Maculopapular Research Articles

Evaluation of Analgesic Effect of Lidocaine Patch 5% in Post-herpetic Neuralgia: An Interventional Study

Introduction: Herpes Zoster (HZ) is a very painful and debilitating condition caused by the reactivation of the Varicella Zoster Virus (VZV). HZ is characterised by a maculopapular or vesicular rash, usually accompanied by pain that is unilateral and restricted to dermatomes. Post-herpatic Neuralgia (PHN) is defined as pain that persists for more than 90 days after the onset of the HZ rash. Aim: To evaluate the analgesic efficacy of a lidocaine patch in PHN. Materials and Methods: This prospective interventional study conducted at the Department of Anaesthesiology and Critical Care, Pt. BD Sharma, PGIMS, Rohtak, Haryana, India, from February 2020 to March 2021. The study included a total of 24 patients (single group), with a male-to-female ratio of 11:13, aged between 18 and 75 years, all with a Visual Analogue Scale (VAS) score greater than 4. An evaluation of patient pain scores using the VAS and the total number of lidocaine patches used per week for four weeks or until the VAS declined to four was conducted. After obtaining informed and written consent, a medicated 5% lidocaine patch was applied to cover the appropriate area for a minimum period of 12 hours, followed by removal for the next 12 hours. This application continued until the VAS declined to four or up to a maximum of four weeks. The level of significance was set at p≤0.05. Results: In the present study, a total of 24 patients were included. The mean age was 59.5±12.85 years, with 54.2% being female and 45.8% male. The VAS scores at baseline were 8.71±0.999, which reduced to 7.08±1.349 at the end of one week, 5.67±0.007 at the end of two weeks, 4.25±0.442 at the end of three weeks and 3.58±0.830 at the end of four weeks. The VAS scores were significantly lower in all patients over the four weeks (p=0.001). The total number of patches used was 1.88±0.338 at one week, 1.46±0.509 at two weeks, 1.04±0.204 at three weeks and 1.00 at four weeks. The total amount of patches used was significantly reduced over the four weeks (p=0.001). No side-effects related to the lidocaine patch were noted. Conclusion: The 5% lidocaine patch demonstrated good tolerability with a minimal risk of systemic adverse drug reactions and is an effective modality for relieving moderate to severe pain. It is concluded that the 5% lidocaine patch is very effective in the treatment of PHN.

Allergic Reaction to Aminophylline in a Case of Lower Respiratory Tract Infection with Measles: A Rare Case Report

Measles is an acute respiratory infectious disease caused by the measles virus. It leads to respiratory involvement with manifestations such as pneumonia, laryngobronchitis, pneumonitis, etc. It can also cause secondary bacterial and fungal infections. Aminophylline is a methylxanthine bronchodilator composed of theophylline and ethylenediamine. Airway blockage is reversed by bronchial smooth muscle relaxation, increased myosin light chain kinase activity, and decreased intracellular calcium concentration. It relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels, reducing airway responsiveness to histamine, methacholine, adenosine, and allergens. Allergic skin reactions secondary to aminophylline administration have been rarely seen. Aminophylline can be given orally as well as intravenously. A seven-month-old male infant presented with a lower respiratory tract infection and a maculopapular rash involving the face and trunk. A history of contact with measles was present. Intravenous aminophylline was administered for persistent wheezing. The infant developed a generalised erythematous papular rash with a more widespread distribution than before within one hour of administration. The child was treated with antihistamines for the same. After a detailed physical examination, looking at the pattern of the rash and excluding other causes like environmental factors and drug history, the diagnosis of an allergic reaction to aminophylline was made. Early identification of allergic reactions is paramount, as prompt cessation of the offending agent and initiation of appropriate medical interventions can significantly mitigate the severity of the reaction and prevent potential life-threatening complications.

The Rate of Anti-measles Immunoglobulin M Positivity among Children with Skin Rash and Fever in Diyala Province

Abstract Background: Measles is an extremely contagious disease characterized by generalized maculopapular rash, fever, cough, coryza, and conjunctivitis. It is caused by the measles virus. Objective: The objective of this study was to explore the anti-measles immunoglobulin (Ig) M positivity rate among children with clinical suspicion of having measles. Subjects and Methods: This is a cross-sectional study carried out in Diyala Province, Iraq, from November/2020 to October/2021. A total of 425 blood samples were collected from children (≤14 years of age): 90 from patients who were clinically suspected as having measles (18 were vaccinated with measles vaccine and 72 were not); 270 from measles-vaccinated children, including those children who received all recommended vaccines in the Iraqi Expanded Program of Immunization (IEPI); and 65 from nonvaccinated children, including those children who received none of the vaccines in the IEPI. Enzyme-linked immunosorbent assay (ELISA) kits for the detection of anti-measles IgM were used. Results: The results found that 14 (15.6%) of clinically suspected children were positive for anti-measles IgM antibody versus 76 (84.4%) who were negative. Whereas, only one (1.5%) of the unvaccinated children was positive, and all vaccinated children were negative. Thus, clinically suspected patients had a significantly higher positivity rate compared to other study groups (P = 0.0001). Similarly, the mean ± standard deviation of anti-measles IgM concentration was significantly higher compared to other study groups (P = 0.0001). Conclusion: About one-sixth of patients clinically comparable to measles in Diyala Province actually had measles, most of them were unvaccinated, and the anti-measles IgM ELISA technique was a good marker for exploring measles cases.

