The Adverse Event Landscape of Stem Cell Transplant: Evidence for aGVHD Driving Early Transplant Associated Toxicities.

Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).

Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD.

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.

D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards models were used to identify sub-distribution hazard ratios (sHR)  for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

Novel approaches to acute graft-versus-host disease prevention.

The field of graft-versus-host disease (GvHD) has experienced significant growth, with increased number of clinical trials and the approval of several agents by the US Food and Drug Administration for both acute and chronic GvHD treatment. In addition, the development of prognostic biomarker algorithms has enabled risk stratification in acute GvHD. However, prevention remains the cornerstone of GvHD management. Notable recent changes include the expansion of donor options with the increased use of haploidentical donor and unrelated donor transplantation, the development of ex vivo selective T-cell depletion strategies, recent approval by the Food and Drug Administration of abatacept for GvHD prevention, and the application of posttransplant cyclophosphamide in matched and mismatched donor settings. In this article, we review the results of recent clinical trials in GvHD prophylaxis and discuss the changes in clinical practice and promising emerging strategies driving the field forward.

Short-Course Empiric Antibiotics in Children Undergoing Allogeneic Hematopoietic Cell Transplantation.

Fever is common in children undergoing hematopoietic cell transplantation (HCT). Empiric antibiotic (EA) therapy is initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to such complications as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA therapy have been studied in adults undergoing HCT without significant safety concerns, but data in children are lacking. We instituted a single-center preintervention/ postintervention quality improvement (QI) project to assess the feasibility of short-course EA therapy for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. Patients were eligible for the intervention, limiting EAs to 7 days for first fever, if they were admitted for their first allogeneic HCT, were afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA therapy for first fever and total broad-spectrum antibiotic use during the period of hospitalization, defined as the time from the start of conditioning to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and intensive care (ICU) admission within 3 days of stopping EA therapy. Project criteria were applied retrospectively to patients who underwent HCT in 2020 to construct a preintervention short-course-eligible cohort. During the intervention period, 41 patients underwent allogeneic HCT, of whom 17 (41%) were eligible for short-course EA therapy. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographic or HCT characteristics between patients eligible for short-course EA during the intervention and preintervention period (n = 24). The short-course EA schedule was adhered to by 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use was significantly decreased in the short-course EA-eligible patients compared to the preintervention cohort, from a median of 17 days to 8 days and from 20 days to 10 days, respectively (P < .01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who received short-course EA. In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome, and HCT outcomes.

Diffuse alveolar hemorrhage after hematopoietic cell transplantation- response to treatments and risk factors for mortality.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of hematopoietic cellular therapy (HCT). This study aimed to evaluate the effect of DAH treatments on outcomes using data from consecutive HCT patients clinically diagnosed with DAH from 3 institutions between January 2018-August 2022. Endpoints included sustained complete response (sCR) defined as bleeding cessation without recurrent bleeding, and non-relapse mortality (NRM). Forty children developed DAH at a median of 56.5 days post-HCT (range 1-760). Thirty-five (88%) had at least one concurrent endothelial disorder, including transplant-associated thrombotic microangiopathy (n=30), sinusoidal obstructive syndrome (n=19), or acute graft versus host disease (n=10). Fifty percent had a concurrent pulmonary infection at the time of DAH. Common treatments included steroids (n=17, 25% sCR), inhaled tranexamic acid (INH TXA,n=26, 48% sCR), and inhaled recombinant activated factor VII (INH fVIIa, n=10, 73% sCR). NRM was 56% 100 days after first pulmonary bleed and 70% at 1 year. Steroid treatment was associated with increased risk of NRM (HR 2.25 95% CI 1.07-4.71, p=0.03), while treatment with INH TXA (HR 0.43, 95% CI 0.19- 0.96, p=0.04) and INH fVIIa (HR 0.22, 95% CI 0.07-0.62, p=0.005) were associated with decreased risk of NRM. Prospective studies are warranted to validate these findings.

Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events.

In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 µg/mL. However, a higher Ctrough_1 (≥39 µg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 µg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 µg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.

BCMA CAR-T induces complete and durable remission in refractory plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options.

A retrospective review on the histopathological pattern of childhood malignant solid tumors in Ethiopia.

In low- and middle-income countries (LMICs), malignancies remain underreported due to lack of quality data. This study outlines the histopathological pattern of pediatric solid malignancies in children aged 0-15 years at the largest referral hospital in Ethiopia. A total of 432 solid malignancies were evaluated. The most common malignancies were lymphoma (21.8%), retinoblastoma (19.4%), and Wilms tumor (13.9%). Burkitt lymphoma accounted for 2.1%, despite being the most reported pediatric malignancy in sub-Saharan Africa in published literature. Definitive diagnosis could not be made in 7% of cases, related to the lack of confirmatory testing. The study highlights the need for improvement in diagnostic capabilities in LMICs.

Abatacept GVHD prophylaxis in unrelated hematopoietic cell transplantation for pediatric bone marrow failure.

Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.

Pulmonary Manifestations and Vascular Changes in Pediatric Transplantation-Associated Thrombotic Microangiopathy.

Although transplant-associated thrombotic microangiopathy (TA-TMA) commonly complicates pediatric hematopoietic cellular therapy (HCT), pulmonary manifestations and histology of TA-TMA (pTA-TMA) are rarely reported, with scant data available on timing, risk factors, pathogenesis, and outcomes. Pulmonary hypertension (PH) and diffuse alveolar hemorrhage (DAH) are recognized manifestations of pTA-TMA. The objective of this study was to characterize the pathologic findings, outcomes, and coincident diagnoses preceding biopsy-proven pTA-TMA. In Institutional Review Board- approved retrospective studies, available lung tissue was reviewed at 2 institutions between January 2016 and August 2021 to include those with pulmonary vascular pathology. Histologic features of pTA-TMA were present in 10 children with prior respiratory decline after an allogeneic HCT (allo-HCT; n = 9) or autologous HCT (n = 1). Pathologic lesions included muscular medialization, microthrombi, and red cell fragments, in addition to perivasculitis and intimal arteritis. Parenchymal findings included diffuse alveolar damage, organizing pneumonia, and plasmocytic infiltrates. Six children were clinically diagnosed with TA-TMA, and all were treated with eculizumab, at a median of 2.5 days after clinical diagnosis (range, 0 to 11 days). Four were identified postmortem. Coincident pulmonary infection was confirmed in 8 of the 10 patients. Five allo-HCT recipients (56%) experienced graft-versus-host disease (GVHD; 4 acute, 1 chronic) prior to the onset of respiratory symptoms. Two patients (20%) had clinically recognized DAH, although 9 (90%) had evidence of DAH on histology. Although all 10 patients underwent echocardiography at the time of symptom onset and 9 had serial echocardiograms, only 2 patients had PH detected. Treatments varied and included sildenafil (n = 3), steroids (n = 1), and eculizumab (n = 6). One patient was alive at the time of this report; the remaining 9 died, at a median of 52 days after onset of respiratory symptoms (range 4 to 440 days) and a median of 126 days post-HCT (range, 13 to 947 days). pTA-TMA is a heterogeneous histologic disease characterized by arteriolar inflammation, microthrombi, and often DAH. pTA-TMA presented with respiratory decline with systemic TA-TMA in all patients. Clinicians should maintain a high degree of suspicion for DAH in patients with TA-TMA and pulmonary symptoms. Coincident rates of GVHD and pulmonary infections were high, whereas the rate of PH identified by echocardiography was 20%. Outcomes were poor despite early use of eculizumab and other therapies. Our data merit consideration of pTA-TMA in patients with acute respiratory decline in the setting of systemic TA-TMA, GVHD, and infection. Investigation of additional therapies for pTA-TMA is needed as well. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Sickle cell disease is a risk factor for transplant-associated thrombotic microangiopathy in children.

