Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.

Retrospective analysis of outcomes for pediatric acute lymphoblastic leukemia in South American centers.

Introduction: Acute lymphoblastic Leukemia (ALL) is the most common pediatric malignancy. While the survival rate for childhood ALL exceeds 90% in high-income countries, the estimated survival in low-and middle-income countries ranges from 22-79%, depending on the region and local resources. Methods: This study retrospectively reviewed demographic, biological, and clinical parameters of children under 18 years of age with newly diagnosed ALL presenting between 2013-2017 across five pediatric centers in 4 countries in South America. Survival analyses were estimated using the Kaplan-Meier method. Results: Across the five centers, 752 patients were analyzed (Bolivia [N=9], Ecuador [N=221], Paraguay [N=197], Peru [N=325]) and 92.1% (n=690) patients were diagnosed with B-cell and 7.5% (n= 56) with T-cell ALL. The median age was 5.5 years old (IQR 7.29). At diagnosis, 47.8% of patients were categorized as standard and 51.9% as high risk per their institutional regimen. Advanced diagnostics availability varied between modalities. MRD was evaluated in 69.1% of patients; molecular testing was available for ETV6-RUNX, BCR-ABL1, TCF3-PBX1, and KMT2A-rearranged ALL in 75-81% of patients; however, karyotyping and evaluation for iAMP21 were only performed in 42-61% of patients. Central nervous system (CNS) involvement was evaluated at diagnosis in 57.3% (n=429) patients; of these, 93.7% (n=402) were CNS 1, 1.6% (n=7) were CNS 2, 0.7% (n=11) were CNS3, 1.9% (n=8) had cranial nerve palsy, and 2.1% (n=9) results unavailable. Chemotherapy delays >2 weeks were reported in 56.0% (n=421) patients during treatment. Delays were attributed to infection in 63.2% (n=265), drug-related toxicities in 47.3% (n=198), and resource constraints, including lack of bed availability in 23.2% (n=97) of patients. The 3-year Abandonment-sensitive EFS and OS were 61.0±1.9% and 67.2±1.8%, respectively. The 3-year EFS and OS were 71.0±1.8% and 79.6±1.7%, respectively. Discussion: This work reveals opportunities to improve survival, including addressing severe infections, treatment interruptions, and modifications due to drug shortages. In 2018, healthcare professionals across South America established the Pediatric Oncology Latin America (POLA) group in collaboration with St. Jude Children's Research Hospital. POLA collaborators developed an evidence-based, consensus-derived, adapted treatment guideline, informed by preliminary results of this evaluation, to serve as the new standard of care for pediatric ALL in participating institutions.

Factors influencing treatment decision-making for cancer patients in low- and middle-income countries: A scoping review.

PURPOSE: In this scoping review, we evaluated existing literature related to factors influencing treatment decision-making for patients diagnosed with cancer in low- and middle-income countries, noting factors that influence decisions to pursue treatment with curative versus non-curative intent. We identified an existing framework for adult cancer developed in a high-income country (HIC) context and described similar and novel factors relevant to low-and middle-income country settings. METHODS: We used scoping review methodology to identify and synthesize existing literature on factors influencing decision-making for pediatric and adult cancer in these settings. Articles were identified through an advanced Boolean search across six databases, inclusive of all article types from inception through July 2022. RESULTS: Seventy-nine articles were identified from 22 countries across six regions, primarily reporting the experiences of lower-middle and upper-middle-income countries. Included articles largely represented original research (54%), adult cancer populations (61%), and studied patients as the targeted population (51%). More than a quarter of articles focused exclusively on breast cancer (28%). Approximately 30% described factors that influenced decisions to choose between therapies with curative versus non-curative intent. Of 56 reported factors, 22 novel factors were identified. Socioeconomic status, reimbursement policies/cost of treatment, and treatment and supportive care were the most commonly described factors. CONCLUSIONS: This scoping review expanded upon previously described factors that influence cancer treatment decision-making in HICs, broadening knowledge to include perspectives of low- and middle-income countries. While global commonalities exist, certain variables influence treatment choices differently or uniquely in different settings. Treatment regimens should further be tailored to local environments with consideration of contextual factors and accessible resources that often impact decision-making.