A clinical case series of Rickettsia spp. from southern Türkiye

Rickettsial infections should be considered in the presence of a maculopapular rash, especially in the endemic area with a history of tick bite. In this study, Rickettsia spp. infections of three cases will be mentioned. Three cases with positive Rickettsia spp immunofluorescent antibody serology were included in the study. Case-1 was a 17-year-old male patient, who had a history of tick bite one week before the admission was admitted with chest pain. He had tachycardia and a "tache noir" rash with a necrotic center in the area of the tick bite. Laboratory parameters showed lymphopenia, cardiac enzymes elevation. The patient’s serelogy of Rickettsia conorii IgM was 1/192 titer positive and IgG was negative. He hospitalized as acute Mediterranean Spotted Fever myocarditis. He recovered with doxycycline treatment. Case-2 was a nine-month-old girl presented with fever, rash and lymphadenomegaly on left axilla two weeks after the tick bite of her left arm. The rash was localized to the arm. R. slovaca and R. aeschlimannii serologies were detected 1/40 titer positive. After ciprofloxacin treatment her symptoms had dissapeared. Case-3 was a seven-year-old girl presented with fever reaching 39ºC for five days, myalgia and rash all over her body. She had scratched the tick from the scalp five days before the admission. Rickettsia conorii IgM serology was 1/768, IgG was 1/640 titer positive. She recovered after doxycycline treatment. Rickettsia spp. infections can lead to infections like myocarditis or the spotted fever group Rickettsiosis diseases. Complications can be prevented with early diagnosis and treatment.

Інфекційна еритема та феномен Рейно в дитини після перенесеної коронавірусної хвороби: опис клінічного випадку

Purpose - to analyze practice cases with an atypical course associated with comorbid pathology; to acquaint pediatricians and family physicians with the diagnostic search algorithm. The article summarizes literature data, and describes a clinical case of erythema infectiousum in combination with Raynaud's phenomenon, which occurred in a 9-year-old child І. with coronavirus disease in anamnesis. It was established that the nature of the pathological changes: periodic hyperemia of the cheeks and auricles, “slapped cheeks”, and, at the same time, palleness of the nasolabial triangle, a pronounced change in color, marbling of the skin on the limbs and on the buttocks, with a lacy pattern of vessels, which are provoked by exposure to cold air or psycho-emotional excitement, clearly indicate both the manifestations of parvovirus infection, and the Raynaud's phenomenon mentioned above. On the other hand, post-covid syndrome is also often accompanied by non-specific changes in the skin and its derivatives (up to 20.4% of cases) in the form of urticaria, erythema, and frostbite. In the same group of patients, there are maculopapular rashes and livedo reticularis, those could be Conclusions. During the pandemic of coronavirus infection, the issues of comorbid pathological conditions in pediatrics, which have a blurred clinical picture, an atypical course, common links of pathogenesis, in particular microcirculation disorders, and require an interdisciplinary approach to the management of these diseases, rehabilitation measures, are becoming more and more relevant. interpreted both as a manifestation of systemic vasculitis, and as independent disease. Thus, the patient was diagnosed with infectious erythema caused by parvovirus B19 in combination with Raynaud's phenomenon, probably caused by a history of coronavirus disease. The multicomponent nature of the patient's symptoms is highlighted, and the diagnostic search algorithm is shown. The study was conducted in accordance with the principles of the Declaration of Helsinki. An informed parental consent was obtained for the study in children. No conflict of interests was declared by the authors.

