Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy.

ABSTRACT: Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.

Safety and efficacy of acalabrutinib plus bendamustine and rituximab in patients with treatment-naive or relapsed / refractory mantle cell lymphoma: phase Ib trial.

This multicenter, open-label, phase 1b study (ACE-LY-106) assessed the safety and efficacy of acalabrutinib, bendamustine, and rituximab (ABR) in treatment-naive (TN) and relapsed or refractory (R/R) mantle cell lymphoma (MCL). Patients received acalabrutinib from cycle 1 until disease progression or treatment discontinuation, bendamustine on days 1 and 2 of each cycle for up to 6 cycles, and rituximab on day 1 of each cycle for 6 cycles, continuing every other cycle from cycle 8 for 12 additional doses (TN cohort). Eighteen patients enrolled in the TN and 20 in the R/R cohort. Median duration of exposure to acalabrutinib was 34.0 and 14.6 months in the TN and R/R cohorts, respectively. No new safety risks were identified, and most adverse events (AEs) were grades 1 or 2. Thirteen patients from the TN cohort (72.2%) and 17 patients from the R/R cohort (85.0%) reported grade 3-4 AEs, most commonly neutropenia (TN: 38.9%, R/R: 50.0%). AEs leading to death were pneumonitis (n=1, TN cohort), COVID-19, and cerebrospinal meningitis (n=1 each, R/R cohort). Overall response was 94.4% and 85.0% in the TN and R/R cohorts, respectively; complete response rates were 77.8% and 70.0%, respectively. After a median follow-up of 47.6 months, median progression-free survival (PFS) and overall survival (OS) were not reached in the TN cohort. After a median follow-up of 20.4 months, median PFS was 28.6 months and OS was not reached in the R/R cohort. Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL. ClinicalTrials.gov identifier: NCT02717624.

Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.

Duvelisib for CLL/SLL and follicular non-Hodgkin lymphoma.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL) represent indolent malignancies characterized by multiple episodes of relapse. Therapy has centered on agents that largely target the B-cell receptor pathway. Duvelisib is a second-generation oral inhibitor of phosphoinositide-3 kinase, downstream of the B-cell receptor pathway, approved in the United States for relapsed CLL/SLL and FL. Duvelisib represents a highly active agent, and ongoing investigations, including fixed-duration drug combinations and alternative dosing schedules, are aimed at reducing immune-mediated toxicities.

Impact of dosing frequency (once daily or twice daily) on patient adherence to oral targeted therapies for hematologic malignancies: a retrospective cohort study among managed care enrollees.

PURPOSE: Existing studies evaluating patient adherence to oral targeted therapies such as tyrosine kinase inhibitors focus on small populations with single malignancies. This study evaluated patterns of use of oral agents in a larger population across multiple hematologic malignancies. METHODS: Adult patients diagnosed with a hematologic malignancy and prescribed oral targeted therapy between 2011 and 2016 (N = 18,976) were identified from the MarketScan Commercial Claims and Encounters, and Medicare Supplemental databases. Eligible patients were enrolled in monthly prescription plans 6 months before and 12 months after the index date (date of first prescription claim; n = 2442). Multivariable logistic regressions were used to determine predictors of adherence using the medication possession ratio (MPR) and persistence through prescription refill gaps. RESULTS: The overall median adherence was 0.9 (MPR ≥ 80%) and was comparable between once-daily (QD) and twice-daily (BID) groups. Overall, 59% of patients were persistent at 12 months. Patients on QD and BID products did not have any significant differences in adherence (fixed-interval MPR, odds ratio 0.94; 95% confidence interval (CI), 0.75-1.18) or persistence (odds ratio 0.93; 95% CI, 0.75-1.17) 12 months from index. Significant predictors of adherence and persistence included patient age, total inpatient admissions, number of adverse events, and total hospital visits. CONCLUSION: Patient-specific clinical factors, rather than regimen-specific factors, were the main predictors of oral targeted therapy adherence and persistence. Adherence to oral targeted therapies appears to be similar for patients on QD and BID regimens in the real-world setting.

The polk county screening tool screening for detecting subarachnoid hemorrhage.

