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1.
Outcome of High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation in Relapsed/Refractory Hodgkin Lymphoma after Different Numbers of Salvage Regimens
Mariotti, J., Ricci, F., Giordano, L., Taurino, D., Sarina, B., De Philippis, C., Mannina, D., Carlo-Stella, C., Bramanti, S., Santoro, A.
Cells. 2024;13(2)
Abstract
The introduction of novel drugs (PD-1 inhibitors and/or brentuximab vedotin) into salvage regimens has improved the response rate and the outcome of patients with relapsed/refractory Hodgkin lymphoma. However, the impact of new drugs on the outcome has not been adequately investigated so far. We retrospectively analyzed 42 consecutive patients treated at our institution with high-dose chemotherapy/autologous stem cell transplantation after either one standard chemotherapy represented by BEGEV (n = 28) or >1 salvage therapy (ST) comprising novel drugs (n = 14). With a median follow-up of 24 months, the 2-year cumulative incidence of relapse was similar between the two cohorts: 26% for 1 ST and 18% for >1 ST (p = 0.822). Consistently, overall survival and progression-free survival did not differ among the two groups: 3-year overall survival was 91% and 89% (p = 0.731), respectively, and 3-year progression-free survival was 74% and 83% (p = 0.822) for only one and more than one salvage regimens, respectively. Of note, the post-transplant side effects and engraftment rates were similar between the 1 ST and >1 ST cohorts. In conclusion, consolidation with high-dose chemotherapy/autologous stem cell transplantation is a safe and curative option, even for patients achieving disease response after more than one rescue line of therapy.
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2.
Brentuximab vedotin plus bendamustine versus platinum-based regimens as 1st salvage therapy and 'bridge' to autologous hematopoietic stem cell transplantation for relapsed/refractory Hodgkin lymphoma
Kaloyannidis, P., Al Zayer, M., Al Darweesh, M., Al Batran, M., Al Garni, A., Al Naim, A., Al Hashmi, H., Kanfar, S.
Leukemia & lymphoma. 2023;:1-4
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3.
Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation
Kamijo, K., Shimomura, Y., Shinohara, A., Mizuno, S., Kanaya, M., Usui, Y., Kim, S. W., Ara, T., Mizuno, I., Kuriyama, T., et al
Annals of hematology. 2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%-60.8%) and 32.2% (95% CI, 22.4-42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30-3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.
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4.
Nivolumab for relapsed/refractory classical Hodgkin lymphoma: 5-year survival from pivotal phase 2 CheckMate 205 study
Ansell, S. M., Bröckelmann, P. J., von Keudell, G., Lee, H. J., Santoro, A., Zinzani, P. L., Collins, G. P., Cohen, J. B., de Boer, J. P., Kuruvilla, J., et al
Blood advances. 2023
Abstract
Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) in whom autologous hematopoietic cell transplantation (auto-HCT) had failed experienced frequent and durable responses to nivolumab in the phase II CheckMate 205 trial. We present updated results (median follow-up ~5 years). Patients with R/R cHL, who were brentuximab vedotin (BV)-naive (cohort A), received BV after auto-HCT (cohort B), or received BV before and/or after auto-HCT (cohort C), were administered nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. Patients in cohort C with complete remission (CR) for 1 year could discontinue nivolumab and resume upon relapse. Among 243 patients (cohort A, n = 63; B, n = 80; C, n = 100), objective response rate (ORR) was 71.2% (95% CI, 65.1-76.8); CR rate was 21.4% (95% CI, 16.4-27.1). Median duration of response, CR, and partial remission were 18.2 (95% CI, 14.7-26.1), 30.3, and 13.5 months, respectively. Median progression-free survival was 15.1 months (95% CI, 11.3-18.5). Median overall survival (OS) was not reached; OS at 5 years was 71.4% (95% CI, 64.8-77.1). In cohort C, all 3 patients who discontinued in CR and were subsequently re-treated achieved objective response. No new or unexpected safety signals were identified. This 5-year follow-up of CheckMate 205 demonstrated favorable OS and confirmed efficacy and safety of nivolumab in R/R cHL after auto-HCT failure. Results suggest patients may discontinue treatment after persistent CR and reinitiate upon progression. This trial is registered on clinicaltrials.gov as NCT02181713.
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5.
