Pembrolizumab (and friends) in pediatric malignancies: should we consider Hodgkin lymphoma a world of its own?
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ABSTRACT:
SUBMITTER: Algeri M
PROVIDER: S-EPMC7576004 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Pembrolizumab (and friends) in pediatric malignancies: should we consider Hodgkin lymphoma a world of its own?
Algeri Mattia M Locatelli Franco F
Annals of translational medicine 20200901 17
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Project description:ObjectivesSurvivors after pediatric Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are with lifetime risk for second primary malignancy (SPM). This necessitates a thorough analysis to better understand the potential long-term health implications for these individuals.MethodsWe used a US-wide population-based cancer registry data to quantify the SPM risk and identify its incidence patterns among pediatric lymphoma patients.ResultsWe observed 4.74-fold (95% CI 4.27-5.25) and 3.40-fold (95% CI 2.78-4.10) increased risks of SPM in survivors after pediatric HL and NHL, respectively. Through over 40 years' follow-up, the cumulative incidence of SPM for pediatric lymphoma was persistently increasing, and here we firstly report the high 40-year cumulative incidence rates of SPM, 22.2% for HL and 12.6% for NHL, suggesting that SPM accounts for a great proportion of deaths among survivors. Of 6805 pediatric lymphomas, 462 (6.36%) developed a SPM, especially second breast and thyroid cancer, followed by hematologic neoplasms including leukemia and NHL. The competing risk analysis demonstrated gender, lymphoma subtype and radiotherapy were significantly associated with SPM. Different risk patterns of SPM were identified between pediatric HL and NHL. Chemotherapy accelerated SPM development but did not increase its incidence risk.ConclusionOverall, patients after pediatric lymphoma can be with high lifetime risk of SPM, and more attention should be paid to SPM-related signs for early detection and intervention.
| S-EPMC10821973 | biostudies-literature
Project description:Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.
| S-EPMC7656920 | biostudies-literature
Project description:Non-Hodgkin lymphoma (NHL) that develops after kidney transplantation belongs to post-transplant lymphoproliferative disorders (PTLD) occurring with an incidence of 2-3%. Most pediatric cases are related to primary infection with Epstein-Barr virus (EBV), able to transform and immortalize B cells and widely proliferate due to the lack of relevant control of cytotoxic T cells in patients receiving post-transplant immunosuppression. NHL may develop as a systemic disease or as a localized lesion. The clinical pattern is variable, from non-symptomatic to fulminating disease. Young age of transplant recipient, seronegative EBV status at transplantation, and EBV mismatch between donor and recipient (D+/R-) are regarded as risk factors. Immunosuppression impacts the development of both early and late NHLs. Specific surveillance protocols, including monitoring of EBV viral load, are used in patients at risk; however, detailed histopathology diagnosis and evaluation of malignancy staging is crucial for therapeutic decisions. Minimizing of immunosuppression is a primary management, followed by the use of rituximab in B-cell NHLs. Specific chemotherapeutic protocols, adjusted to lymphoma classification and staging, are used in advanced NHLs. Radiotherapy and/or surgical removal of malignant lesions is limited to the most severe cases. Outcome is variable, depending on risk factors and timing of diagnosis, however is positive in pediatric patients in terms of graft function and patient survival. Kidney re-transplantation is possible in survivors who lost the primary graft due to chronic rejection, however may be performed after at least 2-3 years of waiting time, careful verification of malignancy-free status, and gaining immunity against EBV.
| S-EPMC9239945 | biostudies-literature
Project description:Background/aimThe role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a median age of 13.6 years, with various types of advanced malignancies treated in pediatric oncology centers in Poland between 2015 and 2023.ResultsThe indications for treatment with anti-PD1 were as follows: Hodgkin lymphoma (11); malignant skin melanoma (9); neuroblastoma (8); and other malignancies (14). At the end of follow-up, complete remission (CR) was observed in 37.7% (15/42) of children and disease stabilization in 9.5% (4/42), with a mean survival 3.6 (95% CI = 2.6-4.6) years. The best survival (OS = 1.0) was observed in the group of patients with Hodgkin lymphoma. For malignant melanoma of the skin, neuroblastoma, and other rare malignancies, the estimated 3-year OS values were, respectively, 0.78, 0.33, and 0.25 (p = 0.002). The best progression-free survival value (0.78) was observed in the group with malignant melanoma. Significantly better effects of immunotherapy were confirmed in patients ≥ 14 years of age and good overall performance ECOG status. Severe adverse events were observed in 30.9% (13/42) patients.
| S-EPMC10931151 | biostudies-literature
Project description:Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed-Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3-18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.