Socio-demographic Profile and Complications of Measles in Children: A Hospital Based Study

Background: Measles is a self-limited viral disease. But it can cause serious complications in young children and still remains as an important cause of mortality and morbidity in under five children worldwide.
 Objectives: The aim of the study was to determine the complications of measles in hospitalized children and to observe the socio-demographic profile of them.
 Methods: A prospective observational study was conducted in Dr M R Khan Shishu Hospital and Institute of Child Health from March to December 2019. Children of 6 months to 10 years who came with signs and symptoms of measles according to the case definition criteria by WHO, like fever with maculopapular rash associated with cough, runny nose and conjunctivitis were included in the study. Their sociodemographic profile was recorded and different complications were noted.
 Results: A total of 86 children suffering from measles with different complications were admitted during the study period. They were from 6 months to 10 years. Among them 59% were below 1 year, 80% were below 4 years and 94% were less than 7 years. Thirty eight percent children were from lower and thirty percent from middle socioeconomic background. Pneumonia was the main complication found in 62(72%) cases followed by diarrhea 28(32%), oral ulcer 26(30%), croup 5(6%) and febrile seizure 4(4.6%). Most (79%) of the children, had normal nutritional status. Among 62 children aged 9 months to 10 years, only 16(26%) received 2 doses of measles vaccine, 14(23%) only the first dose and 32(52%) was not vaccinated at all. Vaccination rate was poor (27%) in low socio-economic condition. The mortality rate was 1(1.16%).
 Conclusion: About 60% of the children, suffering from measles, were less than one year of age. Fifty nine percent of them were not vaccinated. The children developed complications like pneumonia, diarrhea, oral ulcers etc. Vaccination status was poor in low socio-economic condition. So, awareness should be created about timely vaccination of measles.
 DS (Child) H J 2022; 38(2): 84-88

Mucocutaneous and musculoskeletal manifestation as an early symptomatic congenital syphilis: A rare case

Background: Congenital syphilis (CS) is attributable to the transmission of Treponema pallidum from the mother to the fetus transplacental during gestation. The incidence rate of congenital syphilis is 15 per 100,000 newborns by 2020. Mucocutaneous involvement is present in as many as 70% of infants and may be apparent at birth or develop during the first few weeks of life. Cutaneous findings of early CS classically a vesiculobullous or maculopapular rash on the palms and soles may be associated with desquamation. Skeletal manifestations of congenital syphilis occur in 60%-80% of infants, including osteitis (0.7%), metaphysitis (24%), and periosteal reaction (34%). It is important to be fully informed regarding the early diagnosis and treatment of congenital syphilis to prevent its devastating complications to death. This case report describes clinical features, treatment, and prognosis of congenital syphilis presented with mucocutaneous lesions and musculoskeletal manifestations. Case representation: A one-day-old boy preterm infant, 2145 grams, born spontaneously, presented with ruptured bullous lesions and desquamation on the feet and hands. The laboratory revealed thrombocytopenia, elevated C-reactive protein, elevated bilirubin total (10.9 mg/dL) and direct bilirubin (6.21 mg/dL) at 24 days old, indicating an intrahepatic cholestasis caused by syphilis. Serum VDRL 1:128 and TPHA >1:5120. Long bone radiology showed periostitis involving the humerus, ulna, radius dextra and sinistra, femur dextra and sinistra, a feature of congenital syphilis. The patient was treated with procaine penicillin 107,000 international units intravenous every 24 hours for 10 days. Conclusion: The early recognition of mucocutaneous and musculoskeletal involvement as an early manifestation of CS improved with procaine penicillin intravenous for 10 days.

Ciprofloxacin Ophthalmic DRESS Syndrome: Case Report

Introduction: Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is a rare severe systemic hypersensitivity drug reaction. Diagnosing DRESS syndrome is challenging due to non-specific manifestations that can make it difficult to recognize. Therefore, addressing and discussing this issue is extremely important, considering the potential lethality of a treatable syndrome. Clinical case: We describe the clinical characteristics of a 39-year-old female who presented with DRESS syndrome associated with the use of ciprofloxacin ophthalmic. The patient manifested a mild maculopapular rash located in the pelvic limbs with subsequent ascending distribution and generalized erythematoviolaceous affecting four extremities, trunk, facial region and scalp, together with fever and lymphadenopathy. Paraclinical tests revealed leukocytosis and eosinophilia. According to RegiScar's ranking, it scored 6 points, classifying it as the definitive case for DRESS. He concluded a schedule with prednisone 1 mg/kg/day with a slow reduction dose, obtaining a good response to treatment. Conclusions: DRESS syndrome should be suspected in a patient receiving medical treatment who presents with the following signs and symptoms: rash, fever (38°C), facial edema, and lymphadenopathy. Fortunately, this reaction is usually reversible, with a low incidence of residual damage or mortality, in the case of timely discontinuation of antibiotics and use of topical or systemic corticosteroids.