Peri-transplant radiotherapy in refractory or relapsed Hodgkin lymphoma patients undergoing autologous stem cell transplant: long term results of a retrospective study of the Fondazione Italiana Linfomi (FIL)
Levis, M., Campbell, B. A., Matrone, F., Grapulin, L., Russo, A. D., Buglione, M., De, Cumis, II, Simontacchi, G., Ciammella, P., Magli, A., et al
International journal of radiation oncology, biology, physics. 2023
Abstract
PURPOSE In this multicenter collaboration, we report real-world data in the largest published series of long-term outcomes for patients with relapsed/refractory (r/r) Hodgkin lymphoma (HL) treated with peri-transplant radiotherapy (pt-RT) and high-dose chemotherapy with autologous stem cell transplant (ASCT). MATERIALS/METHODS We conducted a retrospective analysis, including data from 12 institutions. Eligibility required histological diagnosis of HL, receipt of ASCT plus pt-RT between 2004-2014 for r/r HL, and age ≥18 years at time of ASCT. All patients received salvage chemotherapy for maximum debulking prior to ASCT. Metabolic responses were scored according to the Lugano Classification. The primary endpoint was overall survival (OS). Univariate and Multivariate (MVA) Cox proportional hazards were calculated to estimate the effect of covariates on patients' outcome. RESULTS 131 patients were eligible: 68 (52%) were male, median age at ASCT was 32 (range, 18-70) years. At time of diagnosis with r/r HL, 92 (70%) patients had limited (stage I-II) disease, and 10 (8%) patients had bulky disease. Pt-RT was given pre-ASCT in 32 patients (24%) and post-ASCT in 99 (76%); median prescribed dose was 30.6 Gy (range, 20-44 Gy). With median follow-up of 60 months, 3- and 5-year OS were 84% and 77%, while 3- and 5-year PFS were 75% and 72%, respectively. On MVA, advanced stage at relapse (HR 2.18, p=0.04), irradiation of >3 sites (HR 3.69, p=0.01), and incomplete metabolic response after salvage chemotherapy (HR 2.24, p=0.01) had a negative impact on OS. The sequencing of pt-RT (pre- vs post-ASCT) did not affect outcome. CONCLUSION Overall, the addition of pt-RT to ASCT for patients with r/r HL is associated with very good outcomes. Limited relapsed disease with ≤3 sites involved, and achievement of complete metabolic response after salvage chemotherapy, were predictive of more favorable prognosis.
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6.
Checkpoint inhibitor-based salvage regimens prior to autologous stem cell transplant improve event-free survival in relapsed/refractory classic Hodgkin lymphoma
Desai, S. H., Spinner, M. A., David, K., Bachanova, V., Goyal, G., Kahl, B., Dorritie, K., Azzi, J., Kenkre, V. P., Arai, S., et al
American journal of hematology. 2023
Abstract
Clinical trials of novel salvage therapies have encouraging outcomes for relapsed/refractory transplant-eligible classic Hodgkin lymphoma (R/R cHL) but comparison with conventional chemotherapy is lacking. Herein, we report the final analysis of a multicenter retrospective cohort of R/R cHL assessing outcomes by type of salvage therapy before autologous stem cell transplant (ASCT). R/R cHL patients who underwent ASCT at 14 institutions across the United States were included. Outcomes were compared among patients receiving conventional chemotherapy, brentuximab vedotin (BV) + chemotherapy, BV alone, and a checkpoint inhibitor (CPI)-based regimens before ASCT. Study endpoints included event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All endpoints are defined from relapse. Of 936 patients, 728 received conventional chemotherapy, 73 received BV + chemotherapy, 70 received BV alone, and 65 received CPI-based regimens prior to ASCT. When adjusted for time to relapse, pre-ASCT response and use of BV maintenance, patients receiving CPI-based regimens had superior 2-year EFS compared to conventional chemotherapy, BV + chemotherapy, and BV alone (79.7, 49.6, 62.3, and 36.9%, respectively, p < .0001). Among 649 patients transplanted after 1 line of salvage therapy, CPI-based regimens were associated with superior 2-year PFS compared to conventional chemotherapy (98% vs. 68.8%, hazard ratio: 0.1, 95% confidence interval: 0.03-0.5, p < .0001). OS did not differ by pre-ASCT salvage regimen. In this large multicenter retrospective study, CPI-based regimens improved EFS and PFS compared to other salvage regimens independent of pre-ASCT response. These data support earlier sequencing of CPI-based regimens in R/R cHL in the pre-ASCT setting.