INTRODUCTION: The subarachnoid space in the brain contains crucial blood vessels and cerebrospinal fluid. Aneurysms in these vessels can lead to subarachnoid hemorrhage (SAH), a serious stroke subtype with high morbidity and mortality rates. SAH treatment includes procedures like coiling and clipping, but these are available only at comprehensive stroke centers (CSCs), necessitating urgent diagnosis and transfer to specialized facilities. METHODS: This IRB-approved study was conducted by Polk County Fire Rescue (PCFR) in Florida. PCFR, serving an 850,000-person population, implemented a three-step SAH protocol. The protocol uses both Ottawa SAH criteria and recurring symptoms, such as new-onset seizures and high systolic blood pressure, that were identified by EMS. Acute management included administering labetalol, levetiracetam, and ondansetron. RESULTS: Of 2175 stroke patients, 80 screened positive for SAH and were eligible for transfer. Patients had a median age of 66, and 33% had an initial systolic BP over 220 mmHg. The interfacility transfer rate dropped from 12.9 to 3.6% after implementing the protocol. CONCLUSION: The PCFR protocol's effectiveness suggests its potential for nationwide implementation. Early SAH recognition and prompt transfer to CSCs reduce complications and improve outcomes. Accurate field diagnosis by EMTs can prevent unnecessary transfers and enhance patient care. Future improvements may include portable diagnostic tools and enhanced EMT training to further improve SAH patients' pre-hospital care.

Management of Crohn's Disease and Its Complexities: A Case Report and Literature Review.

This case report and literature review explore Crohn's disease (CD), a chronic inflammatory disorder of the gastrointestinal tract characterized by unpredictable flare-ups and remissions. The study highlights the diverse clinical manifestations, including abdominal pain, diarrhea, and weight loss, which significantly affect quality of life. It examines the interplay of genetic, environmental, and immune factors in CD's pathogenesis and the complexities in managing the disease. Through a case study of a 20-year-old male, the report addresses various treatment strategies, including medications and surgery, and emphasizes the challenges, particularly post-surgical complications like small bowel leaks. The findings underscore the need for vigilant postoperative care to enhance patient outcomes in this complex condition.

Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction.

Type I interferons (IFNs) increase the excitability of dorsal root ganglia (DRGs) neurons via MNK-eIF4E signaling to promote pain sensitization in mice. Activation of stimulator of interferon response cGAMP interactor 1 (STING) signaling is pivotal for type I IFN induction. We hypothesized that vinorelbine, a chemotherapeutic and activator of STING, would cause a neuropathic pain-like state in mice via STING signaling in DRG neurons associated with IFN production. Vinorelbine caused tactile allodynia and grimacing in wild-type (WT) mice and increased p-IRF3, type I IFNs, and p-eIF4E in peripheral nerves. Supporting our hypothesis, vinorelbine failed to induce IRF3-IFNs-MNK-eIF4E in StingGt/Gt mice and, subsequently, failed to cause pain. The vinorelbine-elicited increase of p-eIF4E was not observed in Mknk1-/- (MNK1 knockout) mice in peripheral nerves consistent with the attenuated pro-nociceptive effect of vinorelbine in these mice. Our findings show that activation of STING signaling in the periphery causes a neuropathic pain-like state through type I IFN signaling to DRG nociceptors.

Pulmonary tuberculosis in an adult presenting with severe hyponatremia: A case report and review of literature.

Key Clinical Message: Identifying pulmonary pathology while evaluating electrolyte disorders is crucial for optimal patient management. Physicians working in endemic regions of tuberculosis should consider this pathology as a differential for electrolyte imbalances. Abstract: Hyponatremia, a common electrolyte imbalance, can arise from various underlying etiologies such as diuretics, diarrhea, vomiting, congestive heart failure, and liver and renal disease. We present a case report of a 74-year-old man highlighting the association between pulmonary tuberculosis (TB) and the development of hyponatremia. GeneXpert assay of the patient's sputum sample led to the identification of underlying active pulmonary TB as the cause of hyponatremia. The patient was started on anti-TB therapy, and concurrent fluid restriction and sodium supplementation were initiated to correct the electrolyte imbalance. Over the next 3 days, the patient demonstrated clinical improvement with the resolution of hyponatremia. This case also highlights the importance of considering TB as a potential etiology in patients presenting with hyponatremia, especially in endemic areas. Further research is warranted to explore the mechanistic pathways linking pulmonary TB and hyponatremia, aiding in the development of targeted therapeutic interventions.