Angioimmunoblastic T-cell Lymphoma Presenting With a Neutrophilic Leukemoid Reaction: A Diagnostic Challenge

Angioimmunoblastic T-cell lymphoma (AITL) accounts for 1-2% of all non-Hodgkins lymphoma. Patients present with lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia and skin lesions. The presence of rash and neutrophilia in the absence of circulating abnormal lymphocytes in the peripheral blood film leads to a misdiagnosis. A 33-year-old presented with cervical lymphadenopathy with WCC of 104.9 g/dl, maculopapular rash, loss of weight and appetite associated with B symptoms. His peripheral blood film revealed hyperleukocytosis with a neutrophilic leukemoid reaction. Neutrophil alkaline phosphatase (NAP) score was high. Bone marrow aspirate and trephine were suggestive of neutrophilic leukemoid reaction with features of granulocytic hyperplasia with no lymphoid aggregates suggestive of neutrophilic leukemoid reaction secondary to underlying malignancy with a differential of myeloproliferative neoplasm if no reactive causes of granulocytic hyperplasia could be found. A lymph node biopsy was done later and was consistent with AITL. This case illustrates the rare presentation of AITL with a neutrophilic leukemoid reaction in the absence of anaemia, eosinophilia and abnormal lymphoid cells.

Phase I/II trial of BMS-986,205 and nivolumab as first line therapy in hepatocellular carcinoma

BackgroundIndoleamine-2,3-dioxygenase (IDO) helps orchestrate immune suppression and checkpoint inhibitor resistance in hepatocellular carcinoma (HCC). BMS-986,205 is a novel oral drug that potently and selectively inhibits IDO. This Phase I/II study evaluated the safety and tolerability of BMS-986,205 in combination with nivolumab as first-line therapy in advanced HCC.MethodsAdults with untreated, unresectable/metastatic HCC received BMS-986,205 at two dose levels (50–100 mg orally daily) in combination with fixed dose nivolumab (240mg/m2 IV on Day 1 of each 14-day cycle). The primary objective was to determine the safety and tolerability of this combination; secondary objectives were to obtain preliminary efficacy.ResultsEight patients received a total of 91 treatment cycles in the dose escalation phase. All patients were Child Pugh A and 6 patients had underlying viral hepatitis. In the 6 evaluable patients, no dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (TRAEs) were aspartate transaminase (AST) and alanine transaminase (ALT) elevation (3 patients) and diarrhea, maculopapular rash and increased alkaline phosphatase (2 patients each). Grade 3 events were diarrhea and AST elevation (1 patient), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 patient). No grade 4–5 events occurred. Partial response was observed in 1 patient (12.5%) and stable disease in 3 patients (37.5%), yielding a disease control rate of 50%. Median PFS was 8.5 weeks; median OS was not reached.ConclusionCombination BMS-986,205 and nivolumab showed a manageable safety profile with durable benefit as first-line therapy in a meaningful subset of advanced HCC patients.

Maculopapular rash in brown skin.

Maculopapular rash in brown skin.

РЕАКЦИЯ ЛЕКАРСТВЕННОЙ ГИПЕРЧУВСТВИТЕЛЬНОСТИ С ЭОЗИНОФИЛИЕЙ И СИСТЕМНЫМИ СИМПТОМАМИ (DRESS-СИНДРОМ) НА КАРБАМАЗЕПИН. Клинический случай и обзор литературы

Abstract. Introduction. A drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially life- threatening T-cell mediated reaction characterized by heterogeneous clinical manifestations and by a variable and unpredictable course. It is difficult to diagnose this reaction due to the long latent period between the start of therapy with a new drug and onset of symptoms, as well as due to no pathognomonic manifestations. Aim. Providing physicians with an algorithm for the diagnosis and treatment of DRESS syndrome exemplified by our own clinical observation. Materials and Methods. A 70-year-old female patient was hospitalized in the Department of Allergology and Immunology, complaining of generalized itchy rash on the face, body, and extremities, swelling of face and hands, and temperature rise to 37.5-38 °C. She was examined using general clinical, laboratory and instrumental methods. Results and Discussion. On examination, we found generalized maculopapular rash, increased levels of hepatic transaminases, reaching the criteria for mild drug-induced liver damage, and peripheral blood eosinophilia 25% (4,260 cells in 1 μl). Using the RegiSCAR scoring system helped to diagnose drug hypersensitivity reaction with eosinophilia and systemic symptoms, while utilizing the algorithm for assessing the causal relationship between the drug and the development of symptoms allowed considering carbamazepine as a possible cause of this reaction. The patient was treated with systemic and topical glucocorticosteroids with positive changes. Conclusions. Using the RegiSCAR scoring system developed by a team of international experts facilitates diagnosing the DRESS syndrome. Identifying and withdrawing the culprit drug is an essential condition of successfully managing patients. Systemic and topical glucocorticosteroids are the drugs of choice for the treatment of drug reactions with eosinophilia and systemic symptoms.

