Freedom From Treatment Failure Research Articles

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: High dose chemotherapy/autologous stem cell transplantation (ASCT) and CD19-directed chimeric antigen receptor-modified T cells (CART19) are potentially-curative treatment options for patients (pt) diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBL). Analysis of a large series of pt receiving ASCT and/or CART19 has not been performed and may reveal differences in treatment failure (TF) which could inform efforts to optimize pt selection for these therapies. Methods: Included pt were age ≤75 years who received ASCT and/or CART19 for R/R DLBCL/HGBL at the University of Pennsylvania between 3/1/13 and 3/1/21. All ASCT pt demonstrated either partial or complete metabolic response to salvage immunochemotherapy (IC). Freedom from TF (FFTF) was defined as the interval between receipt of cell infusion and proven/suspected relapse of lymphoma (DLBCL/HGBL for ASCT pt or any lymphoma for CART19 pt) or last follow-up (f/u) in remission. Data were censored on 3/1/23. Results: Characteristics at the time of relapse preceding ASCT or CART19 are listed in the Table. Minimum prior LOT was 1 for ASCT and 2 for CART19 pt. With a median length of f/u of 62.7 months (mo) for ASCT pt and 37.6 mo for CART19 pt, the estimated (est) rate of FFTF at 36 mo were 59% and 24%, respectively. Cox regression analysis of characteristics predictive of TF at 36 mo revealed history of tIL (hazard ratio [HR] 0.23, P = 0.016) for ASCT pt, and history of tIL (HR 0.48, P = 0.004) as well as IPI score ≥3 (HR 2.7, P < 0.001) for CART19 pt. As depicted in the Figure, ASCT pt experienced significantly higher est rates of FFTF at 36 mo if achieving actual FFTF at 3 mo (64% vs. 38%, P = 0.002), 6 mo (76% vs. 52%, P = 0.02), 12 mo (84% vs. 62%, P = 0.03) and 24 mo (95% vs. 78%, P = 0.03) post-infusion as compared to CART19 pt. For characteristics which predict for TF at 36 mo (no history of tIL and IPI score ≥3), the incidence was either similar or significantly lower for CART19 versus ASCT pt who achieved actual FFTF at 3, 6, 12 and 24 mo. Keyword: Aggressive B-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. D. J. Landsburg Consultant or advisory role: Morphosys, Epizyme, Calithera, ADC Therapeutics, Karyopharm Research funding: Curis, Calithera, Epizyme Educational grants: Novartis S. D. Nasta Research funding: Pharmacyclics, Roche, Rafael, FortySeven J. Svoboda Consultant or advisory role: SEAGEN, Pharmacyclics, Incyte, Genmab, BMS, Atara, Astra Zeneca, Adaptive, ADCT Research funding: TG, SEAGEN, Pharmacyclics, Merck, Incyte, BMS, Astra Zeneca J. N. Gerson Consultant or advisory role: Genentech, Abbvie Research funding: Loxo S. J. Schuster Consultant or advisory role: Novartis, Regeneron, Nordic, Morphosys, MustangBio, Incyte, Genentech/Roche, Janssen, Legend Biotech, Loxo, Acerta, BiGene, Celgene, Nanovecter Research funding: Novartis, Pharmacyclics, Merck, DTRM, Juno Therapeutics, Abbvie, Adaptive Biotechnologies, Incyte, Genentech/Roche, Celgene, TG Therapeutics S. K. Barta Consultant or advisory role: Daiichi Sankyo, Kyowa Kirin, Janssen, Affimed Honoraria: Acrotech, Seagen, Kyowa Kirin E. A. Chong Honoraria: Juno/BMS, Novartis, Beigene, KITE, Tessa A. L. Garfall Consultant or advisory role: Jannsen, GlaxoSmithKline, Bristol-Myers Squibb Research funding: Novartis, Tmunity Therapeutics, Janssen, Crispr Therapeutics E. A. Stadtmauer Research funding: BMS, Celgene, Abbvie, Sorrento N. V. Frey Consultant or advisory role: Sana Biotechnology, Kite Pharma, Syndax Pharmaceuticals Research funding: Research Funding D. L. Porter Consultant or advisory role: Novartis, Kite/Gilead, Incyte, Janssen, Jazz, DeCart, BMS, Bluebird Bio, Angiocrine, Mirror Biologics, Capstan Therapeutics, Instill Bio Research funding: Novartis

Survival Outcomes for Patients with Relapsed/ Refractory Aggressive B Cell Lymphomas Following Receipt of High-Dose Chemotherapy/Autologous Stem Transplantation and/or Chimeric Antigen Receptor-Modified T Cells

