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A real-world analysis of PD1 blockade from the Rete Ematologica Pugliese (REP) in patients with relapse/refractory Hodgkin's lymphoma
Gaudio, F., Loseto, G., Bozzoli, V., Scalzulli, P. R., Mazzone, A. M., Tonialini, L., Fesce, V., Quintana, G., De Santis, G., Masciopinto, P., et al
Annals of hematology. 2023
Abstract
Checkpoint inhibitors have significantly changed the prognosis of patients with relapsing refractory classical Hodgkin's lymphoma (cHL), demonstrating excellent results in heavily pretreated patients. However, there is still limited data on the real-world experience with PD-1 inhibitors in cHL. Within the context of the Apulian hematological network (Rete Ematologica Pugliese, REP), we performed a retrospective, multicenter analysis of 66 patients with relapsing refractory cHL who had received PD-1 inhibitors in the non-trial setting. Forty-three patients (65%) were treated with nivolumab and 23 (35%) with pembrolizumab. Thirty-one (47%) and 8 (12%) patients underwent autologous or allogeneic stem cell transplantation prior to checkpoint inhibitor therapy, respectively. The median number of lines of treatment attempted prior to PD-1 inhibitor therapy was 4 (range, 3 to 7). All patients had received brentuximab vedotin prior to checkpoint inhibitor therapy. The overall response rate to PD-1 inhibitors therapy was 70% (47% complete remission (CR) and 23% partial remission (PR)). Twenty-four immune-related adverse events (19 (80%) grades 1-2; 5 (20%) grades 3-4) were documented (4 gastrointestinal, 4 hepatic, 6 fever, 4 hematological, 3 dermatological, 3 allergic rhinitis). Toxicity resolved in all patients, and there were no deaths attributed to checkpoint inhibitor therapy. After a median follow-up of 26 months (range 3-72 months), 54 patients (82%) are alive, and 12 (18%) died. The cause of death was attributed to disease progression in 9 patients and sepsis in 3 patients. After PD-1 inhibitor therapy, 22 patients (33%) relapsed or progressed. The overall survival and progression-free survival at 5 years were 65% and 54%, respectively. This study confirms the efficacy and tolerability of PD-1 inhibitor therapy in relapsed refractory cHL in a real-world setting, demonstrating similar clinical outcomes and toxicity profiles compared to clinical studies.
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Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents
Faisal, M. S., Hanel, W., Voorhees, T., Li, R., Huang, Y., Khan, A., Bond, D., Sawalha, Y., Reneau, J., Alinari, L., et al
Cancer medicine. 2023
Abstract
BACKGROUND Relapsed or refractory Hodgkin lymphoma (R/R HL) is a challenging disease with limited treatment options beyond brentuximab vedotin and checkpoint inhibitors. Herein we present the time-trend analysis of R/R HL patients who received allogeneic hematopoietic cell transplantation (allo-HCT) at our center from 2001-2017. METHODS The patients were divided into two distinct treatment cohorts: era1 (2001-2010), and era2 (2011-2017). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic graft versus host disease (GVHD). RESULTS Among the 51 patients included in the study, 29 were in era1, and 22 were in era2. There was decreased use of myeloablative conditioning in era2 (18% vs. 31%) compared to era1 and 95% of patients in era2 previously received brentuximab Vedotin (BV). Haploidentical donors were seen exclusively in era2 (0% vs. 14%) and more patients received alternative donor transplants (7% vs. 32%) in era2. The 4-year OS (34% vs. 83%, p < 0.001) and 4-year PFS (28% vs. 62%, p = 0.001) were significantly inferior in era1 compared to era2. The incidence of 1-year NRM was lower in era2 compared to era1 (5% vs. 34%, p = 0.06). The cumulative incidence of acute GVHD at day 100 was similar in both eras (p = 0.50), but the incidence of chronic GVHD at 1 year was higher in era2 compared to era1 (55% vs. 21%, p = 0.03). CONCLUSIONS Despite the advent of novel therapies, allo-HCT remains an important therapeutic option for patients with R/R HL.
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Prognostic Model using 18F-FDG PET Radiomics Predicts Progression-Free Survival in Relapsed/Refractory Hodgkin Lymphoma
Driessen, J., Zwezerijnen, G. J., Schöder, H., Kersten, M. J., Moskowitz, A. J., Moskowitz, C. H., Eertink, J. J., Heymans, M., Boellaard, R., Zijlstra, J. M.
