Previous Regimens Research Articles

Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings.

Background and ObjectivesLiver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART).ObjectiveWe aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital.MethodsWe searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month.ResultsTen HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable.ConclusionsThe management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal.

Control of Glycemia With a Basal-Plus Regimen in People With Type 2 Diabetes Mellitus Insufficiently Controlled by Previous Treatment

Background: Type 2 diabetes mellitus (T2DM) is often characterized by insulin resistance and progressive ?-cell deterioration. With longer duration of T2DM most patients treated with oral antihyperglycemic drugs (OADs), in monotherapy or in combination, will ultimately require basal insulin therapy and even further prandial intensification later on. The basal-plus regimen is one of the proposed approaches for treatment intensification by adding one injection of prandial rapid-acting insulin to basal insulin. The CONBA+ study aimed to collect real-world data of glycemic control of T2DM patients uncontrolled on insulin/OAD therapy using the basal-plus approach in Morocco. Methods: CONBA+ study was a national, prospective, non-interventional, multicenter study involving 50 endocrinologists from Morocco. The study, conducted between June 2015 and June 2017, enrolled T2DM patients uncontrolled on their previous regimen (hemoglobin A1c (HbA1c) ? 7.5% on two OADs, glargine 100 U/mL and OADs or once daily premixed insulin). Patients continued or newly initiated once-daily insulin glargine 100 U/mL (Gla-100) and also received one injection of insulin glulisine (Glu) at the main meal in replacing any previous treatment. Demographics, glycated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial glucose (PPG), insulin doses and the frequency of hypoglycemia were assessed at baseline and at 12 and 24 weeks after study entry. Results: Overall, 854 people (46.8% men) fulfilled the inclusion criteria. At baseline, mean age was 59.0 ± 9.4 years, mean duration of diabetes 10.8 ± 6.7 years (range: 1 - 45 years), mean body mass index (BMI) 27.4 ± 4.0 kg/m 2 and mean HbA1c 9.50±1.51%. After 24 weeks, 33.0% of patients achieved target HbA1c < 7.0% (primary endpoint). In addition, mean FPG and postprandial blood glucose (PPBG) improved significantly at week 24 (change from baseline: -88 mg/dL and -108 mg/dL respectively; P < 0.001) while the number of reported severe hypoglycemia was low. Conclusions: The use of a basal-plus regimen consisting of insulin glargine 100 U/mL and insulin glulisine injected at the main meal resulted in significant improvements of glycemic parameters. In addition, the basal-plus approach showed a good safety profile with a low risk of hypoglycemia. J Endocrinol Metab. 2020;10(1):16-22 doi: https://doi.org/10.14740/jem548

Abstract OT2-02-06: Palbociclib in combination with trastuzumab and endocrine therapy (ET) versus treatment of physician's choice (TPC) in metastatic HER2-positive and hormone receptor-positive (HER2+/HR+) breast cancer with PAM50 luminal intrinsic subtype (SOLTI-1303 PATRICIA II): A multi-center, randomized, open-label, phase II trial

Abstract Background: Efficacy Interim results from PATRICIA phase II trial in HER2+/HR+ advanced breast cancer (BC) showed that PAM50 luminal disease was associated with larger and clinically meaningful progression-free survival (PFS) following palbociclib, trastuzumab and endocrine therapy compared to PAM50 non-luminal disease (Ciruelos E. et al, SABCS 2018). Based on these preliminary results, PATRICIA II was designed to select patients based on PAM50 and to include a randomization to a control arm. Trial Design: PATRICIA II is a randomized open-label, adaptive design, phase II study. Eligible patients must have centrally confirmed HR+/HER2+ and PAM50 Luminal A or B intrinsic subtype tumors and have received at least 1 (and no more than 4) prior lines of anti-HER2 regimens for locally advanced or metastatic BC, including a taxane and trastuzumab. Patients are randomized 1:1 to receive trastuzumab in combination with palbociclib at a standard dose of 125 mg/day orally 3 weeks on/1 week off and endocrine therapy (cohort C1) or treatment of physician’s choice (TPC): TDM1 or chemotherapy (gemcitabine, vinorelbine, capecitabine, eribulin, paclitaxel or docetaxel) in combination with trastuzumab (cohort C2). ET options are either an aromatase inhibitor, fulvestrant or tamoxifen. Premenopausal patients (pts) must receive ovarian suppression. Stratification factors include number of previous regimens for advanced BC (1-2 vs 3-4) and the presence of visceral disease (yes vs no). The primary objective is to assess whether the combination of palbociclib, trastuzumab and endocrine therapy is superior to TPC in terms of progression-free survival (PFS) in HER2+, PAM50 Luminal patients. The study has an 80% power with two-sided alpha=0.05 to detect a hazard ratio of 0.62 in favor of the palbociclib arm. An adaptive design will be used to compare both treatment arms. An interim analysis (IA) adjusted for multiplicity from O’Brien-Fleming method and an estimation of the conditional power (CP) will be performed at 70% of the events by an Independent Data Monitoring Committee (IDMC). Key secondary objectives are response rate, overall survival, safety, and Quality of Life. Tumor tissue and blood samples will be collected for biomarker analyses. A total of 516 patients will be screened and 232 patients will be recruited. The trial was activated in June 2019 and the recruitment is ongoing in 20 sites in Spain. The study is sponsored by SOLTI and financially supported by Pfizer. Citation Format: Eva Ciruelos, Patricia Villagrasa, Mafalda Oliveira, Sonia Pernas, Javier Cortes, Silvia Vazquez, Noelia Martínez, Antonia Perello, Begoña Bermejo, Eduardo Martínez, Isabel Garau, Mireia Melé, Alvaro Montaño, Estela Vega, Blanca Cantos, María Jose Echarri, Tomás Pascual, Jordi Canes, Pamela Céliz, Xavier González, Aleix Prat. Palbociclib in combination with trastuzumab and endocrine therapy (ET) versus treatment of physician's choice (TPC) in metastatic HER2-positive and hormone receptor-positive (HER2+/HR+) breast cancer with PAM50 luminal intrinsic subtype (SOLTI-1303 PATRICIA II): A multi-center, randomized, open-label, phase II trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-06.