Patients diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL) may achieve prolonged survival following receipt of high-dose chemotherapy/autologous stem cell transplantation (HDC/ASCT) or CD19-directed chimeric antigen receptor modified T cell therapy (CART19). Although early results from randomized clinical trials suggest that assignment to CART19 versus salvage immunochemotherapy as second-line therapy results in improved survival, analysis of a large series of patients who actually received HDC/ASCT or CART19 has yet to be performed. Such an analysis may inform future research efforts to optimize the risk stratification of R/R DLBCL/HGBL patients who are candidates for either therapy. The aim of this study was to evaluate clinicopathologic factors predictive of freedom from treatment failure (FFTF) for R/R DLBCL/HGBL patients following receipt of HDC/ASCT or CART19, and to compare patterns of treatment failure (TF) in R/R DLBCL/HGBL patients receiving HDC/ASCT and those receiving CART19. THE STUDY GROUP COMPRISED: patients age ≤75 years with R/R DLBCL/HGBL who received HDC/ASCT demonstrating partial or complete metabolic response to salvage immunochemotherapy and/or CART19 in the standard of care setting at the University of Pennsylvania between 2013 and 2021. Survival analyses were performed from the time of infusion of either HDC/ASCT or CART19, as well as at landmark time points postinfusion for patients who achieved FFTF. For 100 HDC/ASCT patients with a median follow-up of 62.7 months, the estimated 36-month FFTF and overall survival (OS) rates were 59% and 81%, respectively. For 109 CART19 patients with a median follow-up of 37.6 months, the estimated 36-month FFTF and OS rates were 24% and 48%, respectively. HDC/ASCT patients had significantly higher rates of estimated 36-month FFTF when they achieved actual FFTF at 3, 6, 12 and 24 months. Additionally, the rates of baseline characteristics predictive of TF at 36 months for either HDC/ASCT or CART19 patients were either similar to or significantly lower for CART19 patients compared to HDC/ASCT patients who achieved actual FFTF at 3, 6, 12, and 24 months. Patients with R/R DLBCL/HGBL achieving response to salvage immunochemotherapy who received HDC/ASCT had a high rate of estimated FFTF regardless of whether they harbored features predictive of resistance to salvage immunochemotherapy, which may be more durable than that of R/R DLBCL/HGBL patients receiving CART19. These findings support further investigation of disease characteristics, such as molecular features, that may predict response to salvage immunochemotherapy in patients fit for HDC/ASCT.

Long-Term Outcomes of High-Risk Stage 1/2 Classic Hodgkin Lymphoma Managed with an Advanced Stage Treatment Approach

Background: The definition of advanced stage classic Hodgkin lymphoma (cHL) may vary, with bulky stage 2A (> 10cm or > 33% of transthoracic diameter otherwise described as 'large mediastinal adenopathy’ (LMA)) and/or stage 2B with risk factors, included in some studies and clinical guidelines. The ECHELON 1 study recently demonstrated improved overall survival (OS) using AVD-brentuximab vedotin (BV) compared with ABVD in stage 3/4 cHL (Ansell et al. NEJM 2022). Similarly, the pediatric combination BV-AVE-PC demonstrated improved event free survival (EFS) over ABVE-PC in a phase 3 trial of 'high risk patients (pts)’ age 2-21 years (y) (AHOD1331), a definition that included stage 2B bulky (LMA) pts, with a significant benefit shown in this subgroup (HR 0.09 (0.01-0.69)) (Castellino et al. ASCO 2022). Thus, re-evaluation of 'advanced stage’ definitions is warranted, especially in the adult population. Herein, we evaluated the long-term outcomes of pts with stages 1/2 bulky and 2B, a group that has been uniformly included in our advanced stage management approach. Methods: The BC Cancer Lymphoid Cancer Database was screened to identify all pts 16-70 y with 1/2A bulky (≥ 10 cm) and 2B (± bulky) disease treated with ABVD chemotherapy. Since 2005, advanced stage cHL pts in BC have been managed with 6 cycles of ABVD and PET-guided consolidative RT, whereby those with an EOT PET positive (pos) scan received RT. Following report of the RATHL trial in 2015, those pts with an interim PET2 negative (neg) scan had bleomycin omitted from the latter 4 cycles. For the current study, PET scans assessed by the IHP criteria were re-reviewed to assign a Deauville (D) score (PET-neg=D1-3, DX; PET-pos=D4-5). Freedom from treatment failure (FFTF) was measured from diagnosis to relapse/ progression of HL, or death due to HL or treatment toxicity. Results: From 2005-2020, 295 pts (148 M, 147 F) were identified. By stage: 1A bulky n=2, 2A bulky n=71 (henceforth called 'bulky only’ n=73); 2B n=133; 1B bulky n=3, 2B bulky n=86 (henceforth called stage 1/2B bulky n=89). Median age was 30 y (range 17- 69 y), median mass size 10 cm overall and 11 cm in bulky cases (range 10-20 cm). Of those with bulky disease (n=162), 147 (91%) had a bulky mediastinal mass. Using the reverse Kaplan-Meier method, median follow-up was 9.3 y (0.9 -17.3 y). The 5 y FFTF and OS for all pts were 84% and 94%. By stage groups, 5 y FFTF estimates were: 90% for bulky only, 82% in 2B, and 81% in 1/2B bulky pts (p=0.29) (Figure 1a), while corresponding 5 y OS estimates were 95%, 93%, and 94%, respectively (p=0.52) (Figure 1b). An EOT PET was performed in 250 pts and an additional 11 patients were included who only had a PET2-neg scan which was not repeated (total PET scan n= 261). The main reason for not having a PET scan was absence of residual mass on CT scan (21/34); 2 patients had progressive disease (PD) while on treatment (both stage 2B). In total 208/261(80%) had a PET-neg scan (2 pts received RT), and 53/261 (20%) had an EOT PET-pos scan of which, 32 (63%) received RT (mediastinal RT, 30/32). Stage 1/2B bulky cases were more likely to have a PET-pos scan (1/2B 32% vs 2B 18% vs bulky only 10%, p=0.002), and as a result, were more likely to receive RT (1/2B bulky 23% vs 2B 9% vs bulky only 6%, p=0.003). Overall, the 5 y FFTF was superior in PET-neg cases (93% vs 49%, p<0.001 (and 62.5% in PET-pos pts who received RT)), and 5 y OS was 96% vs 88% (p=0.17). For the 259 cases in which the D score was available, 5 y FFTF was similar across PET-neg D categories: DX 95%; D1 92%; D2 94%; D3 93%. For all DX-3, 5y FFTF was 94%, and superior to both D4 70% and D5 17% (p<0.001). Corresponding 5 y OS estimates for DX-D3, D4, and D5, were 96%, 95%, and 77%, respectively, with only the latter demonstrating an inferior prognosis (p=0.005). An EOT D5 PET scan was more common in pts with B symptoms: stage 1/2B bulky cases 12/83, 14.5%; 2B 10/106, 9%; bulky only 2/70, 3% (p=0.048). Conclusion: Applying an advanced stage management approach yields excellent outcomes, particularly in the 80% of patients with a PET-neg scan. Further, use of a PET-scan limited RT use to only 6% of pts with stage 1/2A bulky disease. However, those with stage 1/2B bulky disease have a higher likelihood of an EOT PET-pos scan and subsequent RT. Further, an EOT PET D5 score was more common in those with B symptoms overall, especially when coupled with bulky disease. This data provides further rationale for consideration of BV with upfront therapy in other advanced stage subgroups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Patterns and Survival of Patients with Relapsed and Refractory Classical Hodgkin Lymphoma in Latin America