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Comparison of efficacy and toxicity according to etoposide and cytarabine dosing in BEAM conditioning followed by autologous stem cell transplantation in Hodgkin lymphoma
Vély, A., Couturier, M. A., Delepine, P., Le Calloch, R., Ertault, M., Gastinne, T., Plichon, C., Lebreton, A., Lester, M. A., Larhantec, G., et al
Leukemia & lymphoma. 2023;:1-10
Abstract
The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell transplantation (ASCT) is a commonly used intensification regimen for patients with Hodgkin lymphoma. As etoposide and cytarabine dosing are not defined, we conducted a retrospective, multicenter study, to compare efficacy and toxicity in 130 patients with Hodgkin lymphoma receiving etoposide and cytarabine at either 200 mg/m(2)/d (n = 50), 400 mg/m(2)/d (n = 35), or etoposide 200 mg/m(2)/d and cytarabine 400 mg/m(2)/d (n = 45). Progression-free survival and overall survival were not associated with the intensity of conditioning. Increased conditioning intensity was associated with longer duration of thrombocytopenia, a higher number of transfused RBC and platelet units and a higher frequency of mucositis, but serious adverse events or infectious complications were not increased. The intensity of BEAM regimen was not associated with survival but with the rate of cytopenia and mucositis advocating for the use of lower dosing in frail patients.
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8.
Outcomes of Patients With Classic Hodgkin Lymphoma Who Relapsed After Autologous Stem Cell Transplant
Tun, A. M., Wang, Y., Matin, A., Inwards, D. J., Habermann, T. M., Micallef, I., Johnston, P. B., Porrata, L., Paludo, J., Bisneto, J. V., et al
HemaSphere. 2023;7(4):e869
Abstract
Immune checkpoint inhibitors (ICIs) and brentuximab vedotin (BV) are novel agents for classic Hodgkin lymphoma, including relapse after autologous stem cell transplant (ASCT). However, their impact on survival post-ASCT relapse, in comparison with conventional therapy, is less known due to the lack of randomized controlled trials. Clinical characteristics and outcomes of 115 patients with relapse (or progression) after ASCT are studied. After a median follow-up of 8.59 years from post-ASCT relapse, the median progression-free survival (PFS) and overall survival (OS) were 0.91 and 5.07 years, respectively. Median lines of therapy after post-ASCT relapse was 2 (range, 1-12). The median PFS was not reached (NR) versus 1.11 versus 0.50 versus 0.85 versus 0.78 years (P = 0.006) and OS was NR versus 7.60 versus 3.08 versus 3.51 versus 3.17 years (P = 0.28) in patients first treated with ICIs versus BV versus investigational agents versus chemotherapy versus radiation therapy (RT). First-line treatment with novel agents (ie, ICIs and BV) was associated with superior outcomes compared with investigational agents and chemotherapy/RT with a median PFS of 1.65 versus 0.50 versus 0.79 years (P = 0.003) and a median OS of 7.60 versus 3.08 versus 3.32 years (P = 0.08). Regardless of lines of therapy, the treatment with ICIs had the most favorable outcome with a median PFS and OS of 3.98 and NR years, respectively. Allogeneic stem cell transplant (allo-SCT) was done in 23 patients (20%), and the median post-allo-SCT PFS and OS were 1.31 and 2.35 years, respectively. In conclusion, survival following post-ASCT relapse improves significantly when patients receive novel agents.
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9.