The clinical biochemical and hematological profile of scrub typhus meningoencephalitis

Background: Scrub typhus is a zoonotic infectious disease caused by the Gram-negative coccobacillus Orientia tsutsugamushi. Meningoencephalitis occurs in two-thirds of all the infected cases. Aims and Objectives: The study of these cases was conducted to study the clinical, biochemical, and hematological features of scrub typhus meningoencephalitis. Materials and Methods: We included 12 patients who were admitted in the General Medicine Ward of Medical College and Hospital, Kolkata, between May 2021 and July 2022. The serum scrub typhus immunoglobulin M (IgM) test was used to diagnose the cases after ruling out dengue, malaria, leptospirosis, bacterial, tubercular, and viral meningoencephalitis. Results: A triad of fever, altered sensorium, and meningeal signs were present in all of the cases. 2 patients had seizures, 1 patient had lateral rectus palsy, 1 patient had a generalized maculopapular rash, and eschar was seen in only 2 cases. The most common laboratory abnormalities were hyponatremia, anemia, and transaminitis (each 83.33%). 8 cases (66.7%) had a combination of anemia, hyponatremia, and transaminitis. Cerebrospinal fluid abnormalities included protein elevation (75%) and lymphocytic pleocytosis (83.33%). Scrub typhus IgM was positive in all of them. All the cases showed excellent response to doxycycline. Conclusion: A high degree of clinical suspicion is required to diagnose scrub typhus meningoencephalitis. The eschar is detected in very few cases and it may be difficult to recognize the same among the dark-skinned Indian population. However, as per our study, any case of meningoencephalitis with a combination of anemia, hyponatremia, and deranged liver function tests should always raise the possibility of the aforementioned disease and doxycycline therapy must be started promptly.

Reduced Dose Brentuximab Vedotin for Mycosis Fungoides Appears to Prolong Response Duration By Balancing Efficacy and Tolerability

Introduction: Brentuximab vedotin (BV) is one of the most active systemic agents for treating mycosis fungoides (MF); however, treatment duration and the duration of response is frequently limited by the development of peripheral neuropathy (PN). In the phase III ALCANZA study of BV, 44/66 (67%) of patients (pts) treated with BV developed PN, including grade 2 (G2) in 32% and grade 3 (G3) in 10%. The overall response rate (ORR) to BV was 65% and median duration of response (DOR) was 15.1 months (mo) (Prince et al, Lancet 2017). We hypothesized that reduced-dose BV would improve tolerability without compromising efficacy and therefore facilitate a longer duration of response for pts with MF. Methods: This is a multicenter phase II study evaluating reduced-dose BV in pts with relapsed or refractory MF who are BV-naive. Cohort 1A evaluated BV at 0.9 mg/kg every 3 weeks and cohort 1B evaluated BV at 1.2 mg/kg every 3 weeks. For each dose level, we utilized a Simon two-stage minimax design in which we set the desired ORR at 65% (as reported in ALCANZA) and the null hypothesis at 35%. Accordingly, stage I required 4 responses among the first 9 pts enrolled to expand to a total of 19 pts. In stage II, 11 responses were required to declare the dose promising. Global response was evaluated every 4 cycles using the International Society for Cutaneous Lymphomas consensus criteria (Olsen et al, JCO 2011). PN was evaluated according to the NCI Common Terminology Criteria for Adverse Events v. 4.0.3 and Total Neuropathy Score (TNSc). Additional outcomes include Health Related Quality of Life (HRQoL) measured by the FACT-Lym, FACT-GOG_NTX and Skindex-29 questionnaires completed by pts every four cycles. Results: Among 19 pts enrolled on cohort 1A, median age was 60 years (yrs) (range, 38-85) and 16/19 (84%) were male. Majority had stage I/II disease (n = 16, 84%) and 42% of pts had large cell transformation. Median number of prior therapies was 2 (range 0-9) (Table 1). 8/19 pts (42%) experienced PN, including 3/19 (16%) G2 and 0/19 ≥ G3. ORR was 42% (8/19) (8 PR, 0 CR). Median DOR was 19.6 mo (95% CI, 5.9 - NR) (Figure 1). The primary efficacy endpoint for cohort 1A was not met, leading to enrollment onto cohort 1B. To date, 14 of planned 19 pts enrolled onto cohort 1B. Majority had MF (86%), median age was 62 yrs (range 39-83) and 10/14 (71%) were male. 11/14 (79%) were early stage and 4/14 (29%) had large cell transformation. Median number of prior therapies was 1.5 (range 0-4). 10/14 (71%) pts experienced PN, including 4/10 (40%) G2 and 0/10 ≥ G3. The ORR is 50% (7 PR, 0 CR) and the median DOR has not been reached (95% CI, 5.4 - NR). Across the 2 cohorts, additional BV-related adverse events seen in >10% of pts included infusion-related reactions (G1, n = 3; G2, n = 1), hepatic transaminase elevation (G1, n = 4; G2, n = 1), diarrhea (G1, n = 4; G3, n =1), nausea (G1, n = 4; G2, n =1), fatigue (G1, n = 5; G2, n = 2), and maculopapular rash (G1, n = 4; G2, n = 3; G3, n =2). Conclusion: Treatment of MF with reduced-dose BV of 0.9 mg/kg was associated with lower clinical activity (ORR 42%) than full-dose BV (1.8 mg/kg, ORR 65%). However, while recognizing the limitations of cross-trial comparisons, there were numerically lower rates of PN and a longer median DOR than with full dose BV on the ALCANZA trial. Although unable to reject the null hypothesis for cohort 1A, 0.9 mg/kg dosing allowed for prolonged disease control and diminished toxicity for responding pts. As MF is a chronic, typically incurable condition, prolonged duration of treatment is particularly important. Enrollment onto cohort 1B (1.2 mg/kg) is ongoing; we will present updated results along with pt reported outcomes at the conference.