Alana von Glasenapp, MD1. Luis Villela,MD2,3,4. Henry Idrobo,MD5. Perla Colunga, MD6. Fernando Perez-Jacobo, MD7. Arianna Robles-Rodriguez, MD8. Rosa Oliday Rios, MD9. Diego Fernando Garces Paz, MD10. Denisse Castro Uriol,MD11,12. Sally Paredes, MD 11,12. Brady Beltran Garate, MD11,12. Ana Carolina Oliver Solimano, MD13. Victoria Irigoin, MD14. Alejandro Ospina-Idarraga, MD MSc15,16Humberto Martinez-Cordero, MD MSc15,16. 1Hospital Central Instituto de Prevision Social, Asuncion,Paraguay. 2Universidad Autonoma de Sinaloa Facultad de Medicina, Sinaloa,Mexico. 3Hospital Fernando Ocaranza. ISSSTE, Hermosillo, Sonora Mexico. 4Centro Medico Dr. Ignacio Chavez. ISSSTESON, Hermosillo, Sonora,Mexico. 5Prof. Universidad del Valle,Cali,Colombia. 6Servicio de Hematología, Hospital Universitario, UANL, Monterrey Nuevo León,Mexico. 7Hospital Central Norte PEMEX, Ciudad de México, Mexico. 8Hospital General de Occidente, Servicio hematología, SSA, Guadalajara, Jalisco, Mexico. 9Prof auxiliar Hospital Hermanos Ameijeira. Havanna,Cuba. 10Universidad del Cauca,Colombia. 11Hospital Edgardo Rebagliati Martins, EsSalud, Lima Peru. 12Centro de Medicina de Precisión Universidad San Martin de Porres,Lima, Perú. 13Hospital Britanico y Casmu,Montevideo,Uruguay. 14Casmu y Cosem,Montevideo,Uruguay. 15Instituto Nacional de Cancerologia, Bogota, Colombia. 16Master Program in Epidemiology-Universidad del Bosque, Bogota, Colombia. On Behalf of GELL (Grupo de estudio Latinoamericano de Linfoma)Background The standard of care (SOC) in first relapse/refractory Hodgkin Lymphoma (r/rHL) is salvage therapy, including high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT). This treatment approach has been shown to improve event-free survival (EFS), progression-free survival (PFS), and freedom from treatment failure (FFTF) in controlled clinical trials. This study aims to determine the treatment patterns and outcomes of patients with Hodgkin Lymphoma in Latin America. Materials y Methods Here we present a retrospective international study of patients diagnosed with R/R HL treated at 16 centers in seven countries between 2010 and 2020. Results We found 142 patients with R/R disease fulfilling the inclusion criteria. Clinical characteristics are shown in table 1. Platinum-based regimens were the most widely used, followed by gemcitabine-based regimens and only 36 patients proceeded with ASCT (25.4%). Patients who ultimately did undergo ASCT had the best progression-free survival compared with those who did not. The median progression-free survival for the entire cohort was 17 months (95% CI 8.2-25.7). Progression-free survival for those patients who underwent ASCT was 40 months (95% CI 28-52), and for those who did not proceed to ASCT, it was only 12 months (95% CI 8-16). In the multivariate analysis, the only independent predictor of better survival was having proceeded with the transplant HR: 0.393 p= 0.030 (95% CI 0.17 -0.91). Conclusion Our retrospective study showed that access to ASCT is limited in Latin America, and the survival is lower than reported in the literature. The ASCT is essential for achieving a potential cure in R / RHL patients with the chemotherapy-sensitive disease. Health systems must guarantee access to transplantation for all patients who are candidates for this therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Optimizing Palliative Focal Radiation Therapy Dose in Cutaneous T-Cell Lymphoma: How Low Can You Go?

