Background Patients following Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT), Solid Organ Transplantation (SOT) and with Primary Immunodeficiency (PID) are at high risk of developing refractory ADV and CMV infections. Viral-specific (VS) T-cell immune reconstitution is essential to control ADV and CMV infections in these immunocompromised hosts. We developed a methodology of related donor-derived ADV and CMV CTLs by utilizing the IFN-γ cytokine capture system (CCS®) on the CliniMACS Prodigy® device by direct selection of VS-CTLs. Objective To evaluate genomic and immunomic characteristics, safety and efficacy of related donor-derived VS-CTLs in immunocompromised hosts with refractory viral infection. (IND 17449, NCT03266627, NCT03266640). Methods Patients following HSCT, SOT or with PID with refractory CMV or ADV infection and/or intolerant to anti-viral therapy were eligible. Related donors (HLA ≥ 3/6 matches) who screened positive for memory VS-CTLs underwent non mobilized apheresis collection and donor-derived VS-CTLs were enriched as we previously described by direct selection using the ADV or CMV PepTivator® generously provided by Miltenyi. 0.5 × 104 CD3 cells/kg were infused into recipients every two weeks with a maximum of 5 doses until CR or DLT. CTL characterization was performed utilizing scRNAseq, mass cytometry, NanoString® Immunoprofiling and multidimensional flow cytometry. Results Among the ADV and CMV CTLs recipients (N=20, N=19), median age and gender were (10.1 [0.11-19.1] and 8.0 [0.7-19.0] yrs), M/F (8/12, 13/6), haploidentical vs HLA-matched original AlloHSCT donor (68% vs 32%, and 74% vs 26%), AlloHSCT/SOT/PID (100%, 0, 0) (90%, 5%, 5%), respectively. ADV and CMV CTL post enrichment CD4+/IFN-γ+ and CD8+/ IFN-γ+ (mean ± SEM) percentages are 45 ± 10.1% and 39 ± 8.7%, 42 ± 9.6% and 67.1 ± 15.4%, respectively. Viral CMV CTL demonstrated significant increase in CD8+ TEM, TEMRA and CD4TH, CD4TFH1 subtypes (p < 0.05, 0.05, 0.001, 0.01, Fig 1), distinct gene expression profile highly enriched for IFN-γ and IL-2 (Fig 2A), CD4+ and CD8+ memory T cells CD27-CD45RO+ (Fig 2B) and significantly increased central memory and effector memory T-cells (p<0.01, 0.001), respectively. Both ADV and CMV CTLs were well tolerated. One Grade I and 3 Grade II transient aGVHD, no CRS, IRR, ICANS, GF nor neurotoxicity were reported and resulted in 85% and 84% CR median of 34 (6-112) and 30 (6-82) days, 1 yr OS of 70% and 74%, and 1yr viral associated mortality of 5% and 0%, respectively (Fig 3). Conclusions Related ADV and CMV CTLs enrichment by direct selection using the CliniMACS Prodigy® CCS (IFN-γ) is feasible, well tolerated and are characterized by central & effector memory T-cells secreting IFN-γ and IL-2 and associated with a high CR rate and low 1 yr viral associated mortality.