Use of Telemedicine in the Evaluation of Patients with Mast Cell Activation Syndrome

Eighteen months ago, our office began evaluating patients for Mast Cell Activation Syndrome (MCAS). Patients present with multiple complaints and co-morbidities, often requiring lengthy record reviews. To manage this volume of requests, our team developed an approach that leverages telemedicine for new and established patients. We thus found ourselves capable of determining whether our approach improved care and maintained satisfaction. We employ a three-pronged approach. First, we request records from providers, after which summaries are prepared and billed ahead of initial visits. We then schedule a telemedicine visit with patients to review records and determine subsequent treatment steps. The third step is a mandatory office visit that includes a detailed physical exam and review of ordered scans and laboratory. Subsequent treatment interactions occur via telemedicine or in-office, as dictated by patient preference and office availability. Referring providers sent records prior to initial interaction, usually a telemedicine visit. Telemedicine evaluations were elected primarily due to distance from the office (> 2 hrs. travel in state or out-of-state). Patient satisfaction was approximately 90% with this approach. Compliance with treatment was encouraging considering insurance coverage, concern for adverse drug effects or satisfaction with previous regimens. Reimbursements for pre-visit records review (99358, 99359), consultant level (99244, 99245), new level (99204, 99205) or established level (99214, 99215) with extended time (99354) were acceptable. Telemedicine for MCAS evaluation proved useful for initial and follow-up visits with satisfactory patient acceptance and outcomes. Our three-pronged approach for patients with complex disorders enhanced their evaluation and continuing care.

Efficacy of Arsenic Trioxide Combined with ATRA and Chemotherapy for Relapsed Acute Promyelocytic Leukemia Patients

To investigate the efficacy and safety of arsenic trioxide combined with ATRA and chemo- therapy for treatment of relapsed acute promyelocytic leukemia (APL) patients. The clinic data of 25 patients with relapse APL treated in our hospital from 1996 to 2013 were collected and analyzed. Among the 25 patients, 15 patients suffered first-time hematological relapse (HR), and the other 10 patients showed first-time molecular relapse (MR). The patients with first-time replase were treated with ATO+ATRA+Anthracycline re-induction chemotherapy. The clinical features, complete remission (CR) rate, overall survival (OS), disease-free survival (DFS) and adverse events after re-induction therapy were analyzed. Fourteen of 15 hematological relapsed patients achieved the second-time hematological complete remission (CR2) after re-induction therapy except one patient died of bleeding complication during the re-induction. 8 of 14 patient showed molecular complete remission (CRm) after two cycles of therapy with this regimen. Totally, eleven out of the 14 HR patients were alive without disease till the last follow-up, and 3 of the 14 HR patients died because of bleeding complications. All of the 10 molecular relapsed patients received the second CRm after treated by the regimen. Among these 10 patients, 6 patients suffered only once relapse and continued with the molecular CR2 status, and for the other 4 patients with more than two-relapses, only 1 survived untill 89.3 months after achieved second-time CRm, and other 3 patients died because of bleeding complications. For relapsed APL patients, the treatment with ATO+ATRA+chemotherapy regimen after relapse still shows encouraging efficacy, no matter whether or not the application of ATO in the previous regimens. In addition, patients with more than two molecular relapses show a poor prognosis.

