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1.
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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2.
Anti-CD25 Radioimmunotherapy with BEAM Autologous Hematopoietic Cell Transplantation Conditioning in Hodgkin Lymphoma
Herrera, A. F., Palmer Ph, D. Jm, Adhikarla, V., Yamauchi, D. M., Poku, E. K., Bading, J., Yazaki, P., Dandapani, S., Mei, M. G., Chen, R. W., et al
Blood advances. 2021
Abstract
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL and we hypothesized that the addition of 90Y-antiCD25 (aTac) to BEAM AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled onto this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution and a third developed an unrelated catheter-associated bacteremia; therefore 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed and 0.6mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive > 2500cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with 3 or more risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL and we are further evaluating the efficacy of this approach in a phase 2 trial. The clinical trial was registered at clinicaltrials.gov (NCT01476839).
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3.
Patterns of Failure and Survival Outcomes After Total Lymphoid Irradiation and High-Dose Chemotherapy With Autologous Stem Cell Transplantation for Relapsed or Refractory Classical Hodgkin Lymphoma
Paudel, N., Schulze, D., Gentzler, R. D., Evens, A. M., Helenowski, I., Dillehay, G., Frankfurt, O., Mehta, J., Donnelly, E. D., Gordon, L. I., et al
International journal of radiation oncology, biology, physics. 2019
Abstract
PURPOSE The patterns of failure and long-term outcomes of patients with relapsed or refractory classical Hodgkin lymphoma (cHL) treated with total lymphoid irradiation (TLI) and high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (aSCT) is reported. METHODS AND MATERIALS Patients with biopsy-proven primary refractory/relapsed cHL who received salvage chemotherapy and accelerated hyperfractionated TLI prior to HDCT and aSCT were included. Patterns of failure were delineated after fusing pretransplant planning computed tomography (CT) scan to the scan reporting the first failure. Survival rates were computed via the Kaplan-Meier method. Multivariate analysis using proportional hazards regression was done to determine prognostic factors for overall (OS) and progression-free survival (PFS). RESULTS Between 1993 and 2016, 89 patients underwent salvage treatments. Twenty patients failed at a median of 6.1 months after aSCT. Posttreatment scans were available for 16 patients who combined, failed in 43 different sites; 11 of which were extranodal. Patients failed at multiple sites, mostly within radiation fields. The 5-, 10- and 15-year OS rates were 72.8%, 68.0% and 58.3%; PFS rates were 73.3%, 68.5% and 58.7%; event free survival (EFS) rates were 72.3%, 67.5% and 57.8% respectively. The 5- and 10- year actuarial local control (LC) rates were both 77.6%. Complete response (CR) to salvage chemotherapy was associated with statistically significant improvements in OS and PFS. Eight patients developed secondary malignancies; 5 were hematologic and 3 were solid tumors. CONCLUSIONS Most failures were within the irradiated volume which reflects the treatment-resistant disease biology. As part of a conditioning regimen, TLI yields good survival outcomes, particularly in patients achieving CR prior to transplant. However, need for RT in this setting should be assessed and new strategies should be developed to combat the treatment-resistant biology, especially in patients with less than CR after salvage chemotherapy.
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4.