Introduction Polatuzumab vedotin (Pv) is an antibody-drug conjugate consisting of a humanized monoclonal antibody targeting CD79b on human B cells conjugated to the antimitotic agent monomethyl auristatin E (MMAE).1 CD79b is expressed in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), primary CNS lymphoma (PCNSL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and others. Pv was FDA approved in 2019 for relapsed or refractory (R/R) DLBCL, and later approved for upfront treatment of DLBCL in combination with R-CHP.2,3 DLBCL is the most common non-Hodgkin lymphoma (NHL) in adults. Forty to 50 percent of patients with DLBCL will relapse or have primary refractory disease. Standard of care for R/R DLBCL includes high dose chemotherapy followed by autologous stem cell transplantation (ASCT), however about 50 percent of patients will relapse following ASCT.4,5 There is an urgent need for effective maintenance therapies to decrease post-ASCT relapses. Objectives To evaluate the safety and tolerability of Pv following myeloablative conditioning (MAC) and ASCT in B-NHL. Secondary objectives include measurement of event-free, progression-free and overall survival; and measurement of overall response rate to Pv in patients with partial response (PR) or stable disease (SD) following MAC and ASCT. Methods Patients age 12 to 75 with BL, DLBCL, PCNSL, FL, MCL, marginal zone lymphoma, transformed FL, Richter syndrome, or Hodgkin lymphoma with adequate organ function and the following disease status are eligible: primary induction failure, or first through third relapse or progression having attained a complete response (CR), PR, or SD following reinduction therapy. Double or triple hit B-NHL or B-NHL with an IPI of 3 or greater having attained PR or CR are also eligible. Patients may receive MAC with BEAM (carmustine/etoposide/cytarabine/melphalan), CBV (cyclophosphamide/carmustine/etoposide), or for PCNSL, TT/BCNU (thiotepa/carmustine) at the discretion of the treating physician. Patients may begin Pv maintenance therapy between 30 and 60 days post-ASCT. Patients must not have progressive disease (PD) and must meet hematologic parameters to begin Pv. Pv is given at 1.8mg/kg/dose every 21 days for eight doses. Results Four patients have received at least one dose of maintenance therapy with Pv following MAC and ASCT from 2021 to present. There have been no dose-limiting toxicities or serious adverse events attributable to Pv. Diagnoses included DLBCL in three patients and primary CNS lymphoma in one patient. The patients have ranged in age from 13 to 49 years at enrollment. Two patients have completed the planned two-year follow-up period post-ASCT, and two have ongoing follow-up. All four patients remain in CR. Accrual is ongoing. Conclusion Maintenance therapy with Pv is a promising approach to prevent relapse in patients with CD79b positive lymphoma following MAC and ASCT.

Introduction Allogeneic HCT (AlloHCT) offers curative treatment for high-risk and relapsed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoma (T-LLy), but post-HCT relapses remain an obstacle for long-term survival. CD38 is highly expressed in T-ALL/T-LLy, and significant activity of the anti-CD38 antibody, daratumumab (DARA), was seen in a recent clinical trial for relapsed/refractory disease (Bhatla et al., Blood 2024). We developed a phase 1 trial (NCT04972942) to evaluate targeted immunotherapy with DARA after AlloHCT for relapsed T-ALL/T-LLy. Objectives The primary objective is to determine the safety of targeted immunotherapy with DARA after total body irradiation (TBI)-based myeloablative conditioning and AlloHCT for children, adolescents, and young adults (CAYA) with high-risk T-ALL or T-LLy. Additional exploratory objectives will evaluate outcomes of receiving AlloHCT and post-HCT DARA on study and correlate those outcomes with novel biological and immunological studies, including measurable residual or minimal detectable disease (MRD/MDD). Methods Patients 1 (and ≥ 10 kg) to ≤ 39-years, with relapsed T-ALL in second or subsequent remission or relapsed T-LLy with complete response after reinduction therapy are eligible. Participants will undergo myeloablative TBI-based conditioning and AlloHCT with best available donor. Safety of post-HCT DARA will be determined through a phase 1, time-to-event Bayesian optimal interval study design, evaluating 3 dose levels of DARA IV (IND 159396) in 15 participants. If no dose-limiting toxicity (DLT) is observed, an additional 15 participants will be enrolled in a dose expansion cohort (DEC) for additional correlative studies and to guide selection of a recommended phase 2 dose (RP2D) (Figure 1). Participants will have pre- and post-HCT correlative blood, bone marrow, and cerebrospinal fluid studies collected, including NGS-based MRD/MDD. Results Three participants in CR2 enrolled to date, each at dose level 1 (8mg/kg). Participant 1 completed protocol therapy and is alive in CR2 at 27 months post-HCT. Participant 2 received 4 doses of DARA, came off protocol therapy due to moderate chronic GVHD, and is alive in CR2 at 17 months post-HCT. Early tacrolimus taper for EBV pneumonitis and mixed T-cell chimerism likely contributed to their chronic GVHD. Participant 3 completed protocol therapy and is alive in CR2 at 11 months post-HCT. No DLT related to DARA has been observed to date. Conclusions Novel strategies are needed to reduce relapse and improve survival after AlloHCT for relapsed T-ALL/T-LLy. ALLO-T-DART will (1) determine the safety and RP2D of post-HCT DARA and (2) collect data on novel biomarkers of response, MRD/MDD kinetics, and immune reconstitution after DARA treatment for relapsed T-ALL/T-LLy. Supported by DOD USAMRAA #HT94252310686, Johnson & Johnson Innovative Medicine, and Cures Within Reach.