P674 Monitoring posologic change in adalimumab intensification dosing regimen from 40 mg every week to 80 mg every other week

Abstract Background The previous usual adalimumab (ADA) intensification regimen was 40 mg every week (ew)). Recently the original laboratory commercialised the 80 mg injection pen, with pharmacokinetic studies indicating an alternative intensification dose of 80 mg every other week (eow) similar to 40 mg ew, even though interchangeability has not been assessed in clinical practice. In the biosimilars era, this pen was sold to many Hospitals at the same price as the 40mg pen. For this fact and for patient comfort, we proposed our stable-intensificated-ADA IDB patients on a 40 mg ew regimen, to change the dose to 80 mg eow (clinical practice). Methods In this setting, we designed an observational study to monitor clinical, analytical and pharmacokinetic outcomes through this posologic change, for patients who signed the Informed Consent. Clinical (Harvey–Bradshaw index (HBI), partial Mayo score), analytic parameters and ADA trough levels were prospectively obtained at baseline, 4 and 8 months after posologic change. We describe the evolution of this cohort and calculate savings. Results 12 from 18 patients initially evaluated for new dose regimen were finally changed. All of them agreed to participate in the study. Eighty-three per cent were CD patients, 58% males, median age 51 years old (intecuartil range (IQR) 42–55). Median age at IBD diagnosis was 34 years (IQR 24–44). In 9 patients ADA was the first-line biologic. Median IBD duration before starting ADA was 6 years (IQR 5–8). Median time from ADA initiation to intensification was 31 months (IQR 14–55). The median time of ADA intensification was 37 months (IQR 30–66). Seventy per cent of patients were on immunosuppressors (IS) at the start of the study. Table 1 shows the results of clinical, analytical variables and ADA trough levels at baseline, 4 and 8 months. No differences were found. At 4 months, all patients maintained ADA 80 mg eow. Two patients referred mild worsening, (HBI from 3–4 to 5–6) without significant changes in CRP, calprotectin or ADA levels. They recovered after restoring the previous regimen (ADA 40mg ew). At 8 months, ADA was stopped in one patient in remission with undetectable ADA levels and positive ATI. Total savings in the first 8 months were 59022 €. Conclusion in IBD patients with stable response to ADA intensification regimen of 40 mg ew, changing to 80mg eow seems to maintain response and similar trough levels, although some patients may perceive mild symptoms. Economic savings are 50% per patient.

What are the factors affecting survival after autologous stem cell transplantation in patients with multiple myeloma?

Introduction: High-dose chemotherapy (HDC) and autologous stem cell transplantation(ASCT) still remains in the treatment of myeloma patients even during the period of new agents. Materials and Methods: We analysed the prognostic affect of pretransplant characteristics and transplant modalities on response, in 150 autologous transplant of 144 multiple myeloma (MM) patients who were transplanted in our centre between 2008 to 2017. We evaluated the affect of age, type of MM, previous treatment regimens, status pre and postfrom transplantation, time of ASCT, neutrophil and platelet engraftmant days, dose of reinfused CD34+ cells, plasma cell infiltration, international staging system(ISS) and Durie -Salmon stage at diagnosis. We examined the affect of these status on overall survival(OS) and eventfree survival(EFS). Results: The median OS and EFS after transplanation were 41 and 28 months, respectively. Median OS after the diagnosis was 57 months. Transplant-related mortality was 3,3%. We found that the lower β2- microglobulin levels,lower ISS stage,lower plasma cell infiltration, achievement good responds at the +100th day of post transplant were statistically significant independent predictor factors for longer EFS and OS. When the patients were given chemotherapy regimen with bortezomib before transplantation, these patients were seen to be a better response rate. There was showed a relationship between the using of bortezomib before transplantation with EFS(P = 0.017), but there was no relationship with OS. Conclusions: Our analysis confirms HDCT-ASCT as an effective and safe therapeutic strategy in multiple myeloma patients. This results were independent of age, first line treatment regimens and renal insufficiency. Patients with a high ISS stage were found to have shorter survival(P = 0.002). However, the EFS and OS were longer of the patients whose have good response at the 100th day of transplantation(P = 0,002, P = 0,02).

Direct Thrombin Inhibitors as the Primary Treatment Modality for Cerebral Venous Sinus Thrombosis (CVST)

Background: Cerebral venous sinus thrombosis (CVST) is an uncommon entity with improved clinical outcome over time due to utilization of advanced diagnostic tools and effective treatment modalities. Previous treatment regimen pertained to primarily medical therapies, with use of anticoagulants like Coumadin and Heparin. However the advent of Direct Thrombin Inhibitors (DTI) which do not need regular monitoring of blood coagulation panel and has better safety profile than Coumadin, has been suggested as a treatment modality for CVST in recent literature. Case Description: It is a case series of 3 adult patients presenting with intracerebral hemorrhage secondary to CVST from occlusion of dural venous sinuses. Dabigatran, a DTI was used as the primary treatment modality for a period of 6 months for 2 patients who had identifiable underlying cause and lifelong for 1 patient who had no identifiable underlying cause for dural sinus thrombosis. Patients has been followed for a total period of six months while on DTI treatment, with Magnetic Resonance Venography (MRV) of the brain performed at 6 months follow up visit to assess recanalization of the obstructed dural sinuses. All the 3 patients had improved clinical outcome at 6 months follow up visit with no added morbidity upon using DTI. Two patients had complete recanalization of obstructed venous sinuses, while 1 patient had partial recanalization at 6 months follow-up visit. No patient had increased hematoma volume while on treatment with DTI. Conclusion: This case series suggests DTI are probably effective primary treatment modality for patients with CVST with good safety profile.