Treatment patterns and disease outcomes for pediatric patients with refractory or recurrent Hodgkin lymphoma treated with curative-intent salvage radiotherapy
Tinkle, C. L., Williams, N. L., Wu, H., Wu, J., Kaste, S. C., Shulkin, B. L., Talleur, A. C., Flerlage, J. E., Hudson, M. M., Metzger, M. L., et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2019;134:89-95
Abstract
BACKGROUND AND PURPOSE The use of radiotherapy (RT) for pediatric patients with Hodgkin lymphoma (HL) experiencing disease progression or recurrence (15%) is controversial. We report treatment patterns and outcomes for pediatric patients with refractory/recurrent HL (rrHL) treated with curative-intent RT. MATERIALS AND METHODS Forty-six patients with rrHL treated with salvage RT at our institution were identified. All received risk-adapted, response-based frontline therapy and were retrieved with cytoreductive regimens followed by RT to failure sites, with or without autologous hematopoietic cell transplantation (AHCT). Cumulative incidence (CIN) of local failure (LF) and survival were estimated after salvage RT and regression models determined predictors of LF after salvage RT. RESULTS RT was administered as part of frontline therapy in 70% of patients, omitted for early response assessment in 13%, or deferred for primary progression in 17%. AHCT was omitted in 20% of patients. Median initial and salvage dose/site were 25.5Gy and 30.6Gy, respectively. Eight patients experienced progression. Two died without progression (median follow-up from salvage RT=3.8years). The 5-year CIN of LF after salvage RT was 17.7% (95% confidence interval [CI], 8.2-30.2%). The 5-year freedom from subsequent treatment failure and overall survival (OS) was 80.1% (95% CI, 69.2-92.6%) and 88.5% (95% CI, 79.5-98.6%), respectively. Inadequate response to salvage systemic therapy (p=0.048) and male sex (p=0.049) were significantly associated with LF after salvage RT. CONCLUSION rrHL is responsive to salvage RT, with low LF rates after moderate doses. OS is excellent, despite refractory disease. Initial salvage therapy response predicts subsequent LF.
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5.
A prospective, multicentre study of involved-field radiotherapy with autologous stem cell transplantation for patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma (ALLG HDNHL04/TROG 03.03)
Wirth, A., Prince, H. M., Roos, D., Gibson, J., O'Brien, P., Zannino, D., Khodr, B., Stone, J. M., Davis, S., Hertzberg, M.
International journal of radiation oncology, biology, physics. 2018
Abstract
PURPOSE The role of involved-field radiotherapy (IFRT) with autologous stem cell transplantation (ASCT) for lymphomas remains uncertain. METHODS and materials; In this prospective, multicentre study, patients undergoing ASCT for relapsed/refractory lymphoma received peri-transplant IFRT to disease sites identified at study registration (SR) (before salvage chemotherapy (SC)). Radiation dose was adapted to SC response. Survival, relapse rates/pattern, toxicity, and prognostic factors were evaluated. RESULTS Forty-five patients were accrued (23 Hodgkin lymphoma, 22 aggressive non-Hodgkin lymphoma). Three-year overall survival and cumulative incidence of progression rates post-transplant were 72% (95%CI 59-87%) and 42% (95%CI 27-57%), respectively. Stage (p=0.03) and LDH (p=0.05) were significant risk factors for progression on multivariable analysis. Three-year actuarial in-field, marginal and distant progression rates were 7% (95% CI 0-15%), 9% (95% CI 0-18%), and 36% (95% CI 21-51%), respectively. Progression occurred in 8/30 patients with all sites irradiated and 13/15 patients without all sites irradiated. There were 117 disease sites at SR, and 64 post-ASCT progression sites, of which 15 were involved at SR and 12 only at initial diagnosis. Post-transplant relapse occurred in 3/83 irradiated and 12/34 unirradiated involved sites. Of 28 sites in complete response (CR) to SC on computerised tomography, 0/21 irradiated and 1/7 unirradiated sites relapsed. Of 72 sites in CR on Positron Emission Tomography (PET), 1/50 irradiated and 10/22 unirradiated sites relapsed. No grade-4 non-haematological radiotherapy toxicities were observed. CONCLUSIONS IFRT was well tolerated and associated with a low rate of in-field progression. Progression rates were lower for patients with all disease sites irradiated. Response to SC on both computerised tomography and PET warrants further study to select sites for IFRT.
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6.
Accelerated Total Lymphoid Irradiation-containing Salvage Regimen for Patients With Refractory and Relapsed Hodgkin Lymphoma: 20 Years of Experience
Rimner, A., Lovie, S., Hsu, M., Chelius, M., Zhang, Z., Chau, K., Moskowitz, A. J., Matasar, M., Moskowitz, C. H., Yahalom, J.