Background: Children, adolescents, and young adults (CAYA) with advanced mature B non-Hodgkin lymphoma (MB-NHL) have achieved >= 90% overall survival with intensive chemoimmunotherapy and intrathecal chemotherapy (IT). However, patients receive multiple IT doses requiring sedation with general anesthesia which may be associated with long-term late effects in cognitive development. Liposomal cytarabine (LC) has a half-life of 100-263 h, potentially decreasing the number of IT doses required. LC has been associated with toxicities when used in combination with high-dose methotrexate (HD-MTX) and ARA-C in adults with MB-NHL. Methods: This phase II study incorporated 2 doses of LC to the French-American-British backbone in central nervous system (CNS) negative patients and 4 doses in CNS positive patients. Results: Of 41 patients, 33 (19 FAB Group B, LDH <= 2X ULN; 6 FAB Group B, LDH >= 2X ULN; 8 FAB Group C) received LC and only 1 (3%) had a transient Grade 3 adverse event, likely secondary to disease progression. We successfully reduced the number of IT in Group B patients from 9 to 5 and in Group C CNS negative patients from 10 to 7. CNS positive patients received 9 IT instead of 13. The 2-year event-free survival and overall survival were 94.5% and 97.2%, respectively. We demonstrated that IT LC in CAYA with MB-NHL was feasible and safe in the setting of HD- MTX and ARA-C when decadron was used as a premedication and the LC was given after MTX clearance. Conclusion: We maintained event free survival at numbers consistent with previous reports using the standard increased number of IT injections. We safely decreased the total number of IT without compromising CNS control.

Background: Immune thrombocytopenic purpura (ITP) is an immune-mediated bleeding disorder, occurring mainly in young children, with an overall incidence of 4–5/100,000 per year. ITP is classified into acute and chronic forms, with chronic ITP occurring in 35% of cases. Numerous studies have investigated biomarkers such as platelets (PLT) antibodies, and regulatory T cell ratio, but none are reliable predictors for chronicity. B cells have a well-established role in ITP pathogenesis, as they are the source of antibodies directed against platelet-surface glycoproteins. Rituximab (RITUX), a monoclonal antibody directed against CD20, a glycoprotein expressed on the surface of B cells, leads to a fast and thorough, but reversible B-cell depletion. Chugh et al. (2015, Lancet) conducted a systematic review and meta-analysis of randomized controlled trials that evaluated the efficacy and safety of rituximab in adults with primary ITP. Complete response (CR), defined as platelet count >100×109/L without rescue therapy, was more common with rituximab than with standard of care (weighted proportions: 46.8% vs 32.5%; relative risk [RR] 1.42, 95% CI 1.13–1.77; p=0.002). However, there is a paucity of data on the safety, efficacy, and optimal dosing of RITUX in newly diagnosed pediatric ITP. While existing therapies provide temporary effect on platelets counts, we hypothesized that dose dense RITUX would be safe to use in newly diagnosed ITP and will reduce chronicity rates. Objective: To assess the safety and efficacy of dose dense RITUX in high risk newly diagnosed pediatric ITP patients. Design/Methods: Patients with acute ITP, ages 0.5 to 21 years of age, with a PLT count ≤ 20x109/L and high-risk features such as need for hospitalization were enrolled. Study includes 2 arms: RITUX upfront and a control arm. Eligibility criteria for RITUX arm included: performance status ≥50%, no prior ITP therapy and adequate renal and liver function. The control arm included patients with similar inclusion criteria, who were treated at Maria Fareri Children's Hospital (MFCH), NY, USA, between the years 2019-2025. IV RITUX was administered at 375mg/m2/dose within 24 hours of consent and again on days: 2, 7, 14, and 21. On the control arm patients were either observed without intervention or treated with steroids and/or IVIG. Complete blood counts of patients were taken at various time points and again on day 180 post initial therapy. CR was defined as PLT count ≥ 100x109/L without recent additional ITP directed therapy in the month prior. Days to CR were compared using a Log-rank (Mantel-Cox) calculation using the Prism program, and continuous complete response rate (CCR) by Chi-Square test with Excel. Adverse events (AEs) were defined based on chart review on the control arm or as reported by the investigator on the RITUX arm. Results: Between July 2019 to February 2025, 48 patients presented to MFCH with newly diagnosed ITP and met our inclusion criteria. All patients had at least 6 months follow up post ITP diagnosis. Only 8 of those were enrolled on our RITUX arm, ages 1.9-14 years old (median 4.5 years), and a Male/Female ratio of 7/1. The 40 remaining patients, ages 0.5-19 years old (median 5 years), and M/F ratio of 19/21 were included in our control arm. The mean PLT count at diagnosis was 4.8x109/L on the control arm and 6.1x109/L on the RITUX arm. On the control arm, all patients but two were treated with IVIG (95%), and 28 patients (70%) received a concurrent course of steroids as part of their initial therapy. Most common AEs included epistaxis (28%), headaches (20%) and emesis (15%) on the control arm, with 13% having similar AEs on the RITUX arm. No significant grade III/IV AEs were recorded in both arms. Among those achieving CR on the control arm, the average time to CR was 16.7 days (range: 2-88 days), and only 67.5% of patients on control arm achieved CCR at 6 months post ITP diagnosis. In comparison, on the RITUX arm, the average time to CR was 20 days (range 2-53 days), and all patients were in CCR at 6 months post diagnosis. No difference was observed between time to CR between both arms (p=0.552), however, a trend towards significant difference between CCR (p=0.059) was observed. Conclusions: Dose dense RITUX appears safe and may be considered for newly diagnosed pediatric ITP. Trends indicate improved CCR rates and fewer AEs in the RITUX arm. Accrual is ongoing.