PurposePrimary cutaneous T-cell lymphomas (CTCLs) are radiosensitive tumors with variable and often relapsing courses. Local disease can be treated with low-dose focal palliative radiation therapy (RT), though little data supports the use of a specific dose. This study assesses clinical outcomes after focal RT to a total dose of 4 Gy, 8 Gy, or 12 Gy. Methods and MaterialsAn International Review Board-approved, retrospective, single-institution study was performed of 225 lesions in 41 patients with primary CTCL treated with low-dose focal RT from 2015 to 2020. Patient, tumor, and treatment characteristics were reviewed. The primary outcome was freedom from treatment failure (FFTF), defined as time to requiring local retreatment, and secondary outcomes included response rates and toxicities. ResultsOf the 225 lesions, 90 received 4 Gy, 106 received 8 Gy, and 29 received 12 Gy. Lesions treated with 12 Gy (96%) or 8 Gy (92%) had a significantly higher 1-year FFTF compared with 4 Gy (77%) (P = .034). Overall response rate and complete response rate were not significantly different between different doses (P = .117), though there was a trend toward higher overall response rate at initial assessment with 8 Gy versus 4 Gy (91.5% vs 82.2%, P = .057). Toxicity was low, with 7.1% of lesions having grade 2 or higher radiation dermatitis. ConclusionsIn primary CTCL lesions treated with focal palliative RT, a dose response was noted favoring 8 to 12 Gy, with 1-year FFTF rates over 90%. However, 4 Gy resulted in substantially better outcomes than previously reported, with 77% requiring no further treatment at 1 year and comparable response rates to higher doses. While our data substantiates 8 to 12 Gy as the standard of care, it also suggests that 4 Gy should be considered an acceptable alternative in situations with concern for radiation toxicities, such as with fragile or heavily pretreated skin.

P708: CANADIAN AND RUSSIAN EXPERIENCES OF ASCIMINIB IN CHRONIC MYELOID LEUKEMIA (CML) PATIENTS WHO FAILED MULTIPLE LINES OF TYROSINE KINASE INHIBITOR (TKI) THERAPY.

Background: Asciminib (ASC) is a novel, first in class ‘specifically targeting the ABL myristate pocket (STAMP) inhibitor. Recent update of the ASCEMBL phase 3 data showed a superior cumulative incidence of major molecular rate (MMR) of 33.2% with ASC over bosutinib (BOS) at 18.6% by 48 weeks and higher MR4 rate (BCR-ABL1 ≤0.01%) of 14.0% with ASC over 6.6% with BOS at 48 weeks in CML patients (pts) in chronic phase (CP) who have failed at least two lines of TKI therapy. Aims: Canadian and Russian groups individually reported their real-world experiences of ASC therapy under the Managed Access Program in heavily pre-treated CML patients. Methods: Data was collected, updated and merged from 80 CML pts treated with ASC between Nov 2018 - Dec 2021 (n=57 in Russia; n=23 in Canada). Median age was 57 years (range 20-92). The median number of previous TKIs was 4 (range 2-6); Imatinib (n=74, 93%), dasatinib (n=64, 80%), nilotinib (n=58, 73%), bosutinib (n=51, 64%), ponatinib (n=35, 44%), and others (n=13, 16%). Median duration from diagnosis to ASC treatment was 92 mo (months) (range 11-310). 27 (34%) pts had a past history of clinically significant cardiovascular disease or high risk profile for cardiovascular disease. Of the 80 pts, 27 (34%) had a preexisting T315I mutation and 18 (23%) had a non-T315I mutation. Pts failed previous TKI therapy due to A)resistance or suboptimal response (n=59; 74%) and B)intolerance (n=21; 26%). BCR-ABL qPCRs were monitored at each institution. Achievement of MMR and molecular response of 4 log reduction (MR4) was assessed at 6 and 12 mo. Results: With a median of 9 mo of follow-up (range 1-38), MMR was noted in 15/68 (22%) and 14/36 pts (39%) evaluated at 6 and 12 mo, respectively. MR4 was noted in 11/68 (16%) and 9/36 pts (25%) at 6/12 mo. The cumulative incidence of MMR and MR4 was 32.6% (20.9-44.8%) and 15.9% (7.9-26.3%) at 12 mo. The probability of freedom from treatment failure (FTF) at 12 mo was 42.4% (27.6-56.4%), based on the ELN 2013 failure criteria for 2nd line therapy or beyond. In the overall population (n=80), FTF was significantly associated with reason for switch to ASC (p=0.006), and there was a trend toward association of FTF with disease phase (p=0.08) and ponatinib therapy (p=0.12), but not with ABL1 kinase domain mutation (p=0.402), additional cytogenetic abnormality (p=0.908), nor cardiovascular risk profile (p=0.345). When analysis was restricted to the patients in CML-CP (n=65), a median duration of FTF was calculated as 11.6 mo, while the 12 mo FTF rate was 46.8% (28.9-62.8%). The patients previously treated with ponatinib (n=25) showed a 27.7% (8.4-51.4%) FTF rate at 12 mo, which was lower than that in those naïve to ponatinib (n=40), 61.7% (34.9-80.2%; p=0.023). Those switched to ASC for intolerance (n=21) showed higher 12 mo FTF rate of 81.2% (41.5 -95.2%) compared to 29.4% (11.3-50.2%) in those with resistance (n=44; p=0.008). Fifteen pts discontinued ASC due to treatment failure (n=11), progression of disease to blast phase (n=3) or grade 4 thrombocytopenia (n=1). No cardiovascular event was noted. Image:Summary/Conclusion: This combined Canadian and Russian real-world experience of ASC study includes heavily pretreated CML pts including 15 pts in advanced phase. The MMR and MR4 rates were comparable in those in CP, while it was lower in non-CP pts. The 12 mo FTF rate of 42.4% was comparable to the one reported from the ASCEMBL study, 57.7%, considering that this group includes more patients who had heavily pre-treated with advanced disease. *AGT and FK contributed equally as co-first author.