Blood advances. 2023
Abstract
Investigating prognostic factors in relapsed or primary refractory classical Hodgkin lymphoma (R/R cHL) patients is essential to optimize risk-adapted treatment strategies. We built a prognostic model using baseline quantitative 18F-FDG PET radiomics features and clinical characteristics to predict progression free survival (PFS) in R/R cHL patients treated with salvage chemotherapy followed by autologous stem-cell transplant (ASCT). Metabolic tumor volume (MTV) and several novel radiomics dissemination features representing inter-lesional differences in distance, volume and standard uptake value (SUV) were extracted from the baseline PET. Machine learning using backward selection and logistic regression were applied to develop and train the model on a total of 113 patients from two clinical trials (NCT02280993 and NCT00255723). The model was validated on an independent external cohort of 69 patients (NCT01508312). In addition, we validated four different PET segmentation methods to calculate radiomics features. We identified a subset of high-risk patients with significant inferior 3-year PFS outcomes of 38.1% versus 88.4% for patients in the low-risk group in the training cohort (p<0.001), and 38.5% versus 75.0% in the validation cohort (p=0.015), respectively. The overall survival was also significantly better in the low-risk group (p=0.022 and p<0.001). We provide a formula to calculate a risk score for individual patients based on the model. In conclusion, we developed a prognostic model for PFS combining radiomics and clinical features in a large cohort of R/R cHL patients. This model calculates a PET-based risk profile and can be applied to develop risk-stratified treatment strategies for R/R cHL patients.
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Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents
Spinner, M. A., Sica, R. A., Tamaresis, J. S., Lu, Y., Chang, C., Lowsky, R., Frank, M. J., Johnston, L. J., Miklos, D. B., Muffly, L., et al
Blood. 2023
Abstract
The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade following the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for R/R cHL patients who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011-2020 (N=183) compared to 2001-2010 (N=159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era (4-year estimates 89.1% vs 79.0%, HR 0.53, 95% CI 0.33-0.85, p=0.011) with a trend towards lower non-relapse mortality beyond 2 years post-transplant. Among patients who progressed after AHCT, 4-year post-progression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients transplanted in the modern era, age ³45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, while receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS (HR 0.21, 95% CI 0.05-0.80, p=0.030). Extranodal disease at relapse was associated with inferior OS (HR 3.12, 95% CI 1.25-7.77, p=0.014). Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.
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Prognostic Factors for the Long-Term Survival after Hematopoietic Stem Cell Transplantation in Patients with Hodgkin Lymphoma
Kadkhoda, D., Nikoonezhad, M., Baghestani, A. R., Parkhideh, S., Momeni-Varposhti, Z., Khadem Maboudi, A. A.
Asian Pacific journal of cancer prevention : APJCP. 2023;24(2):417-423
Abstract
OBJECTIVES This study investigated the possible prognostic factors for the long-term survival (Cure Rate) of Hodgkin Lymphoma patients who underwent HSCT. METHODS This retrospective cohort study analyzed 116 Patients diagnosed with Hodgkin Lymphoma who received autologous hematopoietic stem cell transplantation (Auto-HSCT) between the years 2007 and 2014 and followed up until 2017. The information regarding patients' survival had been collected using phone calls, and their pre-transplant information was available in the archived documents. Prognostic effects were investigated using long-term survival models. RESULTS Patients with obesity had five times higher odds of long-term survival (cure) than the others (P=0.06). Also, the recurrence experience after HSCT negatively impacted the curing potential by 78% (P=0.05). Also, with 32 years as the change point, patients younger than 32 had 76% fewer odds of surviving long-term (P=0.03), and Poor transfused stem cell dose of CD34+ (<0.16 × 106 cells/ml) reduced the odds of long-term survival by 92% (P=0.01). CONCLUSION According to the statistical models used in this study, obesity can increase the curing potential of Hodgkin lymphoma after transplantation. Meanwhile, aging, poor transfused CD34+ cells, and recurrence after HSCT were associated with lower survival following HSCT.