Efficacy of salvage therapy with MTX-HOPE for elderly patients with heavily pretreated non-Hodgkin's lymphoma.

Methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide (MTX-HOPE) chemotherapy was originally reported in 2007 as a salvage regimen for relapsed or refractory non-Hodgkin’s lymphoma. To clarify the safety and efficacy of this regimen, we retrospectively analyzed patients at our institute. We analyzed 18 patients, including 16 with diffuse large B-cell lymphoma (DLBCL), one with follicular lymphoma (FL), and one with T-cell lymphoma. The median age at MTX-HOPE therapy was 79 (range: 68-87). Ten patients received more than 3 previous chemotherapy regimens. The median period from the initial treatment to the first MTX-HOPE administration was 53 months. No patient had severe renal dysfunction. The overall response rate was 78%, with 39% achieving CR and 39% achieving PR. The median OS and PFS after the initiation of MTX-HOPE were 10 months (range: 0.5-86 months) and 7 months (range: 0.2-86 months), respectively. The one-year OS rate was 44% and the two-year OS rate was 22%. The median number of treatment cycles was 7 (range: 1-46), and 6 patients received more than 10 cycles. Among eight patients who were over 80 years of age, 7 responded to the therapy, and the median OS and PFS of this subgroup were 19 months and 11 months, respectively. All patients tolerated the treatment well, mostly on an outpatient basis, except for one who died from infection and one who developed intracranial hemorrhage. MTX-HOPE may be a promising treatment option for elderly patients with refractory or relapsed malignant lymphoma.

Factors associated to chronic kidney disease in people living with HIV/AIDS.

Objective:to analyze the factors associated to chronic kidney disease in people living with HIV (PLHIV).Method:a paired case-control study (4 controls for each case) carried out in a specialized care service in the Southeastern of Brazil, by analyzing PLHIV medical records. The sample consisted of 85 participants, corresponding to 17 cases and 68 controls. Pearson’s chi-square test (Χ2) and Fisher’s exact test, logistic regression, Odds Ratio (OR), 95% Confidence Interval (CI) and p<0.05 were used. SPSS version 25.0 and R Core Team, 2018 version 3.5.1 were used.Results:the factors associated with chronic kidney disease identified in this study were the following: presence of Systemic Arterial Hypertension [OR=5.8, CI (95%)=1.84-18.42, p=0.001] and use of nephrotoxic anti-retrovirals in the previous therapeutic regimen [OR=3.3, CI (95%)=1.105-10.221, p=0.028]. On the other hand, age below 40 years old [OR: 0.122, CI (95%)=0.015-0.981, p=0.022] was identified as a protective factor.Conclusion:the PLHIV under study have multi-factorial exposure associated with chronic kidney disease. However, knowing these factors helps to identify the existing risks and/or renal dysfunction, in addition to supporting the clinical decision of the health professionals who directly assist them.

Comparative effectiveness of nivolumab versus clinical practice for advanced gastric or gastroesophageal junction cancer

Aim: To determine the effectiveness of nivolumab compared with routine clinical practice (RCP) for patients with gastric or gastroesophageal cancer refractory to, or intolerant of, two or more previous regimens, using real-world electronic patient records from a US population, a single-arm trial (CheckMate 032) and a randomized controlled trial in an Asian setting (ATTRACTION-2). Materials & methods: A simulated treatment comparison was conducted to predict overall survival for patients treated with nivolumab compared with RCP in the USA. Results: Results of the indirect simulated treatment comparison suggest that nivolumab is associated with a 50% reduction in the risk of all-cause mortality relative to RCP (Hazard ratio: 0.50; 95% CI: 0.36, 0.68). Conclusion: The survival benefit of nivolumab may extend more generally to the USA.

Clinical Outcomes Following the Use of Archived Proviral HIV-1 DNA Genotype to Guide Antiretroviral Therapy Adjustment.