18f-FDG PET-CT Assessment of Responses to Salvage Therapy and Autologous Stem Cell Transplant (ASCT) in Relapsed/Refractory Classical Hodgkin Lymphoma (cHL)

Background:Approximately 25% of patients with cHL have relapsed or refractory (r/r) disease. Although salvage chemo-radiotherapy followed by autologous stem cell transplant (ASCT) offers the best chance of freedom from treatment failure (FFTF) (~50%), a portion patients have a poor prognosis despite this approach. Traditional prognostic scores are less well validated than in de novo disease, and hence 18F-FDG PET-CT, the gold-standard imaging modality in cHL, has an increasing role as a powerful prognostic indicator in this context.Our aims were a) to compare response rates to salvage therapy using 18F-FDG PET-CT (reported according to Lugano 2014 criteria) with trial-reported outcomes; and b) to assess the prognostic value of 18F-FDG PET-CT in this context.Method:Retrospective data were collected on r/r cHL patients treated across 3 UK hospital sites (2011-2017). PET-CT scans were retrospectively reviewed according to Lugano 2014 response criteria i.e. complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR) and progressive metabolic disease (PMD). Prognostic scores were calculated as described by Jostings et al. 2000.Results:34 patients were identified: 21 with refractory cHL (<90 days) and 13 with relapsed disease. Median age was 43 years (range 14-77). Median time to relapse was 94 weeks (193-687). 100% patients had a prognostic score of <2, with 90% <1 (score unable to be calculated: n=2). 88% patients achieved an overall response (ORR) after 1st line salvage therapy, with 33% achieving CMR and 55% PMR (18F-FDG PET not performed: n=1). Patients were treated with 1-4 lines of salvage therapy (median= 1), with 33% receiving brentuximab vedotin. Of the 82% patients that proceeded to ASCT, 46% were in CMR, 50% were in PMR and 4% had mixed disease response. 47% of patients achieved CMR post-ASCT, with FFTF in 37% (Post-ASCT 18F-FDG PET unavailable: n=3). As shown in the table below, there was a 55% rate of FFTF in patients with CMR post 1st line salvage therapy, compared with a 23% rate of FFTF in patients with PMR post 1st line salvage. 38% of patients with an overall CMR pre-ASCT had FFTF, compared with 43% with overall PMR.Conclusion:There is a wide discrepancy in FFTF, comparable with previous trial data, between patients achieving CMR and those achieving a PMR on 18F-FDG PET-CT post 1st line salvage chemotherapy. However, patients who received multiple lines of salvage therapy achieved similar rates of FF2F, irrespective of their metabolic response on their pre-ASCT 18F-FDG PET-CT. This suggests that 18F-FDG PET-CT may have limited prognostic value in this setting. [Display omitted] DisclosuresHildyard:ADC Therapeutics: Research Funding. Collins:Pfizer: Consultancy, Honoraria; ADC Therapeutics: Research Funding; MSD: Consultancy, Honoraria; Celleron: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Amgen: Research Funding.

Hematopoietic Cell Transplant for Adult Patients with Severe Sickle Cell Disease: Improving Outcomes and Improving Options