Pembrolizumab Added to Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Relapsed or Refractory Classic Hodgkin Lymphoma: A Multi-institutional Phase 2 Investigator-Initiated Nonrandomized Clinical Trial
Bryan, L. J., Casulo, C., Allen, P. B., Smith, S. E., Savas, H., Dillehay, G. L., Karmali, R., Pro, B., Kane, K. L., Bazzi, L. A., et al
JAMA oncology. 2023
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Abstract
IMPORTANCE To our knowledge, this is the first clinical trial designed to investigate concurrent treatment with a checkpoint inhibitor and conventional chemotherapy in relapsed or refractory classic Hodgkin lymphoma in patients destined for an autologous stem cell transplant. OBJECTIVE To evaluate the complete response rate as assessed by 18F-fluorodeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) after salvage therapy for patients with relapsed or refractory classic Hodgkin lymphoma. DESIGN, SETTING, AND PARTICIPANTS A single-group, phase 2, multi-institutional nonrandomized clinical trial to evaluate the addition of pembrolizumab to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy was conducted from April 20, 2017, to October 29, 2020, at 5 US sites. The 42 patients were aged 18 years or older, with an Eastern Cooperative Oncology Group Performance Status Scale score of 0 or 1 and biopsy-proven relapsed or refractory classic Hodgkin lymphoma after 1 or 2 prior lines of chemotherapy. Patients were required to be appropriate candidates for transplant, with measurable lesions detected by FDG-PET/CT. INTERVENTIONS Two cycles of pembrolizumab (200 mg intravenously on day 1) with ICE chemotherapy every 21 days, followed by stem cell mobilization and collection, and then 1 cycle of pembrolizumab monotherapy followed by FDG-PET/CT response assessment. MAIN OUTCOMES AND MEASURES The primary end point was complete response rate detected by FDG-PET/CT, defined as a Deauville score of 3 or lower. Patients with a complete response proceeded to an autologous stem cell transplant. Secondary end points included progression-free survival, overall survival, stem cell mobilization, and neutrophil and platelet engraftment. Adverse events were monitored to assess safety. RESULTS Forty-two patients were enrolled, with 37 evaluable for the primary end point. The median age was 34 years (range, 19-70 years), 25 patients were female (68%), 6 were African American (16%), and 26 were White (70%). The complete response rate for the 37 patients assessed by FDG-PET/CT imaging was 86.5% (95% CI, 71.2%-95.5%); the overall response rate was 97.3% (36 patients), with 10.8% partial responses (4 patients). New areas of FDG-PET positivity in 2 patients were biopsied, showing noncaseating granuloma in 1 case and a reactive lymph node in a second. Progression-free survival and overall survival 2-year estimates were 87.2% (32 patients; 95% CI, 77.3%-98.3%) and 95.1% (95% CI, 88.8%-100%), respectively. The addition of pembrolizumab to ICE chemotherapy did not negatively affect stem cell mobilization or collection or engraftment, similar to prior experience in this patient population and setting. CONCLUSIONS AND RELEVANCE Results suggest that the addition of pembrolizumab to ICE chemotherapy was well tolerated and highly effective in comparison with prior reports of chemotherapy-only regimens, supporting further investigation in patients with relapsed or refractory classic Hodgkin lymphoma eligible for an autologous stem cell transplant. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03077828.
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10.
Impact of pre transplant salvage therapies on outcome of hodgkin lymphoma patients performing allogeneic transplant
Fanelli, F., Hohaus, S., Cantonetti, M., Cimino, G., Pennese, E., Battistini, R., Galli, E., Cerretti, R., Proia, A., Fatone, F., et al
Chemotherapy. 2022
Abstract
BACKGROUND Allogeneic transplant is an effective salvage therapy in patients with Hodgkin lymphoma (HL) relapsed or refractory to previous treatments. In recent years, immunotherapies (conjugated antibody and checkpoint inhibitors) showed interesting results and were used as bridge therapies to allotransplant. AIM: The aim of this retrospective study in Lazio Region was to evaluate the impact of these new therapies on outcome after allogeneic hematopoietic stem cell transplantation (allo-SCT) in comparison with standard chemotherapies used in the past. METHODS We selected all consecutive patients with diagnosis of HL transplanted in four Hematology Transplant Unit and we collected data obtained from patients' records concerning all the treatments before allo-SCT. RESULTS A total of 56 patients were enrolled into this study. All patients underwent allo-SCT for relapsed or refractory HL. Seventeen patients (30%) received chemotherapy prior to allo-SCT (group B), they were treated between 2008 and 2015, and 39 patients (70%) received BV or CPI or both before allo-SCT as bridge to transplant (group A), they were treated between 2012 and 2020. Twenty-five patients were treated with BV alone, 2 with CPI alone and 12 first with BV and then with CPI. No patient received concomitant BV and CPI. At five years from allo-SCT, OS was 59% and PFS was 65%. No statistical differences in OS or PFS were observed between patients of group A and B. Relapse was significantly associated with a lower survival. The only factor associated with a reduced risk of relapse was development of any grade acute GVHD (p>0.02). CONCLUSIONS This regional real-world experience shows the changes that have taken place in the last 10 years in R/R HL using new drugs to render a patient eligible to allo-SCT. This strategy appears to guarantee an impressive disease control with an increased risk of complications, as aGVHD, that appear to nullify this advantage at least in part.