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Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma
Aoki, T., Jiang, A., Xu, A., Yin, Y., Gamboa, A., Milne, K., Takata, K., Miyata-Takata, T., Chung, S., Rai, S., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;:Jco2301115
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Abstract
PURPOSE About a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL. PATIENTS AND METHODS We performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes. RESULTS Highly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5(+) Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4(+) T cells, CD68(+) tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay. CONCLUSION We identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.
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Impact of risk factors and long term survival analysis of patients with primary refractory Hodgkin lymphoma who underwent high dose chemotherapy and autologous stem cell transplant
Akhtar, S., Rauf, M. S., Elhassan, T. A. M., Khan, Z. A., Elshenawy, M. A., Maghfoor, I.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Patients with primary refractory Hodgkin lymphoma (ref-HL) can still be salvaged with high dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). Outcome of patients with ref-HL is poorer than those with relapsed HL, but most studies have included patients with both relapsed and refractory diseases, and separate analyses or studies on patients with ref-HL are limited. OBJECTIVE This study aimed to evaluate the outcomes of HDC auto-SCT and impact of various prognostic factors on patients with ref-HL both at the time of primary treatment failure and also on subsequent survival at the time of failure post HDC auto-SCT. STUDY DESIGN This was a retrospective, single-institution, cohort analysis using HDC and auto-SCT database, approved by the Institutional Research Advisory Counsel and Ethics Committee for identifying patients. We used Fine and Gray competing risk analysis method, regression model for outcome analysis and Kaplan-Meier method (KM) for survival. RESULTS Two hundred consecutive ref-HL patients underwent HDC auto-SCT between 1996 to 2019. Median age was 22.75 years, median follow-up 106 months. Post auto-SCT, disease status was complete remission (CR), partial remission, and progressive disease in 122 (61%), 22 (11%), and 47 (23.5%) patients, respectively. KM median progression-free survival (PFS) after auto-SCT was 43.9 months (5:10 years, 49.3%:45.5%). Median overall survival (OS) was 168.6 months (5:10 years, 61.2%:56.2%). Eighty-five patients (44.5%) died - 69 (34.5%) due to disease. For both PFS and OS, multivariate analysis identified similar adverse factors. For PFS, stage III-IV at relapse (HR=1.65, P=0.045), mediastinal involvement (HR=2.01, P=0.009), and no CR after salvage chemotherapy (HR=2.2, P=0.001) as adverse factors. PFS with 0-1 (not reached), 2 (40.8), 3 adverse factors (5.4 months) were significant (p<0.001). For OS, stage III-IV at relapse (HR=1.68, P=0.045), mediastinal involvement (HR=2.52, P=0.007), and no CR after salvage chemotherapy (HR=2.15, P=0.004) were significant. OS with 0-1 (not reached), 2 (148.5) 3 adverse factors (34.4 months) were significant (p<0.001). Median OS after auto-SCT failure was 23.6 months; patients received post auto-SCT brentuximab/second SCT (not reached), other treatments (22.5 months), and supportive care (8.4) (p<0.001). OS with five risk factors, present at HDC auto-SCT failure, (stage III-IV, failure <12 months, tumor >5 cm, B-symptoms, low albumin) showed that 0-1:2:3-5 risk factors had 152:30.9:9.45 months OS (p<0.001). CONCLUSION Ref-HL patients have encouraging survival after HDC auto-SCT and can even be salvaged after auto-SCT failure. Based on prognostic factors, survival prediction is possible. Patients who fail to respond to HDC auto-SCT may benefit from newer treatments strategies and may qualify for enrollment in clinical trials.