▪Introduction:The estimated number of newborns with sickle cell disease (SCD) globally will increase from about 300,000 to more than 400,000 by 2050 according to current projections. Improved newborn screening, better supportive care, use of hydroxyurea therapy have decreased early childhood mortality among individuals affected with SCD, but the mortality in affected adults remains largely unchanged. Despite hematopoietic stem cell transplant (HCT) being curative in SCD, its impact on disease free survival remains unknown, partly due to limitation in donor options and perceived mortality in adults using myeloablative conditioning. Novel non-myeloablative and reduced intensity conditioned protocols have made HCT available to adult SCD patients who were previously excluded. Compared to the disease burden, HCT attempts globally is relatively small. Primary reason for this disparity is the non-availability of adequate donors, referral bias, procedure risks, costs and limited logistic resources in both the developed and the developing world. Our study focuses on recent outcomes of HCT for adult patients with SCD, with particular emphasis on comparative outcomes in pediatric patients transplanted for severe SCD.Methods:A comprehensive electronic search was conducted based on strict selection criteria for studies for meta-analysis. Adults, older than 16 years with SCD of all phenotypes, both genders and in all settings. All pediatric SCD studies were excluded. Outcome measures include:median overall survival (OS), freedom from treatment failure (FTF), mortality (overall and at 100-days, and 1-year post-HCT), transplant-related mortality (TRM), acute graft versus host disease (aGVHD), chronic graft versus host disease (cGVHD), progression free survival (PFS), incidence of late organ complications, graft rejection with recurrence or persistence of SCD. We found 391 articles with the above-mentioned keywords, out of which 177 were shortlisted and among these only 28 articles met our inclusion criteria.Results: GVHDIn 28 studies, only 16 showed the presence of GVHD in adults, while only five studies showed a high incidence of severe GVHD as in Table 1. Graft RejectionWe did not find a high incidence of graft rejection compared to historical controls in pediatric populations, however, multiple exposures to the blood transfusion prior to HCT and usage of chelation therapy for iron overload in the body system due to the repeated blood transfusion were found to be associated with increased incidence of graft rejection. Adult HCT studies showed a very low incidence of graft rejection once above-mentioned risk factors had been controlled (tables 1 and 2). OSWe observed a similar transplant outcome, seen in pediatric HCT for SCD, were the unavailability of a healthy HLA-identical sibling lead to alternate donor transplantation, with associated increase in overall mortality, though no association was found on overall survival in relation to age of patient. Nine studies reported median OS of 100%, and two studies found a 70-80% overall survival (tables 1 and 2). PFSSixteen studies included in our study revealed an acceptable PFS of more than 90%, whereas four studies revealed PFS of below 90% (87%, 85%, 82%, and 68% respectively) (table 1). TRMWe observed that TRM has significantly reduced over the past few years. Most optimum outcomes were observed when recipients had good functional status at baseline. The main causes of death in transplanted patients were found to be sepsis, hemorrhage, severe lung injury and CNS hemorrhage with organ failure (table 1-2)Conclusions:Clinical data from current studies in our review demonstrate improved outcomes using HCT as a curative therapy for adults with SCD. However, lack of suitable HLA-identical sibling and matched unrelated donors severely limits accessibility of HCT therapy for eligible adults with SCD. Encouraging preliminary results using umbilical cord blood and haploidentical transplantation for SCD may solve the problem of this rarity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparable Efficacy of Reduced Dose Radiation Therapy for the Treatment of Early Stage Gastric Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue

PurposeThis study compares reduced (<27 Gy) to standard dose (≥30 Gy) radiation therapy (RT) in the treatment of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (gMALT lymphoma). Methods and MaterialsForty-two patients with stage I or II disease were retrospectively reviewed. Response to RT was assessed with endoscopy after RT. Complete response rate (CR), freedom from treatment failure, and overall survival (OS) were calculated. ResultsAll patients were stage I (n = 40) or II (n = 2). All patients had residual biopsy proven gMALT lymphoma before RT. Twenty-six patients (61.9%) were treated with standard dose RT, 30 to 36 Gy, and 16 (38.1%) with the reduced dose RT, 23.5 to 27 Gy. The median follow-up was 29.5 months (range, 6-85). Thirty-six patients (86%) achieved complete response (CR), and 6 patients (14%) achieved partial response (PR). The complete response rate (CR) at the first endoscopic assessment, median time of 3 months, was 81% (95% confidence interval, 0.61%-0.93%) for standard RT, and 94% (confidence interval, 0.69%-0.99%) for reduced RT. Among CR patients, one patient had locally relapsed disease at 50 months. The 1-year overall survival (OS) was 100% in both groups. The 1-year freedom from treatment failure (FFTF) was 100% in the reduced RT group and 92% in the standard RT group. The 2-year FFTF and OS of the whole cohort were 92% and 96%, respectively. There was no significant difference in the OS, FFTF, and CR between the 2 treatment groups (P = .38, P = .18, and P = .267, respectively). For toxicity, the mean liver dose and the mean V20 heart dose were significantly lower in the reduced RT group (P <.001 and P = .001, respectively). However, incidence and severity of reported toxicities were similar between the 2 groups. ConclusionsReduced dose RT (23.5-27 Gy) achieved excellent complete response rates with minimal toxicity, comparable with standard dose RT (30-36 Gy), for gMALT.

Prognostic Significance of IL-6 in Hodgkin Lymphoma

Elevated serum interleukin-6 (IL-6) in Hodgkin lymphoma (HL) is reported to correlate with B symptoms, response rate and survival in adult patients. The authors studied prognostic significance of IL-6 expression by immunohistochemistry on Hodgkin-Reed Sternberg cells and background reactive cells in a retrospective cohort of pediatric HL patients treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) from January 2009 through December 2013. Of 142 patients, tissue blocks were retrieved in 110 patients. On logistic regression analysis, IL-6 expression on background cells alone was among the factors associated with inferior response rate (OR-9.9, 95%CI-1.2, 78.3; p = 0.03). On multivariate analysis, IL-6 expression on background cells alone had significant impact on 5 y freedom from treatment failure (FFTF) (HR-7.7, 95% CI-1.2, 48.6; p = 0.03). IL-6 expression by immunohistochemistry in the background cells is an independent poor predictor of response and FFTF in pediatric HL. Further prospective studies in children are needed to confirm the current findings and whether IL-6 expression can be used to stratify treatment.

