baseline demographics are listed in Table 1. Overall the combination was well tolerated with no patients discontinuing selinexor secondary to treatment related adverse events. In the standard arm 3 of 6 patients achieved a complete remission. Of the 3 responders 1 has relapsed, 1 has gone on to transplant and one has completed consolidation chemotherapy. In the selinexor arm 5 of 6 patients achieved a complete remission and 1 patient achieved a morphologic leukemia free state. All patients given selinexor achieved a response. Of the 5 responders 3 have gone on to transplant, 1 is on maintenance therapy (completed 14 cycles) and one is completing consolidation therapy. In the standard arm no patients died during induction and 3 of 6 patients have died from progressive disease. In the selinexor arm 1 patient died during induction and none of the remaining patients have progressed (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. The patient on long term maintenance selinexor is tolerating it without significant AEs to date. Blood samples were available from 3 patients from the selinexor arm. RPPA based protein pathway activation mapping analysis of PBMCs revealed a significant increase in phosphorylation of AMPK, BAD and LC3B at one-hour post treatment that returned to baseline by 2 hours suggesting a transient increase in these pathways that was subsequently suppressed (Figure 2). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older de novo AML patients. Selinexor may increase response by modulation of AMPK, autophagy and BAD phosphorylation. Enrollment is ongoing. Disclosures Pardee: Spherix Intellectual Property: Research Funding; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics/Janssen: Speakers Bureau; Karyopharm: Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding. Manuel:Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Powell:Pfizer: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Janssen: Research Funding. OffLabel Disclosure: Selinexor is not approved for the treatment of AML

A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria

BackgroundAcute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital.MethodsChildren 24–83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects.The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken.ResultsAmong 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose.Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects.ConclusionEnteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital.Trial registrationNCT01660672.NCT01982812.

1445. Antimicrobial Activity of Novel β-Lactamase Inhibitor Combinations Tested against Organisms Causing Complicated Urinary Tract Infections in United States Medical Centers

BackgroundHigh-dose extended-infusion cefepime-tazobactam (FEP-TAZ) is in clinical development at 2g/2g q8 hours administered over 90 minutes. We evaluated the potency and spectrum of activity of FEP-TAZ, ceftolozane–tazobactam (C-T), ceftazidime–avibactam (CAZ-AVI), and comparators tested against gram-negative bacilli (GNB) causing complicated urinary tract infections (cUTIs) in United States (US) hospitals.MethodsIn 2018, 3,023 GNBisolates (1/patient) were consecutively collected and susceptibility tested against FEP-TAZ (TAZ at fixed 8 mg/L) and comparators by reference broth microdilution methods. Percentage of isolates inhibited at ≤8 mg/L (CLSI, cefepime high dose) and at ≤16 mg/L (pharmacokinetic/pharmacodynamic [PK/PD] susceptible [S] breakpoint based on extended infusion and high dosage) were evaluated.ResultsFEP-TAZ (99.9% inhibited at ≤16 mg/L; Table), CAZ-AVI (99.9%S), and meropenem (MEM; 99.5%S) were the most active agents against Enterobacterales (ENT). An ESBL phenotype (CLSI criteria) was observed in 12.5%, 12.9%, and 3.6% of E. coli (EC), K. pneumoniae (KPN), and P. mirabilis (PM), respectively. FEP-TAZ and CAZ-AVI exhibited complete activity against EC, whereas C-T and piperacillin–tazobactam (PIP-TAZ) were active against 91.5% and 88.1% of ESBL-phenotype EC isolates, respectively. The most active agents against KPN were FEP-TAZ (99.6% inhibited at ≤16 mg/L), CAZ-AVI (100.0%S), and amikacin (AMK; 99.4%S). All PM isolates were S to FEP-TAZ (highest MIC, 0.12 mg/L), C-T, CAZ-AVI, MEM, PIP-TAZ and AMK. FEP-TAZ was highly active against E. cloacae (n = 94; MIC90, 0.5 mg/L; 98.9% inhibited at ≤16 mg/L) and Citrobacter spp. (n = 91; MIC90, 0.12 mg/L; highest MIC, 0.5 mg/L). Against P. aeruginosa (PSA), FEP-TAZ inhibited 97.6% of isolates at ≤16 mg/L, with spectrum of activity similar to CAZ-AVI (96.4%S), C-T (99.4%S) and AMK (97.6%S), and greater than MEM (85.5%S) and PIP-TAZ (87.3%S).ConclusionFEP-TAZ showed potent activity against ENT and PSA isolated in US hospitals in 2018, with overall spectrum (ENT + PSA) similar to CAZ-AVI and greater than C-T, PIP-TAZ, and MEM when FEP-TAZ proposed PK/PD S breakpoint of ≤16 mg/L was applied. FEP-TAZ may represent a valuable option for treating cUTIs caused by resistant GNB. Disclosures All authors: No reported disclosures.