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Prognostic value of TARC and quantitative PET parameters in relapsed or refractory Hodgkin lymphoma patients treated with brentuximab vedotin and DHAP
Driessen, J., Kersten, M. J., Visser, L., van den Berg, A., Tonino, S. H., Zijlstra, J. M., Lugtenburg, P. J., Morschhauser, F., Hutchings, M., Amorim, S., et al
Leukemia. 2022
Abstract
Risk-stratified treatment strategies have the potential to increase survival and lower toxicity in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) patients. This study investigated the prognostic value of serum (s)TARC, vitamin D and lactate dehydrogenase (LDH), TARC immunohistochemistry and quantitative PET parameters in 65 R/R cHL patients who were treated with brentuximab vedotin (BV) and DHAP followed by autologous stem-cell transplantation (ASCT) within the Transplant BRaVE study (NCT02280993). At a median follow-up of 40 months, the 3-year progression free survival (PFS) was 77% (95% CI: 67-88%) and the overall survival was 95% (90-100%). Significant adverse prognostic markers for progression were weak/negative TARC staining of Hodgkin Reed-Sternberg cells in the baseline biopsy, and a high standard uptake value (SUV)mean or SUVpeak on the baseline PET scan. After one cycle of BV-DHAP, sTARC levels were strongly associated with the risk of progression using a cutoff of 500 pg/ml. On the pre-ASCT PET scan, SUVpeak was highly prognostic for progression post-ASCT. Vitamin D, LDH and metabolic tumor volume had low prognostic value. In conclusion, we established the prognostic impact of sTARC, TARC staining, and quantitative PET parameters for R/R cHL, allowing the use of these parameters in prospective risk-stratified clinical trials. Trial registration: NCT02280993.
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Prognostic value of minimal residual disease among patients with classical Hodgkin lymphoma undergoing autologous stem cell transplantation
Taranto, E., Redd, R., Jeter, E., McHugh, K., Crombie, J. L., Fisher, D. C., Jacobsen, E., Jacobson, C. A., Kim, A. I., LaCasce, A. S., et al
Leukemia & lymphoma. 2022;:1-6
Abstract
Improved biomarkers are needed to guide patient selection for autologous stem cell transplantation (ASCT) and post-ASCT maintenance therapies in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the prognostic value of minimal residual disease (MRD) using immunoglobulin-based high-throughput sequencing (Ig-HTS), we analyzed pre- and post-ASCT peripheral blood and pre-ASCT apheresis stem cell (ASC) samples in 36 cHL patients. A tumor clonotype was detected in only 12 patients (33%). Among these patients, MRD within plasma samples was closely associated with impending relapse. All patients (n = 3) with detectable MRD in any post-ASCT plasma sample relapsed (100% specificity), and MRD was not detected in any patients in remission. MRD testing from cellular specimens (peripheral blood mononuclear cell or ASC samples) was not associated with relapse. In this small cohort, plasma-based MRD testing appeared to be a promising biomarker in cHL, but given low clonotype detection rates with Ig-HTS, alternative MRD approaches should be investigated.
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Risk stratification for relapsed/refractory classical Hodgkin lymphoma integrating pre-transplant Deauville score and residual metabolic tumor volume
Yhim, H. Y., Eshet, Y., Metser, U., Lajkosz, K., Cooper, M., Prica, A., Kukreti, V., Bhella, S., Lang, N., Xu, W., et al
American journal of hematology. 2022
Abstract
Pre-transplant Deauville score (DS) is an imaging biomarker used for risk stratification in relapsed/refractory classical Hodgkin lymphoma (cHL). However, the prognostic value of residual metabolic tumor volume (rMTV) in patients with DS 4-5 has been less well characterized. We retrospectively assessed 106 patients with relapsed/refractory cHL who underwent autologous stem cell transplantation. Pre-transplant DS was determined as 1-3 (59%) and 4-5 (41%), with a markedly inferior event-free survival (EFS) in patients with DS 4-5 (hazard ratio [HR], 3.14; P = 0.002). High rMTV(41%) (rMTV(high) , ≥4.4 cm(3) ) predicted significantly poorer EFS in patients with DS 4-5 (HR, 3.70; P = 0.014). In a multivariable analysis, we identified two independent factors predicting treatment failure: pre-transplant DS combined with rMTV(41%) and disease status (primary refractory vs. relapsed). These two factors allow to stratify patients into three groups with divergent 2-year EFS: 89% for low-risk (51%; relapsed disease and either pre-transplant DS 1-3 or DS 4-5/rMTV(low) ; HR 1), 65% for intermediate-risk (28%; refractory disease and either DS 1-3 or DS 4-5/rMTV(low) ; HR 3.26), and 45% for high-risk (21%; DS 4-5/rMTV(high) irrespective of disease status; HR 7.61) groups. Pre-transplant DS/rMTV(41%) combination and disease status predict the risk of post-transplant treatment failure and will guide risk-stratified approaches in relapsed/refractory cHL. This article is protected by copyright. All rights reserved.