Outcomes After Reduced-Dose Intensity Modulated Radiation Therapy for Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma

In patients with gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, the standard radiation therapy (RT) dose is ≥30Gy. We report the outcome of patients treated with reduced dose 24Gy compared with those treated with ≥30Gy. We reviewed results from 32 patients who received a diagnosis of gastric MALT lymphoma between 2007 and 2017 who were treated with involved site RT using intensity modulated radiation therapy (IMRT). Response to therapy was based on post-RT endoscopic biopsy. Freedom from local treatment failure (FFLTF), freedom from treatment failure (FFTF), and overall survival (OS) outcomes were determined. The median age of patients at diagnosis was 58years. Therapy for MALT was given prior to RT in 14 patients with residual biopsy proven disease documented in all cases (anti-microbial, n=11; rituximab, n=2; rituximab, cyclophosphamide, doxorubicin, vincristine, n=1). One patient received RT (36Gy) and concurrent rituximab. The median RT dose was 30Gy; it was 30 to 36Gy in 66% of patients (n=21) and 24Gy in 34% of patients (n=11). Post-RT biopsy documented a complete response in all patients. Failures occurred in the stomach and duodenum, respectively, at 3.6 and 4.5years, after 30Gy. At a median follow-up of 55.2months (73.8 for ≥30Gy compared with 28.7 for 24Gy; P<.001), the 2-year FFLTF, FFTF, and OS were 100%, 100%, and 97%, respectively. No association was found between the lower (24-Gy) dose and FFLTF (P=.819), FFTF (P=.819), or OS (P=.469). Contemporary RT with involved site targeting using IMRT is associated with high complete response rates for patients with gastric MALT lymphoma, even using reduced doses of 24Gy. Additional follow-up and increased patient numbers are required to confirm equivalent disease control.

Hodgkin lymphoma in children: clinical analyses of 20 cases

Objective To summarize the long-term outcomes and safety of childhood Hodgkin lymphoma (HL) with protocol ABVD. Methods The clinical data of 20 children with HL admitted to the Union Hospital of Fujian Medical University from July 2010 to June 2017 were retrospectively analyzed. Among the 20 children with HL, 15 were male and 5 were female. The median age of initial diagnosis was 6.5 years old (3-12 years old). The pathological types were as follow: 1 case was nodular lymphocyte-predominant HL (NLPHL) and 19 cases were classical HL (cHL), including 9 cases of mixed cell type, 9 cases of nodular sclerosis type and 1 case of lymphocyte rich type. Basing on Ann Arbor staging system, 1 patient was evaluated as stage Ⅰ, 4 patients were stage Ⅱ, 10 patients were stage Ⅲ, and 5 patients were stage Ⅳ. There were 3 patients in the low-risk group, 7 patients in the intermediate-risk group, and 10 patients in the high-risk group. There were 9 patients with B symptoms. All patients were treated with the ABVD regimen. Results All the 20 patients completed all chemotherapy courses. After 2 courses, the effective rate was 100% (20/20), including 12 cases of complete remission (CR) and 8 cases of partial remission (PR). After the treatment, 19 cases achieved CR, and at the end of the 6 courses, the evaluation showed that 1 case had residual lesions. Follow-up to February 2018, clinical symptoms of 18 cases achieved CR, 2 cases relapsed (all high-risk group); the median follow-up time was 42 months (10.1-87.9 months), the overall survival rate was 100% (20/20), the estimated 5-year rate of freedom from treatment failure (FFTF) was (89.1±7.3)%. Conclusions According to the risk stratification, ABVD regimen has good safety and long-term efficacy for children with cHL. Even the patients in low-risk or intermediate-risk group do not achieve CR after 2 courses and do not receive radiotherapy, the prognosis of them is still good. Key words: Lymphoma, Hodgkin; Child; Antineoplastic combined chemotherapy protocols; Treatment outcome

Reduced-Intensity Chemotherapy in Patients With Advanced-Stage Hodgkin Lymphoma: Updated Results of the Open-Label, International, Randomised Phase 3 HD15 Trial by the German Hodgkin Study Group.