Observing your child in pain is inherently distressing. In the context of chronic pain, caregiver responses can powerfully impact child pain-related functioning. The Parent Empathy in the Context of Pain model postulates that parent empathic distress may hinder adaptive responses to child pain, thus playing a key role in the link between parent responses and child functioning. Here, we examined how parent empathy is related to parent and child pain-related constructs within the Parent Empathy in the Context of Pain model, using an adapted Empathy for Pain Scale (EPS) for use in parents (P-EPS). Data were collected from 190 parents of youth with chronic pain (170 mothers; children aged 8-18y) and their children. Structural equation modeling (SEM) showed support for the theoretical model. Parent pain-related beliefs were associated with behavioral responses via affective responses of empathy for pain (affective distress) and emotion regulation (emotional suppression), which in turn were associated with child pain-related functioning. Moreover, higher levels of parent empathic distress to observing their child’s pain was significantly associated with more general empathic distress, poorer perspective taking and more maladaptive emotion regulation strategy use (emotional suppression). Our findings underscore the involvement of parent affective responses in driving parent maladaptive behavioral responses to their child’s pain and emphasize the role of affective empathic distress as well as its regulation. In addition to providing information on its assessment, this empirical investigation provides novel insights into the construct of empathy in this context. Perspective This article presents initial data supporting the Parent Empathy in the Context of Pain model. Findings show involvement of parent affective responses in driving parent maladaptive behavioral responses to their child’s chronic pain and emphasize the role of affective empathic distress as well as its regulation.

Introduction: Despite excellent survival outcomes, significant chronic health conditions occur among pediatric, adolescent, and young adult (CAYA) classic Hodgkin lymphoma (cHL) survivors as a result of current chemotherapy and radiation regimens. Targeting both the tumor microenvironment (TME), as well as tumor-specific antigens has proven to be an effective and safe approach for the treatment of CAYA cHL patients. Here we report on our cHL immunotherapy treatment protocols over the past 13 years. Our approach combines the use of the antibody-drug conjugat,e brentuximab vedotin (Bv), targeting Reed-Sternberg (RS) cells, along with the anti-CD20 antibody rituximab (RTX) and checkpoint inhibitor nivolumab (N) targeting the TME, added to risk-adapted chemotherapy in newly diagnosed CAYA cHL patients. This chemoimmunotherapy approach allows for anthracycline dose reduction and radiation sparing in intermediate and high-risk patients. Methods: Our early cHL clinical trial enrolled patients 3-39yr old who received a backbone of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine, and rituximab (Bv-AVD-R) given on Day 1, 2 and Day 15,16 of each cycle. Early response utilizing FDG-PET scan was performed following 2 cycles of therapy (PET2) with PET2 negativity defined as Deauville score of 1, 2 or 3. Rapid early responders (RER) or slow early responders (SER) received an additional 2 to 6 cycles of treatment based on risk assignment and early response. Following completion of our initial trial, subsequent patients were enrolled on our follow-up study evaluating the addition of nivolumab beginning with cycle 3 of therapy and omitting further anthracycline (Bv-NVD-R). This limited the total anthracycline dose to 100mg/m2 per patient. Radiation therapy was initially planned for high-risk patients with slow responding lesions. Subsequently, on our current study, only patients not achieving metabolic CR by FDG-PET at the completion of all chemoimmunotherapy receive radiation therapy. Results: A total of 54 patients completed therapy with a median age of 17yrs (4-25yrs). Thirty-four patients received Bv-AVD-R for all cycles and 20 patients are enrolled on our follow up study and received