Tislelizumab, an Anti-PD1 Antibody, in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma in Tirhol Bgb-A317-210: A Prospective Multicenter Lysa Phase 2 Study Conducted in Western Countries

Background: Programmed cell death protein 1 (PD-1) blockade is commonly used to treat relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) but the overall response rates (ORR) and complete response rates (CRR) of approved anti-PD1 antibodies remain suboptimal. Tislelizumab blocks PD-1 with a high specificity and affinity and minimized FcγR binding on macrophages leads to reduced clearance. Results of the initial phase 2 study of tislelizumab in Chinese patients with RR cHL were impressive, with ORR and CRR of 87% and 63%, respectively, and 3-year progression free survival (PFS) of 40%, warranting further evaluation in a Western population with different standard of care, including more frequent use of autologous stem cell transplantation (ASCT) and targeted agents. Methods: TIRHOL (NCT04318080) is an international, prospective phase 2 study for patients with RR cHL conducted in France, Belgium, USA and Australia. Cohort 1 includes patients who previously underwent ASCT; cohort 2 includes patients who were ineligible for ASCT. Prior therapy with brentuximab vedotin (BV) was required in initial design; the protocol was amended to remove this criterion for both cohorts in October 2021. Tislelizumab 200 mg is given intravenously every 3 weeks until progressive disease (PD), unacceptable toxicity, or study withdrawal; tumor assessments are performed every 12 weeks. The primary endpoint is the ORR (best overall response of CR or partial response [PR]), as assessed by investigator, according to PET-CT International Lugano 2014 criteria. Null hypothesis is ORR = 45 % based on previous clinical trials and alternative hypothesis is ORR > 45%. Assuming the observed ORR = 65%, a sample size of 42 patients provides ≥ 80% power of at the one-sided 5% significance level. Secondary endpoints are CRR, time to response (TTR), duration of response (DOR), safety and tolerability of tislelizumab. Main exploratory endpoints are PFS and overall survival (OS). Results: Patients who received at least 1 dose of tislelizumab were included in the analysis. Between August 2020 and September 2022, 45 patients (14 in cohort 1 and 31 in cohort 2) were enrolled and dosed. At inclusion, the median age was 64 years (range 18-87), 67% were male and all had ECOG performance status 0-1; most patients had advanced stage disease (38% III, 42% IV), 11% had bulky disease, 18% had B symptoms and 29% had disease refractory to last therapy. The median prior lines of therapy received was 2 (1 - 4); 12 patients (27%) received ≥3 prior lines of therapy and 33 (73%) received prior BV. At last follow-up, the median number of tislelizumab doses (cycles) was 8 (1 - 33), corresponding to a median duration of treatment 24 weeks (range 3-105). The ORR was 64.4% (90% CI, 51% - 76%) with 14 (31%) patients achieving CR and 15 (33%) patients achieving PR (Figure 1). Remaining patients had stable disease (n=2, 4%), PD (n=13, 29%), or were not evaluated (n=1, 2%). The ORR was similar in cohort 1 (n=9/14, 64.3%) and cohort 2 (20/31, 64.5%). The median TTR was 2.69 months (range 0.3-5.6). The median DOR was 12.3 months (95% CI, 3 - NR) and was not reached for patients achieving CR. Three patients with objective response underwent subsequent ASCT (1) or allogeneic SCT (2). With a median follow-up of 11.4 months (95% CI, 6.7-13.5), the median PFS was 5.6 (95% CI, 5 - 14), 8, and 5 months for both cohorts combined, cohort 1, and 2, respectively. Thirteen patients with SUV increase meeting PD criteria but continued clinical benefit continued tislelizumab for a median of 3.6 months (range Q1:1.8 - Q3: 9.5) after PD. At last follow-up, 19 patients remain on tislelizumab and 11 (24%) have continued treatment for >1 year. The median OS was not reached with a 1-year OS rate of 93.5% (4 deaths; 95%CI, 75.0-98.5) and no treatment-related deaths. Grade ≥ 3 treatment emergent adverse events (TEAE) occurred in 15 (33%) patients, leading to discontinuation or interruption of tislelizumab in 9 and 2 patients, respectively. Immune-related (ir) AEs were observed in 15 (33%) patients and 3 patients had grade ≥ 3 irAEs (maculo-papular rash, hepatitis, hemolytic anemia). Conclusions: TIRHOL met its primary endpoint with an ORR of 64% and a CRR of 31% with an acceptable safety profile. This study confirmed that tislelizumab is a promising treatment option in cHL. Study follow-up is ongoing, but durable responses have been observed, especially in patients achieving CR.