BackgroundEvidence regarding the safety of using proviral HIV-1 DNA genotype (DNA GT) to guide antiretroviral therapy (ART) is limited. We hypothesized that HIV RNA would not increase following ART adjustment guided by DNA GT in a university HIV clinic.MethodsData were obtained from electronic medical records of adult persons living with HIV-1 (PWH) who underwent DNA GT testing and changed ART between October 2014 and November 2017. Logistic regression was used to evaluate the effect of ART switch on HIV RNA over time.ResultsEighty-three PWH had DNA GT performed, 66 (80%) switched ART, and 59 had postswitch follow-up. Data were analyzed pre-/postswitch for these 59 PWH (median age, 54 years; 71% LWH ≥10 years; 46% ≥2 previous regimens; 36% recent low-level viremia; 34% unknown medication history). On DNA GT, 58% had ≥1-class ART resistance, 34% ≥2-class, and 10% 3-class. Median follow-up (range) was 337 (34–647) days. There was no change in probability of HIV RNA ≥50 copies/mL over time (P > .05). At baseline, 76% had HIV RNA <50 vs 88% at last postswitch follow-up (P = .092). Protease inhibitor use decreased from 58% to 24% (P < .001). Average daily pills and dosing frequency decreased from 3.48 to 2.05 (P < .001) and 1.39 to 1.09 (P < .001), respectively; ART cost did not change.ConclusionsDNA GT facilitated changes in ART in a treatment-experienced population without increases in HIV RNA. Decreased pill burden occurred without increased ART cost. Further studies to identify optimal use of DNA GT are needed.

Clinical analysis of 211 cases of cesarean scar pregnancy

Objective: To investigate the rational choice of early diagnosis and treatment of cesarean scar pregnancy (CSP). M ethods: The clinical data, including age, gravidity, time to previous cesarean section, first symptom, auxiliary examination, regimen, and therapeutic outcomes, of 211 patients with CSP admitted to Sichuan Provincial People’s Hospital from March 2016 to February 2018 were retrospectively analyzed. Results: Of the 211 patients, 165 patients were first diagnosed with CSP in this hospital, and eight of them (4.85%) were misdiagnosed; 46 patients were referred to thus hospital by physicians in other hospitals, and 21 of them (45.65%) were misdiagnosed. After admission, transvaginal color Doppler sonography was performed with a blood β-human chorionic gonadotropin (β-hCG) study to confirm the diagnosis. According to the surgical approaches, 211 patients were divided into six groups: group A: hysteroscopy group (141 patients), group B: uterine artery embolization (UAE) plus hysteroscopy group (38 patients), group C: hysteroscopy plus laparoscopy group (seven patients), group D: UAE with hysteroscopy plus laparoscopy group (six patients), group E: laparotomy group (12 patients), and group F: uterine evacuation group (seven patients). There were no significant differences in age, number of cesarean sections, time from previous cesarean section, days of the missed period, diameter of the gestational sac, or blood β-hCG levels among the six groups (p &gt; 0.05). However, the cure rate, complication rate, mean intraoperative blood loss, mean operative time, mean length of hospital stay, and mean medical cost were all statistically significant between the six groups (p &lt; 0.05). Conclusions: Women who have a history of cesarean section should be vigilant and undergo a transvaginal ultrasound examination as early as possible to exclude CSP and avoid a missed diagnosis or misdiagnosis. For patients at less than or equal to eight weeks of gestation and with a gestational sac diameter less than or equal to 3.0 cm, hysteroscopy is the preferred treatment that is safe and effective. Hysteroscopy combined with laparoscopy and laparotomy are suitable for patients with a high risk of massive bleeding, for instance, patients with a thin anterior myometrium on which abundant blood flow signals are shown, or should be considered as emergency backup plans for other surgical approaches. UAE can effectively reduce intraoperative blood loss but increases the risk of postoperative complications, length of hospital stay, medical costs, and it is suitable for patients with massive bleeding during or after CSP surgery and in need of emergency hemostasis or for patients with a very high risk of bleeding confirmed by a preoperative assessment.

Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand.

Paracetamol is a common agent taken in deliberate self-poisoning and in accidental overdose in adults and children. Paracetamol poisoning is the commonest cause of severe acute liver injury. Since the publication of the previous guidelines in 2015, several studies have changed practice. A working group of experts in the area, with representation from all Poisons Information Centres of Australia and New Zealand, were brought together to produce an updated evidence-based guidance. The optimal management of most patients with paracetamol overdose is usually straightforward. Patients who present early should be given activated charcoal. Patients at risk of hepatotoxicity should receive intravenous acetylcysteine. The paracetamol nomogram is used to assess the need for treatment in acute immediate release paracetamol ingestions with a known time of ingestion. Cases that require different management include modified release paracetamol overdoses, large or massive overdoses, accidental liquid ingestion in children, and repeated supratherapeutic ingestions. The new guidelines recommend a two-bag acetylcysteine infusion regimen (200mg/kg over 4h, then 100mg/kg over 16h). This has similar efficacy but significantly reduced adverse reactions compared with the previous three-bag regimen. Massive paracetamol overdoses that result in high paracetamol concentrations more than double the nomogram line should be managed with an increased dose of acetylcysteine. All potentially toxic modified release paracetamol ingestions (≥10g or ≥200mg/kg, whichever is less) should receive a full course of acetylcysteine. Patients ingesting ≥30g or ≥500mg/kg should receive increased doses of acetylcysteine.