| S-EPMC7761312 | biostudies-literature
Project description:Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.
| S-EPMC7955404 | biostudies-literature
Project description:Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) who respond to salvage chemotherapy. However, relapse after ASCT remains a frequent cause of treatment failure, with poor subsequent prognosis. Because cHL is uniquely vulnerable to programmed cell death-1 (PD-1) blockade, PD-1 blockade given as consolidation after ASCT could improve ASCT outcomes. We therefore conducted a multicohort phase 2 study of pembrolizumab in patients with RR cHL after ASCT, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary end point) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Thirty patients were treated on this study. The median age was 33 years, and 90% were high-risk by clinical criteria. Seventy-seven percent completed all 8 cycles. Toxicity was manageable, with 30% of patients experiencing at least 1 grade 3 or higher adverse event (AE), and 40% at least 1 grade 2 or higher immune-related AE. Two patients were lost to follow-up in complete remission at 12 months. The PFS at 18 months for the 28 evaluable patients was 82%, meeting the primary end point. The 18-month overall survival was 100%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with RR cHL, and resulted in a promising PFS in a high-risk patient cohort, supporting the testing of this strategy in a randomized trial. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
| S-EPMC6609955 | biostudies-literature
Project description:Programmed death-1 inhibitors are approved for patients with relapsed or refractory classic Hodgkin lymphoma (RRcHL). We present the 2-year follow-up of the phase 2 KEYNOTE-087 study of pembrolizumab in 210 patients, based on HL progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV; cohort 1); salvage chemotherapy and BV, with ineligibility for SCT owing to chemorefractory disease (cohort 2); and progression after SCT without BV (cohort 3). With a median follow-up of 27.6 months, the objective response rate (ORR) by blinded independent central review was 71.9% (95% CI, 65.3-77.9), the complete response rate (CRR) was 27.6%, and the partial response (PR) rate was 44.3%. Median duration of response was 16.5 months (range, 0.0+ to 27.0+ [+, no progressive disease at last assessment]) in all patients, 22.1 months in cohort 1, 11.1 months in cohort 2, and 24.4 months in cohort 3. Median progression-free survival was not reached in all patients with CR: 13.8 months (95% CI, 12.0-22.1) for patients with PR and 10.9 months (95% CI, 5.6-11.1) for patients with stable disease. Median overall survival was not reached in all patients or in any cohort. Treatment-related adverse events (TRAEs) of any grade occurred in 153 (72.9%) patients; grades 3 and 4 occurred in 25 (12.0%) patients; none resulted in death. Results confirmed effective antitumor activity, durability of response, and manageable safety of pembrolizumab monotherapy in RRcHL, regardless of prior treatment and including chemoresistant cHL. This trial was registered at www.clinicaltrials.gov as #NCT02453594.
| S-EPMC6776792 | biostudies-literature
Project description:Rhesus macaque rhadinovirus (RRV) is closely related to Kaposi sarcoma-associated herpesvirus (KSHV) and is associated with the development of B-cell hyperplasia and persistent lymphadenopathy resembling multicentric Castleman disease in rhesus macaques (RMs) coinfected with simian immunodeficiency virus (SIV). Here we investigated whether RMs experimentally infected with SIV and RRV can develop other disease manifestations observed in HIV- and KSHV-infected patients. As reported earlier, inoculation of SIV-infected RMs with RRV results in persistent RRV infection, whereas immunocompetent animals infected with RRV exhibit viremia 2 weeks after infection, followed by a period of no virus detection until they are subsequently made immunodeficient by SIV infection. A subset of animals developed abnormal cellular proliferations characterized as extranodal lymphoma and a proliferative mesenchymal lesion. In situ hybridization and immunohistochemistry analysis indicate RRV is present in both malignancies, and DNA microarray analysis detected viral interleukin-6 (vIL-6) and viral FLICE-like inhibitory protein (vFLIP) transcripts. Reverse-transcriptase polymerase chain reaction analysis confirmed vIL-6 and vFLIP expression, and that of RRV open reading frames 72 and 73, homologs of KSHV open reading frames shown to be expressed in primary effusion lymphoma. These data support the utility of the RRV-/SIV-infected RM as an excellent animal model to investigate KSHV-like pathogenesis.
| S-EPMC2582004 | biostudies-literature
Project description:KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD; ≥10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (>90%) and through week 24 (>80%) was demonstrated across treatment groups (PRO analysis set: pembrolizumab, n = 146; BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.31]; P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.74]; P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with R/R cHL who are ineligible for or experience relapse after ASCT.
| S-EPMC8791579 | biostudies-literature