1775. Predictor Factors Of Severe Forms Of Rickettsial Infections

Abstract Background Rickettsial infections usually mimic benign viral infection due to similarities in clinical symptoms. However, severe forms and complications might occur changing therfore the prognosis of the disease. We aimed to study the predictor factor of severe forms of rickettsial infections. Methods We conducted a retrospective study including all patients hospitalized in the infectious diseases department for rickettsiosis. The diagnosis was confirmed by serologies (seroconversion) and/or positive polymerase chain reaction for Rickettsia in skin biopsy. Severe forms included cases with acute respiratory distress syndrome, myocarditis, meningitis, meningoencephalitis, renal failure or septic shock. Results We encountered 472 cases among which 98 cases were severe (20.8%). Median age was 43[25-60] years among severe forms and 38[24-53] years among non-severe forms (p=0.132). Maculopapular skin rash (56.7% vs 88% ; p< 0.001), arthralgia (56.1% vs 77.3% ; p< 0.001) and eschar (16.3% vs 27% ; p=0.029) were significantly less frequent among severe forms. Meningeal syndrome (34.7% vs 8.3% ; p< 0.001), vomiting (56.1% vs 41.8% ; p=0.011) and cough (28.6% vs 13.9% ; p=0.001) were significantly more frequent among severe forms. Leukocytosis was significantly more frequent among severe forms (35.7% vs 20.6% ; p=0.002). The optimal cut-off value of white blood cell count for predicting severe forms was 7595/mm3, with a sensitivity of 61.9% and a specificity of 59.7%. The area under the curve was 0.622 and the 95% confidence interval ranged from 0.558 to 0.686. Elevated C-reactive protein levels (66.3% vs 65.5%; p=0.879) and accelerated erythrocyte sedimentation rate (36.7% vs 40.1%; p=0.543) were noted among severe and non-severe forms of rickettsiosis, with no significant difference. Conclusion The revealing symptoms of severe forms were characterized by the presence of vomiting, cough and meningeal syndrome, in the absence of the typical maculopapular skin rash and eschar. Leukocytosis was more frequent among severe forms of rickettsiosis. The diagnosis of severe forms should be kept in mind in order to promptly initiate the adequate treatment. Disclosures All Authors: No reported disclosures

First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations

BackgroundWe investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations. MethodsThis first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety. ResultsA total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively. ConclusionsNaporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.

Mayaro virus pathogenesis and immunity in rhesus macaques.

Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes debilitating and persistent arthritogenic disease. While MAYV was previously reported to infect non-human primates (NHP), characterization of MAYV pathogenesis is currently lacking. Therefore, in this study we characterized MAYV infection and immunity in rhesus macaques. To inform the selection of a viral strain for NHP experiments, we evaluated five MAYV strains in C57BL/6 mice and showed that MAYV strain BeAr505411 induced robust tissue dissemination and disease. Three male rhesus macaques were subcutaneously challenged with 105 plaque-forming units of this strain into the arms. Peak plasma viremia occurred at 2 days post-infection (dpi). NHPs were taken to necropsy at 10 dpi to assess viral dissemination, which included the muscles and joints, lymphoid tissues, major organs, male reproductive tissues, as well as peripheral and central nervous system tissues. Histological examination demonstrated that MAYV infection was associated with appendicular joint and muscle inflammation as well as presence of perivascular inflammation in a wide variety of tissues. One animal developed a maculopapular rash and two NHP had viral RNA detected in upper torso skin samples, which was associated with the presence of perivascular and perifollicular lymphocytic aggregation. Analysis of longitudinal peripheral blood samples indicated a robust innate and adaptive immune activation, including the presence of anti-MAYV neutralizing antibodies with activity against related Una virus and chikungunya virus. Inflammatory cytokines and monocyte activation also peaked coincident with viremia, which was well supported by our transcriptomic analysis highlighting enrichment of interferon signaling and other antiviral processes at 2 days post MAYV infection. The rhesus macaque model of MAYV infection recapitulates many of the aspects of human infection and is poised to facilitate the evaluation of novel therapies and vaccines targeting this re-emerging virus.