From the Editor’s Desk…: December 2019

From the Editor’s Desk…: December 2019

Changing the Fate of Children with Acute Lymphoblastic Leukemia (ALL) in a Limited Resources Setting

Introduction Pediatric acute Lymphoblastic Leukemia (ALL) patients have about 90% overall survival (OS) in developed countries. However, many children in low-middle income countries (LMIC) do not have access to appropriate drugs at optimal doses, a multidisciplinary medical team, laboratory resources for diagnosis and follow-up, and appropriate support therapy for morbidities and treatment-related toxicities. A 50-60% five-year OS has been reported in children with ALL in Mexico, and our center is not the exception. This low survival rate has pushed Mexican centers to develop strategies highlighting collaboration between centers with economic, research and teaching resources ("Mexico en Alianza con St. Jude MAS"), and outpatient treatment. However, each center must adapt their chemotherapy protocol to its own supplies and possibilities. We report the results of a risk adapted therapy protocol in a limited-resource treatment setting. Materials and Methods All pediatric patients with a diagnosis of ALL from January 2017 to December 2018 were classified according to risk as shown in Figure 1. Depending on risk classification, modifications to the induction, consolidation and intermediate maintenance regimens were made. The higher the risk, the higher the intensity of the regimen, as defined by the number of anthracycline doses, the presence or absence of high-dose methotrexate, and the duration of the consolidation and maintenance phases (Table 1). Demographic data is reported using distribution analysis, and the Kaplan-Meier method is used to analyze and predict overall survival, event-free survival (EFS) and relapse. Our results were compared with previous results from our institution. Results There were 35 male and 25 female patients; median age at diagnosis was 5.5. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 57 (95%), and 3 (5%) patients, respectively, with a follow-up of 16 (8-30) months. Twenty-three (38%), 21 (35%), and 16 (26%) children were classified as high, intermediate and low risk ALL, respectively. After one week of corticosteroids 46 (77%) of patients had a good response. At the end of induction 53 patients had an evaluable MRD (88%), out of which 9 were positive (17%). Median follow-up was 16 (0.6-30) months. Mortality at induction was 6 (10%) patients. Very early relapse was observed in 3(5%) of patients. Estimated 2-year relapse rate was 6%, event-free survival was 84.1%, and OS was 85%. A comparison of results obtained with previous regimens (protocols 1 and 2) and the risk-adapted treatment (protocol 3) is observed in Table 2. Conclusions The implementation of a modified chemotherapy regimen based on adjusted stratification risk was associated to improved responses as reflected by MRD. A decrease in very early relapse rate to 5%, without increasing the toxicity and death during induction was observed. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and to standardize therapy. Long-term follow-up of this patient group is required to compare OS and EFS at 5 years. This is a preliminary report, but it seems that we are changing the fate of Mexican children with ALL. Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

Impaired Nodal Shrinkage and Apoptosis Lacking Define the Adverse Independent Clinical Outcome of NOTCH1 mutated Chronic Lymphocytic Leukemia (CLL) Patients in the Age of Targeted Agents (TA)