Bv-AVD-R followed by Bv-NVD-R (total doxorubicin dose 100mg/m2). All 54 patients achieved a CR to therapy at a rate of 100%. Early PET2 negativity was achieved in 47 patients (87%). Due to excellent overall rapid response, only four patients have required radiation therapy and no patient received radiation therapy in the follow-up study. The EFS and OS is 100% with a median follow up time of >90 months (range 2-159 months). Accrual is ongoing for the current trial. Adverse events (AEs) included grade IV myselosuppression in the majority of patients, supported with growth factor. There have been no admissions for fever and neutropenia and no infectious complications with either regimen. Among all patients, a total of four (7%) experienced grade 3 or greater non-hematological AEs. These included two (3.7%) grade 3 neuropathy, one (1.9%) grade 3 allergic reaction to Bv, and one (1.9%) grade 3 mucositis. Immune profiles at a median of 18 months of follow-up post-rituximab have demonstrated normal IgG, absolute CD19 and absolute CD3 levels. We have completed the nivolumab safety run in for the follow-ups study in the current trial. There have been no unexpected AEs related to therapy and no dose limiting toxicities with the addition of nivolumab to the immunochemotherapy backbone. Conclusions: The addition of immunotherapy to a reduced-intensity chemotherapy backbone is safe, effective and well tolerated. Targeting the HRS cell as well as the TME via the PD1/PD-L1 axis is a promising approach in CAYA with cHL and allows for reduction in both anthracycline and radiation exposure. This is important in limiting short- and long-term adverse effects. The use of rituximab added to this approach may have contributed to the excellent response observed in this CAYA cHL cohort.

Background:Children with relapsed/refractory acute leukaemias have lower response rates to reinduction and decreased overall survival. Mitoxantrone and clofarabine both have proven efficacy in acute leukaemia. We present our final results utilising this novel reinduction platform as a bridge to haematopoietic stem cell transplantation (HSCT) in children with high-risk pediatric leukaemias. Methods:From 2013 to 2021, patients 0-30.99 yr old with acute lymphoblastic leukaemia (ALL) or acute myelogenous leukaemia (AML) with relapse/refractory disease were given 1 to 3 cycles of clofarabine (escalating doses 20, 30, 35 and 40 mg/m2/day to establish the maximal tolerated dose [MTD]) days 1-5, in combination with mitoxantrone 12 mg/m2/day on days 3-6. The primary objective was to determine the maximal tolerated dose (MTD) or maximal acceptable dose of clofarabine in combination with mitoxantrone 12 mg/m2/day. The key secondary objective was to determine the overall response rate of the combination of mitoxantrone and clofarabine. The protocol was registered with clinicaltrials.gov (NCT01842672). Findings:Forty patients enrolled (18 phase I, 22 phase II) with median age 13 yrs (8 months-23 yrs). Demographics: 22 ALL (10 = induction failure [IF]/minimal residual disease [MRD], 9 = Relapse 1, 3 = Relapse 2), 17 AML (9 = IF/MRD, 6 = Relapse 1, 2 = Relapse 2). During phase I, there were 2 dose-limiting toxicities (DLTs) at dose level 4 requiring de-escalation to dose level 3. The phase I MTD was established at 35 mg/m2/dose clofarabine and continued in phase II. One patient with Burkitt Lymphoma was not included in this efficacy analysis. Thirty-three of 39 (85%) leukaemia patients achieved a complete response (CR). Of these, 88% achieved MRD negativity. Thirty-two of 33 patients went on to allogeneic HSCT. The event free survival/overall survival (EFS/OS) at 1 year was 74% for the entire cohort and 85% for responding/bridging patients at a median follow-up time of >75 months (range 30-120). Interpretation:The MTD of clofarabine in combination with mitoxantrone reinduction therapy was 35 mg/m2/dose x 5 days and was safe, well-tolerated and resulted in an 85% CR rate with 88% MRD negativity and, following HSCT, a 1 yr EFS/OS of 85%. Funding:Pediatric Cancer Research Foundation, Pediatric Cancer Foundation, Children's Cancer Fund, St. Baldrick's Foundation, Carolinas Healthcare, and NCCF subcontract #16252.