CTNI-37. CLINICAL ACTIVITY OF RAF INHIBITOR TOVORAFENIB ACCORDING TO PRIOR MAPK INHIBITOR TREATMENT IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY

Abstract BACKGROUND Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Genomic alterations of RAF are common oncogenic drivers in pLGG. Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. METHODS FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib monotherapy. Registrational arm 1 enrolled patients aged 6 months–25 years of age with recurrent or progressive LGG harboring an activating BRAF alteration. Tovorafenib 420 mg/m2 (600 mg max) was administered weekly (tablet or liquid suspension). Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints. RESULTS As of December 22 2022, 69 (RANO-HGG) and 76 (RANO-LGG) of 77 patients in arm 1 were evaluable at baseline and had ≥9 months of follow-up. Median age at enrollment was 8 years (range 2–21), and 60% (n = 46) patients had received prior MAPK inhibitor (MAPKi) therapy. Among the evaluable patients, the ORR was 62% (RANO-HGG, n = 69) and 45% (RANO-LGG, n = 76), respectively. The ORR in patients previously treated with MAPKis (n = 41 [RANO-HGG]; n = 45 [RANO-LGG]) was 68% (4 CRs; 24 PRs) (RANO-HGG) and 44% (5 PRs; 15 MRs) (RANO-LGG). In MAPKi-naïve patients (28 [RANO-HGG]; 31 [RANO-LGG]), the ORR was 54% (15 PRs) (RANO-HGG) and 45% (7 PRs; 7 MRs) (RANO-LGG). Among 136 patients in arms 1 and 2 of FIREFLY-1, the most common treatment-related adverse events (TRAEs) of any grade were hair color changes (71%), fatigue (40%) and maculopapular rash (38%). Tovorafenib dose modifications occurred in 39 (29%) and discontinuations in 4 (3%) patients due to TRAEs. CONCLUSIONS Tovorafenib provided clinically meaningful tumor responses, including those with a best response reported of SD or PD using another MAPKi, in patients with BRAF-altered pLGG regardless of prior MAPKi therapy, and has a manageable safety profile.

CTNI-24. CLINICAL ACTIVITY AND SAFETY OF THE RAF INHIBITOR TOVORAFENIB IN PATIENTS WITH OPTIC PATHWAY GLIOMAS IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY

Abstract BACKGROUND Optic pathway gliomas (OPG) are low-grade gliomas (LGG) comprising 3-5% of pediatric brain tumors. Morbidity may include visual loss (acuity and visual fields), hypothalamic/pituitary dysfunction, and/or impaired motor function. Genomic alterations of MAPK/BRAF are frequent oncogenic drivers in pediatric LGG. Activity of tovorafenib, an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor in OPGs was analyzed. METHODS FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib (420 mg/m2 weekly) in patients 6 months–25 years with BRAF-altered recurrent/progressive LGG or solid tumors. Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints. RESULTS Of the 77 patients enrolled in arm 1 (measurable disease per RANO-HGG), 42 (55%) had tumors located in the optic pathway. Median age at enrollment was 8 years (range: 2–16); 37 (88%) harbored a BRAF fusion and 5 (12%) a BRAF V600E mutation. The median prior lines of systemic therapy was 3 (range: 1–9), with 69% having received prior MAPK inhibitors. Of the 39 evaluable patients (RANO-HGG), the ORR was 59% (1 CR, 22 PRs) with a median time to response (TTR) of 2.8 months; 14 (36%) had stable disease (SD). Per RANO-LGG (n = 42), the ORR was 43% (5 PRs; 13 MRs) with a median TTR of 4.1 months; 20 (48%) had SD. Visual acuity remained stable in 79% (23) of patients (Cycle 9, n = 29 assessed). The most common treatment-related adverse events (TRAEs) of any grade in this subgroup were hair color changes (81%), increased creatine phosphokinase (55%), anemia (48%), maculopapular rash (45%), and fatigue (41%). Dose modifications occurred in 14 (33%) and discontinuations in 3 (7%) patients due to TRAEs. CONCLUSIONS Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.