International Journal of Radiation Oncology, Biology, Physics. 2017;97(5):1066-1076
Abstract
PURPOSE We report the long-term results of integrated accelerated involved field radiation therapy (IFRT) followed by total lymphoid irradiation (TLI) as part of the high-dose salvage regimen followed by autologous bone marrow transplantation or autologous stem cell transplantation in patients with relapsed or refractory Hodgkin lymphoma (HL). METHODS AND MATERIALS From November 1985 to July 2008, 186 previously unirradiated patients with relapsed or refractory HL underwent salvage therapy on 4 consecutive institutional review board-approved protocols. All patients had biopsy-proven primary refractory or relapsed HL. After standard-dose salvage chemotherapy (SC), accelerated IFRT (18-20 Gy) was given to relapsed or refractory sites, followed by TLI (15-18 Gy) and high-dose chemotherapy. Overall survival (OS) and event-free survival (EFS) were analyzed by Cox analysis and disease-specific survival (DSS) by competing-risk regression. RESULTS With a median follow-up period of 57 months among survivors, 5- and 10-year OS rates were 68% and 56%, respectively; 5- and 10-year EFS rates were 62% and 56%, respectively; and 5- and 10-year cumulative incidences of HL-related deaths were 21% and 29%, respectively. On multivariate analysis, complete response to SC was independently associated with improved OS and EFS. Primary refractory disease and extranodal disease were independently associated with poor DSS. Eight patients had grade 3 or higher cardiac toxicity, with 3 deaths. Second malignancies developed in 10 patients, 5 of whom died. CONCLUSIONS Accelerated IFRT followed by TLI and high-dose chemotherapy is an effective, feasible, and safe salvage strategy for patients with relapsed or refractory HL with excellent long-term OS, EFS, and DSS. Complete response to SC is the most important prognostic factor.
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7.
A multi-institutional analysis of peritransplantation radiotherapy in patients with relapsed/refractory Hodgkin lymphoma undergoing autologous stem cell transplantation
Milgrom, S. A., Jauhari, S., Plastaras, J. P., Nieto, Y., Dabaja, B. S., Pinnix, C. C., Smith, G. L., Allen, P. K., Lukens, J. N., Maity, A., et al
Cancer. , 2016 Dec 16. 2016
Abstract
BACKGROUND No consensus exists regarding the use of radiotherapy (RT) in conjunction with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with relapsed/refractory classical Hodgkin lymphoma (HL). The objectives of the current study were to characterize practice patterns and assess the efficacy and toxicity of RT at 2 major transplantation centers. METHODS Eligible patients underwent HDC/ASCT from 2006 through 2015 using the combination of either carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, BCNU, and etoposide (CBV). RESULTS For the cohort of 189 patients, the 4-year overall survival rate was 80%, the progression-free survival rate was 67%, and the local control (LC) rate was 68%. RT was used within 4 months of ASCT for 22 patients (12%) and was given more often for disease that was early stage, primary refractory, or [18 F]fluorodeoxyglucose (FDG)-avid at the time of HDC/ASCT. Disease recurrence occurring after HDC/ASCT was associated with primary refractory disease and FDG-avidity at the time of HDC/ASCT. RT was not found to be associated with LC, progression-free survival, or overall survival on univariate analysis. In a model incorporating primary refractory HL and FDG-avid disease at the time of HDC/ASCT, RT was found to be associated with a decreased risk of local disease recurrence (hazard ratio, 0.3; P=.02). In patients with primary refractory HL and/or FDG-avid disease at the time of HDC/ASCT, the 4-year LC rate was 81% with RT versus 49% without RT (P=.03). There was one case of Common Terminology Criteria for Adverse Events grade>3 RT-related toxicity (acute grade 3 pancytopenia). CONCLUSIONS In patients undergoing ASCT for relapsed/refractory HL, peritransplantation RT was used more often for disease that was early stage, primary refractory, or FDG-avid after salvage conventional-dose chemotherapy. RT was associated with improved LC of high-risk localized disease and was well tolerated with modern techniques. Cancer 2016. © 2016 American Cancer Society. Copyright © 2016 American Cancer Society.