Treatment-related mortality in children with cancer in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Approximately 90% of children with cancer live in low-income and middle-income countries (LMICs), where 5-year survival is lower than 20%. Treatment-related mortality in high-income countries is approximately 3-5%; however, in LMICs, treatment-related mortality has been reported in up to 45% of children with cancer. This study aimed to systematically explore the burden of treatment-related mortality in children with cancer in LMICs and to explore the association between country income level and treatment-related mortality. METHODS: For this systematic review and meta-analysis we identified articles published between Jan 1, 2010, and June 22, 2021, describing treatment-related mortality in paediatric patients (aged 0-21 years) with cancer in LMICs. We searched PubMed, Trip, Web of Science, Embase, and the WHO Global Metric Index databases. The search was limited to full-text articles and excluded case reports (<10 patients) and haematopoietic stem-cell transplantation recipients. Two reviewers independently screened studies for eligibility, extracted data from included publications, and evaluated data quality. Random and mixed-effects models were used to estimate treatment-related mortality burden and trends. The Cochran-Q statistic was used to assess heterogeneity between studies. This study is registered on PROSPERO (CRD42021264849). FINDINGS: Of 13 269 identified abstracts, 501 studies representing 68 351 paediatric patients with cancer were included. The treatment-related mortality estimate was 6·82% (95% CI 5·99-7·64), accounting for 30·9% of overall mortality (4437 of 14 358 deaths). Treatment-related mortality was inversely related to country income. Treatment-related mortality was 14·19% (95% CI 9·65-18·73) in low-income countries, 9·21% (7·93-10·49) in lower-middle-income countries, and 4·47% (3·42-5·53) in upper-middle-income countries (Cochran-Q 42·39, p<0·0001). In upper-middle-income countries, the incidence of treatment-related mortality decreased over time (slope -0·002, p=0·0028); however, outcomes remained unchanged in low-income (p=0·21) and lower-middle-income countries (p=0·16). INTERPRETATION: Approximately one in 15 children receiving cancer treatment in LMICs die from treatment-related complications. Although treatment-related mortality has decreased in upper-middle-income countries over time, it remains unchanged in LMICs. There is an urgent need for targeted supportive care interventions to reduce global disparities in childhood cancer survival. FUNDING: American Lebanese Syrian Associated Charities and National Cancer Institute.

Giant focal nodular hyperplasia with a background of hepatic steatosis in a 14-year-old boy.

Giant focal nodular hyperplasia (GFNH) is rarely seen in children, presenting complex diagnostic and management considerations. Pathognomonic radiographic findings can be absent in this population, and the nuances of pathologic examination are critical. We present a child with a GFNH involving the right side of the liver arising in the background of hepatic steatosis. The details of the diagnosis and therapeutic decisions involved in his treatment are discussed.

Evaluating blinatumomab implementation in low- and middle-income countries: a study protocol.