Medicare Utilization and Cost Trends for CAR T Cell Therapies Across Settings of Care in the Treatment of Diffuse Large B-Cell Lymphoma.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR T) therapies have transformed diffuse large B-cell lymphoma (DLBCL) treatment. It is important to better understand their use in Medicare Fee-for-Service (FFS) patients, who often differ from commercially insured populations in important ways. METHODS: We analyzed Medicare FFS claims data, focusing on the utilization patterns across three CAR T products-lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel), and axicabtagene autoleucel (axi-cel)-which are indicated for the treatment of DLBCL. Our investigation covered the period from 2021 through 2022. This analysis spanned a 180-day period prior to CAR T procedure and extended to a 90-day post-CAR T. Utilization of healthcare services, healthcare spending, and comorbidities were assessed in the pre- and post-periods. Clinical trial and PPS-exempt center claims were removed from the analysis. Statistical comparisons between inpatient and outpatient cohorts were made using Wilcoxon's rank-sum tests for continuous variables and Chi-square tests or Fisher's exact tests for categorical variables. RESULTS: Among the total 391 CAR T claims assessed, most of the CAR T therapies were administered in the inpatient setting (79%) compared to outpatient (21%). CAR T therapy in the inpatient setting received an average Medicare cost of US$498,723 ($276,138-$1,066,524), while the average Medicare cost for outpatient CAR T claims was $414,393 ($276,980-$849,878). There was a higher 3-month average post-period cost for those hospitals utilizing CAR T in the outpatient setting than the inpatient setting ($15,794 vs. $10,244). Despite the higher post-period cost, when looking at the CAR T procedure and pre- and post-periods as a single episode, beneficiaries receiving outpatient CAR T had less cost for the total episode of care ($587,908 vs. $529,188). Follow-up inpatient claims were also assessed post-CAR T procedure for 30 days. The rate of post-CAR T inpatient re-admission was significantly lower for beneficiaries receiving the index CAR T in the inpatient setting (21%) compared to outpatient CAR T (59%). Days between index CAR T discharge and IP admission were also significantly shorter for OP CAR T compared to IP CAR T (8.0 vs. 14.1 days, p < 0.0001). Additionally, IP CAR T had a longer ALOS on the admission claim (6.9 vs. 6.2 days). CONCLUSION: CAR T therapy for the treatment of LBCL has become more common within the Medicare population, primarily in the inpatient setting. This study helps understand providers' cost and associated patient care around CAR T administration. The data show that the average cost received by hospitals encompasses the expenses related to both the CAR T drug and the medical services delivered to patients.

Prevalence and impact of correlative science in breast cancer phase II trials.

Correlative science (CS) can potentially augment clinical trial results by identifying biomarkers of response and resistance to a novel intervention. We evaluated recently published breast cancer phase II trials (BP2T) to determine prevalence, characteristics, and outcomes of CS. Through Pubmed, we identified BP2T of systemic therapy published between June 2005 and June 2010. A study-specific abstraction tool recorded trial characteristics, CS endpoints, source of tissue, adequacy of samples, biopsy safety, and CS outcomes. BP2T authors were contacted to verify abstraction results. Results were abstracted from 298 eligible trials enrolling 18,782 patients, of which 81 (27.2 %) involved CS. Of these, 57 (70.4 %) included tissue with 16 (28 %) using optional research biopsies and 17 (30 %) requiring mandatory research biopsies. No trial addressed biopsy safety issues. Trials were more likely to include CS if they were: industry versus non-industry sponsored (33.7 % vs. 17.1 %, p = 0.0017), neoadjuvant versus metastatic setting (47 % vs. 21.2 %, p = 0.0001), or U.S. versus non-U.S. trials (37 % vs. 21 %, p = 0.005). A minority of phase II breast cancer trials include CS representing a missed opportunity to learn more from clinical research. When CS is included, consistent reporting of endpoints, feasibility, outcomes, and safety is needed.

Treatment selection for patients with relapsed or refractory follicular lymphoma.

Follicular lymphoma (FL) is the second most common lymphoma in the United States and is characterized by a variable clinical course, disease heterogeneity, and a relapse-and-remittance pattern historically accompanied by successive shortening of clinical response with every line of treatment. Factors such as progression of disease within 24 months of initial treatment are associated with poor survival outcomes. Although rituximab-based regimens are preferred for early lines of treatment, no clear standard of care exists for treatment of FL in the third-line setting or later as approved third-line treatments have not been compared in a prospective, randomized clinical trial. Rather, physicians may choose from several therapeutic classes with different safety profiles and dosing regimens, with consideration of patient and disease factors. Here we describe 2 hypothetical patients with relapsing or remitting FL, an elderly patient with comorbidities, and a younger patient whose FL progressed within 24 months. These cases are used to highlight key factors that clinicians should consider when selecting therapies for relapsed or refractory FL, such as patient frailty, age, comorbidities, as well as quality of life and patient-specific preferences for less intrusive treatment regimens or longer remission times.

Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction.