The advent of agents inhibiting the BCR-associated kinases (ibrutinib and idelalisib) and the antiapoptotic protein Bcl-2 (venetoclax) has dramatically changed treatments algorithms of CLL as well as the role of different adverse prognosticators. The marked benefit of these new drugs has been investigated in the context of NOTCH1 mutations (M). In fact, NOTCH1 M were significantly correlated with CD49d overexpression identifying CLL with reduced lymphocytosis and inferior nodal response (Tissino, 2018). Moreover, NOTCH1 M were characterized by overexpression and increased activity of the NF-kB pathway genes, promoting tumor cell proliferation and survival (Benedetti, 2017). The primary aims of our clinical research were: i) to correlate NOTCH1 M with CD49d expression and bax/bcl-2 ratio in ibrutinib-treated patients; ii) to verify the impact of NOTCH1M on the peripheral lymphocytes redistribution and on the nodal response calculated as percentual reduction from baseline (SPD); iii) to evaluate the impact of NOTCH1 M on overall response rate (ORR), progression free survival (PFS) and overall survival (OS); iiii) finally, to assess NOTCH1 M as an independent prognostic factor. Therefore, we evaluated the efficacy of ibrutinib as single agent, in a real-life contest, on 180 patients recruited from three independent cohorts from Italy, median age 69 years (36-90), median number of previous regimens 2 [range 0-4; 26 patients (14.4%) previously untreated]. Noteworthy, 24/64 (37.5%) TP53 mutated patients were treated in first line with ibrutinib (p&lt;0.0001). Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Median follow up on TA was 25 months. NOTCH1 M were investigated with next generation sequencing (NGS) method. CD49d antigen was evaluated by flow cytometry and the threshold of positivity was set &gt;30%. Bax/bcl-2 ratio, evaluated in 113 patients, was calculated by flow cytometry, dividing mean florescence intensity (MFI) of bax by MFI of bcl-2 on CLL cells. The threshold of positivity was set at the median value &gt;1.5 (range 0.41-5.10). Sixty-five patients were NOTCH1 M (36.11%). NOTCH1 M were strongly correlated both with CD49d &gt;30% (51/65; p=0.0001) and bax/bcl-2 ratio &lt;1.5 (34/38; p=0.00007). Absolute lymphocyte counts (ALCs) were collected at days ranging from 30 to 90 on ibrutinib. NOTCH1 M were correlated with significant lower median ALCs than all other patients (10.7 x 106/ml vs 31.0 x 106/ml; p=0.0003). Moreover, the median SPD, calculated at 3-6 months on ibrutinib, was lower in NOTCH1 M patients (53% vs 80%; p&lt;0.0001), confirming a significant poor nodal response. ORR was 90% [complete response (CR): 18%, partial response (PR): 28%, PR with lymphocytosis (PR-L): 44%]. The estimate 2-year PFS and OS were 80% and 84%, respectively. Sixty nine patients (39%) discontinued ibrutinib either for progression (n=38) or for adverse events (n=31). With regard to clinical outcome, NOTCH1 M were significantly correlated with PR and PR-L (30/65 and 22/65, respectively; p=0.00002). Moreover, NOTCH1M were significantly associated with disease recurrence (23/38; p=0.0005). Significant shorter PFS and OS were observed in NOTCH1 M patients (36% vs 84% and 58% vs 84% at 3 years, respectively; p&lt;0.0001 and p=0.00075; Figure 1A and 1B). Thirty-seven patients underwent subsequently venetoclax [13 for toxicity (grade 3 or 4 WHO) and 24 for progression]. OS for this subgroup was 70% at 3 years (Figure 1C). In multivariate analysis of PFS, including previous chemotherapy regimens, NOTCH1, TP53 and IGHV status, NOTCH1 was confirmed as an independent prognostic factor (p=0.0002) together with TP53 (p=0.003). On the other hand, in multivariate analysis of OS, NOTCH1 remained as an independent prognostic factor (p=0.009) together with previous therapy (p=0.013) and TP53 (p=0.019). In conclusion, NOTCH1M are characterized by resistance to apoptosis, lower peripheral lymphocytosis and lower nodal shrinkage, all responsible for partial responses, subsequent relapses, shorter PFS and OS under ibrutinib treatment. The prognostic impact of NOTCH1 M on patients treated subsequently with venetoclax is unclear due to the low number of our cases (Roberts, 2019). Probably the therapeutic answer for NOTCH1 M patients could come either from TA combination approaches or from new gamma-secretase inhibitors or also from new antibodies targeting NOTCH1. Disclosures No relevant conflicts of interest to declare.

Safety and Efficacy of Mitoxantrone Hydrochloride Liposome in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma and Extranodal NK/T-Cell Lymphoma: A Multicenter, Single-Arm, Open-Label, Phase 2 Clinical Trial

Background: Peripheral T cell lymphoma (PTCL) and Extranodal NK/T cell lymphoma (ENKTCL) are rare types of non-Hodgkin's lymphoma (NHL), with a higher incidence in Asian countries. Outcomes for patients (pts) with relapsed or refractory(R/R) PTCL and ENKTCL are very poor, there is still lack of effective treatment for this patients population. Mitoxantrone is a syntheticc anthracenedione anticancer drug, which is effective on lymphoma, leukemia and other solid tumors. Tissue distribution or accumulation in tumor tissue of hydrochloride liposome (PLM60) was increased in our preclinical investigation. The pharmacokinetic parameters especially half-life of PLM60 was prolonged significantly in phase 1 trial. Phase Ib clinical studies showed good results of PLM60 in relapsed NHL. Therefore, we conduct this phase II clinical studies to evaluate the efficacy and safety of PLM60 in patients with R/R PTCL and ENKTCL. At present time, this is the first clinical study to evaluate PLM60 in treating R/R PTCL and ENKTCL worldwide. Methods : This is a single-arm, open-label, multi-center, phase II clinical study. The major inclusion criteria include age≥18 years old, pts with histologically confirmed PTCL (mainly including peripheral T cell lymphoma, NOS,PTCL-U; angioimmunoblastic T-cell lymphoma,AITL; anaplastic large cell lymphoma,ALCL; and other invasive NHL derived from T cells) and ENKTCL that was treated at least 1st line of chemotherapy, ECOG performance status 0 or 1. The main exclusion criteria included cumulative dose of doxorubicin &gt;360mg/m2 and patients has clinically significant cardiac malfunction and uncontrollable underlying cardiovascular diseases. PLM60 20mg/m2 was administered intravenously , every 4 weeks for up to 6 cycles or until disease progression, intolerable toxicity, death or withdrawal due to the investigator's decision. The primary endpoint was objective response rate (ORR) based on investigator and independent central review (ICR) per Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma 2007. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Adverse events will be rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.03. This trial is registered at ClinicalTrials.gov, number NCT03776279. Results: 62 eligible patients were treated in 18 institutions in China between April 2018 and July 2019. Patient characteristics are summarized in Table 1. Median number of previous chemotherapy regimens was 2(1-7). At the cut-off day of July 20, 2019, 9 pts remained on treatment and 3 pts withdrew due to protocol violation and lost follow-up. 50 patients were evaluable for response, the investigator-assessed ORR was 54.0%(27/50)with CR rate 20.0%(10/50) (CR). The subtype CR rate were 17.6%(3/17), 17.6%(3/17), 18.2%(2/11), 13.3%(2/15)for PTCL-U, AITL, ALCL and ENKTCL respectively. The ORR were 42.1%(8/17), 42.1%(8/17), 45.5(5/11), 40.0(6/15), respectively (Figure 1). The median time to response was 8 weeks (ranged from 4 to 24 weeks) . Median follow-up was 3.8 (ranged from 0.2 to 14.4 m) months. Median PFS was 8.0months (95% CI, 6.1-9.9m), with a 6-month PFS rate of 73.1±9.4%. Median OS was not reached, with a 6-month OS rate of 77.3±6.9%(Figure 2a,b). All-grade treatment-emergent adverse events (TEAEs) are listed in Table 2. The most common toxicity of PLM60 was myelosuppression. The most common grade 3/4 toxicity(&gt;10% TEAEs) was neutropenia(25.8%) and lymphocytopenia(11.3%). There were no treatment-related deaths. Conclusion: PLM60 monotherapy yielded promising results for patients with R/R PTCL and ENKTCL with moderate toxicities. Further investigation is urgently needed. Disclosures No relevant conflicts of interest to declare.