2192. Comparative Antimicrobial Susceptibility of Gram-Negative Bacteria Isolated from Patients with Bloodstream Infections and Pneumonia when Tested against Tazobactam Combinations

BackgroundCefepime–tazobactam (FEP-TAZ) is in clinical development at 2g/2g q8 hours administered over 90 minutes (high-dose extended infusion). We compared the susceptibility (S) of Gram-negative bacilli (GNB) from patients with bloodstream infections (BSI) and pneumonia (PN) against FEP-TAZ, piperacillin–tazobactam (PIP-TAZ), and ceftolozane–tazobactam (C-T).MethodsIn 2018, 3,389 GNB isolates (1/patient) were consecutively collected from patients with BSIs (1,349) and PN (2,040) in 40 United States (US) medical centers, and tested by reference broth microdilution methods for S against FEP-TAZ (TAZ at fixed 8 mg/L), PIP-TAZ, C-T, and comparators. The percentage of isolates inhibited at ≤8 mg/L (CLSI, cefepime high dose) and at ≤ 16 mg/L (pharmacokinetic/pharmacodynamic [PK/PD] S breakpoint based on extended infusion and high dosage) of FEP-TAZ were evaluated.ResultsFEP-TAZ (MIC50/90, 0.06/0.25 mg/L) was the most active TAZ combination against Enterobacterales (ENT) with a spectrum similar to that of meropenem (MEM; 99.3/97.2%S for BSI/PN), ceftazidime–avibactam (CAZ-AVI; 99.8/99.9%S), and amikacin (AMK; 99.3/98.3%S) and retained good activity against ceftriaxone-non-S (CRO-NS) and multidrug-resistant (MDR) ENT (table). Among the β-lactams (BLMs) tested, only FEP-TAZ (57.1/58.6% [BSI/PN] inhibited at ≤ 16 mg/L) and CAZ-AVI (71.4/96.6%S) were active against carbapenem-resistant ENT (CRE). CAZ-AVI (96.7/95.2%S for BSI/PN) and C-T (96.5/94.5%S) were the most active BLMs tested against P. aeruginosa (PSA), followed by FEP-TAZ (95.0/92.1% inhibited a ≤ 16 mg/L), FEP (89.3/78.2%S), and CAZ (85.1/79.0%S). FEP-TAZ (77.8/77.3% inhibited at ≤ 16 mg/L), C-T (81.2/82.9%S), and CAZ-AVI (77.8/84.5%S) retained activity against MEM-NS PSA. FEP-TAZ was the most active BLM against Acinetobacter spp. when the proposed PK/PD breakpoint was applied.ConclusionS rates were markedly lower among isolates from PN compared with BSI. FEP-TAZ was the most active TAZ combination tested against GNB isolated from patients with BSI and PN from US hospitals and exhibited greater spectrum than the carbapenems. The results of this study support further clinical development of high-dose extended-infusion FEP-TAZ for treatment of GNB infections. Disclosures All authors: No reported disclosures.