Transplant-associated thrombotic microangiopathy (TA-TMA) and sickle cell disease (SCD) share features of endothelial and complement activation. Thus, we hypothesized that SCD is a risk factor for TA-TMA and that prehematopoietic cellular transplantation (HCT) markers of endothelial dysfunction and complement activation would be higher in patients with SCD. Children who underwent initial haploidentical or matched sibling donor HCT between January 2015 and June 2020 were included in this institutional review board-approved, single institution, retrospective study. Of the 115 children, 52 had SCD, and 63 underwent HCT for non-SCD indications. There was no significant difference in severe grade 3 to 4 acute graft-versus-host disease (GVHD) between recipients of HCT with or without SCD. The non-SCD cohort had significantly more cytomegalovirus-positive recipients, radiation-containing preparative regimens, and peripheral blood stem cell graft sources (P ≤ .05), all described risk factors for developing TA-TMA. Despite this, 7 of 52 patients (13%) with SCD developed TA-TMA compared with 1 of 63 patients (2%) without SCD (P = .015). Risk was highest in those who underwent haploidentical HCT (odds ratio [OR], 33; 95% confidence interval [CI], 1.4-793.2). Adjusting for HLA match, GVHD, post-HCT viral infection, stem cell source, and myeloablation, SCD remained a risk for developing TA-TMA (OR, 12.22; 95% CI, 1.15-129.6). In available pre-HCT samples, there was no difference in complement biomarkers between those with SCD and those without, though patients with SCD did have significantly higher levels of markers of endothelial activation, soluble vascular cell adhesion molecule 1, and P-selectin. In conclusion, children with SCD merit careful screening for TA-TMA after HCT, particularly those receiving a haploidentical HCT.

Controversies and expectations for the prevention of GVHD: A biological and clinical perspective.

Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Historically, cord blood and matched sibling transplantation has been associated with the lowest rates of GVHD. Newer methods have modified the lymphocyte components to minimize alloimmunity, including: anti-thymocyte globulin, post-transplant cyclophosphamide, alpha/beta T cell depletion, and abatacept. These agents have shown promise in reducing severe GVHD, however, can be associated with increased risks of relapse, graft failure, infections, and delayed immune reconstitution. Nonetheless, these GVHD prophylaxis strategies have permitted expansion of donor sources, especially critical for those of non-Caucasian decent who previously lacked transplant options. This review will focus on the biologic mechanisms driving GVHD, the method by which each agent impacts these activated pathways, and the clinical consequences of these modern prophylaxis approaches. In addition, emerging novel targeted strategies will be described. These GVHD prophylaxis approaches have revolutionized our ability to increase access to transplant and have provided important insights into the biology of GVHD and immune reconstitution.

Case Report: The First Case Report of Visceral Leishmaniasis in Cambodia.

Leishmaniasis is considered a neglected tropical disease that is commonly found in Asia, Africa, South America, and Mediterranean countries. Visceral leishmaniasis (VL) is the most severe form of the disease and is almost universally fatal if left untreated. The symptoms of VL overlap with many infectious diseases, malignancies, and other blood disorders. The most common findings include fever, cytopenias, and splenomegaly. Given the nonspecific symptoms, the diagnosis requires detailed laboratory investigations, including bone marrow examination, that can be challenging in low- and middle-income countries. Diagnostic limitations likely lead to the underdiagnosis or delay in diagnosis of VL. We describe, to our knowledge, the first case report of VL in Cambodia in a child presenting with fever, anemia, and thrombocytopenia. The diagnosis required a liver biopsy and multiple bone marrow biopsies to visualize intracellular Leishmania spp. Our case illustrates the diagnostic challenges and the importance of timely diagnosis. This case also highlights the need for heightened awareness of the diagnostic findings of VL and improved reporting of tropical diseases.