BACKGROUND: The recent implementation of novel therapies has accelerated progress in pediatric cancer care. Despite the significantly poorer survival of patients in low- and middle-income countries (LMICs), administation complexities and other significant resource barriers have limited the translation of these novel therapies in these regions. This study aims to develop a model that can be used to support the implementation of novel therapies, such as blinatumomab (bispecific antibody therapy for B-cell acute lymphoblastic leukemia [B-ALL]) in LMIC centers, with the long-term goal of developing an implementation framework for similar future efforts. METHODS: In this study, mixed methods will be applied to understand the key contextual considerations that can be accounted for through a training program and prospectively designed implementation activities. The Consolidated Framework for Implementation Research will guide the activities related to implementation evaluation in parallel with a drug donation program. A multidisciplinary research team comprising high- and low-middle income healthcare professionals, industry, and implementation scientists has been assembled with the common goal of improving safe access to blinatumomab. To assess the factors affecting blinatumomab administration, semi-structured interviews with diverse collaborators and quantitative assessments of organizational characteristics will be conducted, together with quantitative and qualitative assessments of feasibility, acceptability, appropriateness, and cost of blinatumomab implementation. A quantitative assessment of stakeholder perceptions of different implementation strategies used as part of the multifaceted approach will also be performed. Finally, we will examine the key domains and processes used and construct the implementation roadmap for translation of novel therapies. DISCUSSION: This study will rigorously develop an implementation roadmap for translation of novel therapies in low-resource settings. The knowledge gained in the formative assessment will reveal the priority areas and key implementation strategies. Thereby, the resultant roadmap will facilitate future scale-out strategies for novel therapies in LMICs, thus increasing access, building capacity for management, and ultimately improving the care for children in LMICs.

Multiple Concurrent Illnesses Associated with Anemia in HIV-Infected and HIV-Exposed Uninfected Children Aged 6-59 Months, Hospitalized in Mozambique.

Anemia is an increasingly recognized problem in sub-Saharan Africa. To determine the magnitude, severity, and associated factors of anemia among hospitalized children aged 6-59 months, HIV-infected and HIV-exposed uninfected children (a child born to a known HIV-infected mother) with a documented fever or history of fever within the prior 24 hours of hospital admission (N = 413) were included in this analysis. Of 413 children enrolled, 364 (88%) were anemic, with 53% classified as mild anemia (hemoglobin [Hb] 7-9.9 g/dL). The most common diagnoses associated with hospital admission included acute respiratory illness (51%), malnutrition (47%), gastroenteritis/diarrhea (25%), malaria (17%), and bacteremia (13%). A diagnosis of malaria was associated with a decrease in Hb by 1.54 g/dL (P < 0.001). In HIV-infected patients, malaria was associated with a similar decrease in Hb (1.47 g/dL), whereas a dual diagnosis of bacteremia and malaria was associated with a decrease in Hb of 4.12 g/dL (P < 0.001). No difference was seen in Hb for patients on antiretroviral therapy versus those who were not. A diagnosis of bacteremia had a roughly 4-fold increased relative odds of death during hospitalization (adjusted odds ratio = 3.97; 95% CI: 1.61, 9.78; P = 0.003). The etiology of anemia in high-burden malaria, HIV, tuberculosis, and poor nutrition countries is multifactorial, and multiple etiologies may be contributing to one's anemia at any given time. Algorithms used by physician and nonphysician clinicians in Mozambique should incorporate integrated and non-disease specific approaches to pediatric anemia management and should include improved access to blood culture.

Steroid-induced Bradycardia During Induction Chemotherapy in Children and Young Adults Diagnosed With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.

Systemic corticosteroids are widely used for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. Anecdotal case reports demonstrate bradycardia in patients receiving corticosteroids; however, a more in-depth analysis is lacking. This study aimed to describe the incidence, timing, and outcomes of bradycardia in children with ALL receiving corticosteroids during induction chemotherapy at our center from 2010 to 2016. A total of 153 children were included, with 150 (98%) demonstrating decreased heart rate following steroid administration with a median HR decrease of 23 beats per minute. Bradycardia ≤first percentile for age developed in 90 (59%) patients, with nadir occurring, on average, 7 doses into treatment, corresponding to 79 hours after initiation of therapy. No patient experienced adverse events related to bradycardia. Resolution of bradycardia at outpatient follow-up occurred in 62 of 71 (87%). Examination of nadir heart rate during subsequent hospitalizations in which steroids were not being administered did not demonstrate a significant incidence of bradycardia. Corticosteroid-induced bradycardia is common in children with ALL receiving induction chemotherapy. It was not associated with clinical adverse events and self-resolved without intervention. Therefore, further cardiac assessment may not be warranted in the presence of asymptomatic bradycardia suspected to be secondary to steroid administration.