Multimodal Analgesia in Lumbar Fusion Surgery: Impact Amidst the Opioid Epidemic

Abstract INTRODUCTION Spine surgery traditionally relies on opioid analgesics for postoperative pain management. Opioids are associated with prolonged hospital stays and opioid use disorders. Opioid-focused prescribing habits in surgery have partially contributed to the opioid epidemic. METHODS A retrospective analysis was performed comparing patients receiving a multimodal analgesia regimen after lumbar fusion surgery vs control group receiving standard analgesia regimen. The multimodal regimen consisted of Acetaminophen 975 mg TID, Toradol 7.5 mg Q6 hours for 24-ho followed by Celebrex 100 mg BID for 7-d, Robaxin 500 mg Q6 hours prn for muscle spasms, Gabapentin 300 mg/100 mg TID for 4-wk, and prn narcotic. The standard regimen consisted of Acetaminophen 975 mg TID, narcotic prn, and muscle relaxant prn. There were 12 patients in the multimodal group and 26 patients in the control group evaluated over 3-mo and 6-mo time periods respectively. Primary outcomes included hospital length-of-stay, total and IV narcotic requirements in Morphine Milligram Equivalent (MME), and VASS pain scores. RESULTS Study results demonstrate differences between patient populations when focusing on the opioid-naïve participants. Opioid-naïve patients in the multimodal group were found to have significantly lower IV narcotic requirement than the control (0.22+/−0.67 mg/d for multimodal vs 5.36+/−5.56 mg/d for standard group, P-value = .001). These patients also had shorter hospital stays than the control (2.78+/−0.83 d for multimodal vs 3.53+/−1.17 d for standard group) but the difference was just below our threshold for significance (P-value = .066). Including both opioid-naïve and opioid-tolerant patients, no significant differences were found in hospital length-of-stay, MME, IV narcotic requirement nor VASS score between the multimodal group and the control groups (P-values of .46, .81, .36, and .91, respectively). CONCLUSION Overall, the study favors using multimodal analgesia in those undergoing lumbar spinal fusion surgeries as evident by considerably reduced IV narcotic requirement and nearly significant shortened hospital length-of-stay in opioid-naïve patients compared to control.

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial.

To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. Prospective, randomized, controlled study. Thirty-three hospitals in China. A total of 710 adults 18-75 years old with severe community-acquired pneumonia. Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9-21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4-15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay.

(403) Desmetramadol has the Safety and Analgesic Profile of Tramadol but not its Metabolic Liabilities: Double-Blind, Randomized, Placebo-Controlled Trials in 103 Subjects

Desmetramadol (INN) is an investigational analgesic consisting of the (+) and (-) enantiomers of the tramadol active M1 metabolite. Tramadol is schedule IV with better safety than schedule II opioids. Tramadol is racemic and exerts analgesia by a monoaminergic effect mediated by (-)-tramadol and (-)-M1, and an opioid effect mediated by (+)-M1. CYP2D6 metabolizes (+)-tramadol to (+)-M1. CYP2D6 ultra-metabolizers can produce dangerous (+)-M1 levels and respiratory depression, whereas poor metabolizers produce insufficient (+)-M1 for analgesia. The objectives of this study were to test the hypotheses that (i) desmetramadol and tramadol doses giving equal plasma (+)-M1 yield equal hypoalgesia in metabolically normal subjects, but that (ii) the same doses in metabolically deficient subjects result in desmetramadol having greater plasma (+)-M1 and greater hypoalgesia than tramadol. Consecutive double-blind, randomized, placebo-controlled, three segment cross-over trials ‘A’ and ‘B’ investigated steady-state pharmacokinetics and hypoalgesia of 20 mg desmetramadol and 50 mg tramadol in healthy subjects without (N=43) and with (N=60) cotreatment with the potent CYP2D6 inhibitor paroxetine (20 mg daily). In the absence of CYP2D6 inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed q6 hours gave bioequivalent plasma (+)-M1: Cssmin, 26 + 6 vs. 28 + 7 ng/mL (90% CI, 0.85-1.08); Cssmax, 36 + 10 vs. 37 + 10 ng/mL (90 CI, 0.88-1.13). Hypoalgesia (cold pressor) of desmetramadol and tramadol were significantly greater than placebo, but equal to each other. In trial B, CYP2D6 inhibition significantly depressed tramadol (+)-M1 Cssmin (-58%) and Cssmax (-60%), but increased desmetramadol (+)-M1 Cssmin (46%) and Cssmax (41%). In trial B desmetramadol produced significant hypoalgesia as it did in trial A, whereas in trial B tramadol hypoalgesia was insignificant and comparable to placebo. Desmetramadol offers tramadol analgesia without metabolic liabilities. Supported by grant R44 DA027304 from the National Institute on Drug Abuse (NIDA) of NIH.