Correlation of Bridging and Lymphodepleting Chemotherapy with Clinical Outcomes in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with Tisagenlecleucel

Correlation of Bridging and Lymphodepleting Chemotherapy with Clinical Outcomes in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with Tisagenlecleucel

Tailored Prophylaxis in Mexican Pediatric Patients with Hemophilia a By Determining the Pharmacokinetics of Factor VIII

Introduction. Prophylactic replacement of factor VIII (FVIII) is the gold standard for the management of severe hemophilia, preventing bleeding and its complications. One of the most commonly used methods in developing countries is the Swedish regimen that consist in the administration of 25-40 IU/kg of FVIII three times per week. However, the actual required levels may vary considerably, these depend on the dose administered, the dosage interval and the pharmacokinetic profile of the patient. Pharmacokinetic calculations based on bayesian estimation are useful for designing an optimal dosage of the minimum required factor levels for each individual patient, nevertheless in our country it is not accessible to all patients mainly due to the cost of the multiple samples needed to obtain the pharmacokinetic profile. This report describes our experience determining the pharmacokinetics of FVIII in a cohort of pediatric patients with hemophilia A in order to establish a personalized prophylaxis and to compare the infusion frequency and factor consumption with the dosage regimen previously mentioned. Methods. Pediatric patients with severe and moderate hemophilia A were included, with one or more years in prophylaxis and monthly follow-up at the hemophilia clinic of our centre. Patients with inhibitors and/or documented renal and/or hepatic alterations were excluded. We administered 50 U/kg of FVIII to all patients and 4 blood samples were collected for the estimation of FVIII phamacokinetics (0, 4, 24 and 48 hours after the application). FVIII was measured using one-stage assay. The FVIII pharmacokinetics of each patient were obtained using the WAPPS-Hemo app. Results. The pharmacokinetics of FVIII were determined in 10 male patients (9 severe, 1 moderate), with a median age of 9 years (2-13) and a mean BMI of 18.6 (15.1-23.6). One patient was excluded for having an atypical t1/2 for FVIII, not within the population curve, in him the existence of an inhibitor was suspected and later corroborated. We observed an average estimated time of 70.6 hr (53.5-89.5) in which the FVIII concentration reached &lt;1% and an average half-life of 9.3 hr (6.25-14.25). Using the clinical calculator of the application, a prophylactic regimen was obtained for each patient in order to maintain FVIII trough levels ≥1%. In 22.2% the factor dose was not modified and in the remaining 77.8% it was necessary to elevate the dose with an average increase of 23.2 IU / kg / week. Conclusions. Tailored prophylaxis is easy to obtain with the currently available digital tools. In our study, unlike what is reported in previous similar studies, almost 80% of patients required an increase in the dose of factor according to their pharmacokinetics profile. We also found a clearance time lower than that reported in other populations groups maily based in adults cases, but very similiar to what was previously reported in a pediatric population from southern Mexico. Most of our patients had not reported clinically significant bleeding, but it is possible that they had had subclinical bleeding during the time they maintained a trough level of FVIII &lt;1% with their previous prophylactic regimen. The impact of the implementation of prophylaxis by pharmacokinetics and its cost-effectiveness is currently being evaluated prospectively. Disclosures No relevant conflicts of interest to declare. Disclosures Gomez-Almaguer: Celgene: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.