Type I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation of STING signaling is a key component of type I IFN induction. Manipulation of STING signaling is an active area of investigation in cancer and other therapeutic areas. Vinorelbine is a chemotherapeutic that activates STING and has been shown to cause pain and neuropathy in oncology clinical trials in patients. There are conflicting reports on whether STING signaling promotes or inhibits pain in mice. We hypothesized that vinorelbine would cause a neuropathic pain-like state in mice via STING and signaling pathways in DRG neurons associated with type I IFN induction. Vinorelbine (10 mg/kg, i.v.) induced tactile allodynia and grimacing in WT male and female mice and increased p-IRF3 and type I IFN protein in peripheral nerves. In support of our hypothesis, vinorelbine-mediated pain was absent in male and female StingGt/Gt mice. Vinorelbine also failed to induce IRF3 and type I IFN signaling in these mice. Since type I IFNs engage translational control via MNK1-eIF4E in DRG nociceptors, we assessed vinorelbine-mediated p-eIF4E changes. Vinorelbine increased p-eIF4E in DRG in WT animals but not in StingGt/Gt or Mknk1-/- (MNK1 KO) mice. Consistent with these biochemical findings, vinorelbine had an attenuated pro-nociceptive effect in male and female MNK1 KO mice. Our findings support the conclusion that activation of STING signaling in the peripheral nervous system causes a neuropathic pain-like state that is mediated by type I IFN signaling to DRG nociceptors.

A Rare Presentation of Adult-Onset Bartter Syndrome: A Case Report.

Bartter syndrome is a rare, salt-wasting tubulopathy with impaired ion reabsorption in the ascending limb of the loop of Henle, which results in hypokalemia, hypochloremia, and hypercalciuria. It usually presents in neonates, with vomiting, dehydration, and failure to thrive. It results from mutations in several genes, including KCNJ1, CLCNKB, CLCNKA, BSND, and ROMK, which encode ion transporters. We report a rare presentation of adult-onset Bartter syndrome. In this case, a 27-year-old man presented to the hospital with upper and lower limb weakness. Bartter syndrome was suspected based on serum electrolytes assessment and arterial blood gas analysis. The patient was initiated on potassium chloride (KCL) infusion and potassium chloride syrup to correct hypokalemia.

Clinical outcome of established diagnostic and treatment modalities of COVID-19-associated myocarditis: a systematic review.

Despite the significant research and development of COVID-19 diagnostic and therapeutic approaches, the virus still poses a concern, particularly to groups that are already vulnerable. Several individuals experienced cardiac problems like myocardial infarction, arrhythmia, heart failure, cardiomyopathy, myocarditis, and pericarditis after they had recovered from the infection. Early diagnosis and timely management of sequelae are part of the therapy. However, there are gaps in the knowledge of the diagnostic and definitive treatment options for COVID-19 myocarditis. This review focuses on myocarditis associated with COVID-19. Objective: This systemic review provides the most recent overview of myocarditis caused by COVID-19, including clinical manifestations, diagnostic techniques, available treatments, and outcomes. Methods: The PubMed, Google Scholar, and ScienceDirect servers were used to conduct a systematic search in compliance with the PRISMA guidelines. Boolean search terms included "(COVID-19)" OR "(COVID19)" OR "(COVID-19 VIRUS INFECTION)" AND "(MYOCARDITIS)". The results were tabulated and analyzed. Results: A total of 32 studies, including 26 case reports and 6 case series, were included in the final analysis, and 38 cases of COVID-19-associated myocarditis were analyzed. Middle-aged men constituted the most affected population (60.52%). Dyspnoea (63.15%), chest pain or discomfort (44.73%), and fever (42.10%) were the prevalent presentations. ST-segment abnormalities were reported in 48.38% of cases on electrocardiography testing. Leucocytic infiltration (60%) was the frequent finding obtained on endomyocardial biopsy. Cardiac magnetic resonance imaging yielded myocardial oedema (63.63%), and late gadolinium enhancement (54.54%) as the most common findings. Reduced ejection fraction (75%) was the frequent result obtained on echocardiography. Corticosteroids (76.31%) and immunomodulators (42.10%) were the well-established in-hospital medications. Veno-arterial extracorporeal membrane oxygenation (35%) was the most common intervention used to support the treatment. The frequent in-hospital complications were cardiogenic shock (30.76%), followed by pneumonia (23.07%). The mortality rate was 7.9%. Conclusion: Early detection and timely management of myocarditis are essential to reduce the risk of developing further complications. It is crucial to emphasize the need to evaluate COVID-19 as a possible cause of myocarditis in populations that are young and healthy to avoid fatal consequences.