Evaluation of Underlying Cause of Genitourinary (GU) Adverse Events (AEs) in Patients with Myelodysplastic Syndromes upon Oral Administration of Rigosertib: Safety and Pharmacokinetic Analysis of Rigosertib across Three Clinical Trials

Introduction: Oncogenic mutations of Ras genes have been implicated in number of human cancers whereby the cells grow uncontrollably, and evade death signals (Ledford, Nature, 520, 278, 2015). Rigosertib is a small molecule that inhibits cellular signaling in cancer cells by acting as a Ras mimetic (Athuluri-Divakar SK, Cell 2016). Rigosertib, as a single agent, was evaluated in a Phase III clinical trial in refractory MDS patients where the drug was administered as a 3 day continuous IV infusion every other week (NCT01241500). Rigosertib has also been evaluated in Phase I/II trials via oral route of administration in patients with solid malignancies (NCT01168011); and with myelodysplastic syndromes (NCT01926587). We performed pharmacokinetic and safety analysis of 253 patients across three different trials. The pharmacokinetics and safety profile of orally administered Rigosertib was evaluated in patients with MDS and solid malignancies. The results were compared to data obtained from high risk MDS patients receiving intravenous rigosertib therapy. In this investigation, we present evidence that differential GU toxicity of Rigosertib is probably related to the route of administration and dosing regimen; and independent of the underlying disease state.Methods: Data was analyzed from three clinical studies. Study NCT01241500 was conducted with MDS patients (n = 184) who were administered Rigosertib by continuous IV infusion (1800 mg/day for 72 hours) every 2 weeks. Blood samples were collected at 6, 24, 30, 48, 56 and 72 hours after infusion initiation. In Study NCT01168011, patients with advanced solid tumors (n=33) received oral Rigosertib (560 mg) Q12 hours of a 28-day cycle (3 weeks on, 1 week off). Study NCT01926587, conducted in MDS patients (n=36) with oral administration Rigosertib in combination with parenteral Azacitidine, evaluated the same AM dose but a lower 280 mg PM dose. In both studies, pharmacokinetic assessment was conducted after administration of the AM dose (560 mg) on day 1 of cycle 1. Blood samples were collected predose and 0.5, 1, 1.5, 2, 4, 6 and 8 hours after administration. For Study NCT01168011, urine was collected for 24 hours (0-4, 4-8 and 8-24 hrs) to determine the percent of dose excreted in urine. Rigosertib concentrations in plasma and urine were determined by a validated LC/MS-MS method. Rigosertib pharmacokinetic parameters were estimated using non-compartmental analysis. Treatment emergent adverse events were recorded throughout each study.Results: There was no difference in Rigosertib pharmacokinetic parameters between the two patient populations (Table 1) upon oral administration, and the plasma concentration-time profiles were super imposable (Figure 1). Approximately 2% of the orally administered dose was recovered in the urine. In both studies, the most common AEs observed were GU AEs (dysuria, hematuria). The incidence of grade ≥2 GU toxicity observed with oral dosing was 17 of 33 (52%) and 17 of 36 (47%) in Study NCT01168011 and NCT01926587, respectively. The incidence of GU AEs in both the studies was comparable even though the PM dose was lower (560 mg vs 280mg) in study NCT01926587. Peak plasma concentration and AUC0-∞ were similar in patients with or without urinary symptoms. Compared to oral dosing, the incidences of GU AEs were dramatically lower (10%) following IV infusion despite 8-fold higher and more prolonged systemic exposure (Table 2).Conclusions: This study demonstrates that the urinary adverse events and systemic exposure are similar in patients with either solid malignancies or MDS treated with orally administered rigosertib. The incidence of GU AEs is relatively high in spite of the very low amount (2%) of the administered dose eliminated through the renal route. In contrast, the GU AEs are significantly lower when Rigosertib is administered by IV infusion despite of 8 fold higher exposure. This is probably due to the short half-life of drug and dosing holiday of 12 days between two doses within the cycle. The higher incidence of GU AE upon oral administration is likely related to the dwell time of high concentration of drug in the bladder at night in patients treated daily for 3/4 weeks. This was successfully addressed in the clinical trial, NCT01926587 expansion with risk mitigation strategies, by deploying a novel dosing regimen derived through pharmacokinetic modeling and simulation (Taft, et al; ASH 2018 Abstract Submitted). [Display omitted] DisclosuresManiar:Onconova Therapeutics, Inc: Employment, Equity Ownership. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Taft:Onconova Therapeutics, Inc: Research Funding.