The international, randomized phase 3 HD15 trial established 6xeBEACOPP as standard therapy for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) within the German Hodgkin Study Group (GHSG). We performed a follow-up analysis to assess long-term efficacy and safety of this approach. Between 2003 and 2008, 2182 patients aged 18 to 60 years were recruited and randomized in a 1:1:1 ratio between 8 or 6 cycles of eBEACOPP or 8 cycles of the dose-dense BEACOPP-14 regimen, each followed by 30 Gy radiotherapy in case of positron emission tomography (PET)-positive residual lesions ≥2.5 cm. The study aimed at demonstrating non-inferiority regarding efficacy of the 2 experimental arms on a significance level of 2.5% each. The intention-to-treat analysis comprised 2126 patients with a median follow-up of 102 months. Ten-year progression-free survival was 81% (97.5% CI 77–85) with 8xeBEACOPP, 84% (80–87) with 6xeBEACOPP, and 84% (80–87) with 8xBEACOPP-14; the non-inferiority margin of 1.51 for the hazard ratio (HR) could be excluded for both comparisons (6xeBEACOPP, HR = 0.7, 97.5% CI 0.5–1.0; 8xBEACOPP-14, HR = 0.9, 97.5% CI 0.7–1.2). Overall survival at 10 years was 88% (85–91), 90% (88–93), and 92% (89–94), respectively. A total of 142 second malignancies corresponding to 10-year cumulative incidences of 10%, 7%, and 7% and standardized incidence ratios of 4.3, 2.5, and 2.8 were reported for 8xeBEACOPP, 6xeBEACOPP, and 8xBEACOPP-14, respectively. This updated analysis of the HD15 trial thus confirms the efficacy and reports on the long-term safety of a shortened first-line chemotherapy consisting of 6xeBEACOPP followed by PET-guided radiotherapy in advanced-stage HL.

Extrafollicular PD1 and Intrafollicular CD3 Expression Are Associated With Survival in Follicular Lymphoma.

Both microenvironment and tumor biomarkers impact outcome in follicular lymphoma (FL). We aimed to study the effect of Ki-67, CD3, CD68, and PD1 expression on outcome of FL. Forty-eight patients were included. Stained slides were visually assessed and marker expression was correlated with outcome. Both intra- and extrafollicular expression of Ki-67, CD68, and PD1 were evaluated. CD3 was evaluated only in the intrafollicular area. The median values of expression served as a cutoff point for low- and high-expression groups. High extrafollicular PD1 expression predicted superior FFTF (freedom from treatment failure) compared with low expression (5-year 52% vs. 44%, P= .04). Five-year FFTF markedly increased from 37% to 67% (P= .057) in patients with low intrafollicular CD3 expression. Our study supports the hypothesis that survival in FL depends on the immunologic cross talk between malignant cells and microenvironment; however, the specific types of cells that influence the clinical behavior of FL are still unknown.

ABVD-Based Therapy for Hodgkin Lymphoma in Children and Adolescents: Lessons Learnt in a Tertiary Care Oncology Center in a Developing Country.

As Hodgkin lymphoma (HL) is a highly curable malignancy, most current pediatric trials focus on strategies aimed at reducing late effects of therapy. We report our results with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) therapy. We retrospectively analyzed 17 years (1996-2013) data of patients ≤18 years of age with HL. All patients received ABVD chemotherapy and involved field radiotherapy (IFRT) was reserved for those with bulky disease or partial response. The analysis was carried out to assess overall survival (OS) and freedom from treatment failure (FFTF) and factors predicting the events. Of 167 eligible patients, 72 (43.1%) had B symptoms, 28 (16.7%) had bulky disease, 31 (18.6%) had >4 lymph node regions, and 53 (31.8%) had advanced disease (stages III and IV). In all, 87% patients received six cycles of ABVD and IFRT was administered to 51 (30.5%) patients. The 5-year OS and FFTF were 95.9% and 79%, respectively, and were similar in patients treated with or without IFRT. On multivariable analysis, advanced disease (stages III and IV), involvement of >4 lymph node regions, and serum lactate dehydrogenase (LDH) ≥500 IU/l at diagnosis were statistically significant factors for FFTF (P = 0.03, 0.003, 0.048, respectively). The excellent survival of HL patients in the setting of a developing country reported in this retrospective analysis warrants treatment reduction, especially for early-stage patients. The use of risk- and response-based stratification incorporating disease stage, involved lymph node regions, and serum LDH, along with fluorodeoxyglucose-positron emission tomography-based response, may guide development of effective and less toxic protocols.

Advanced Stage Classical Hodgkin Lymphoma Patients with a Negative PET-Scan Following Treatment with ABVD Have Excellent Outcomes without the Need for Consolidative Radiotherapy Regardless of Disease Bulk at Presentation

Background: Consolidative radiotherapy (RT) is frequently administered to patients (pts) with classical Hodgkin lymphoma (CHL) that have bulky disease at diagnosis and/or residual abnormalities on post-chemotherapy CT imaging. However, this may contribute to the development of secondary malignancies and cardiac disease. The HD15 trial demonstrated that RT can be omitted in cases with residual disease on CT imaging following BEACOPP-based chemotherapy that are PET-negative (PET-neg). It is unknown whether this can be extended to patients treated with ABVD chemotherapy including patients presenting with a bulky disease at diagnosis. Further, it is unclear whether consolidative RT can be used to salvage cases that are PET positive (PET-pos) following ABVD.Methods: The British Columbia (BC) Cancer Agency Centre for Lymphoid Cancer Database and case records were screened to identify all adult (> 16 y) pts with advanced stage CHL (stage 1 bulky (> 10cm), stage 2 with B symptoms and/or bulky disease and all stage III/IV) treated with curative intent using ABVD chemotherapy who underwent a restaging PET scan at the end of treatment. Clinical factors including mass size at diagnosis, mediastinal involvement, residual mass size post therapy and relapse site were collected. Patients that were HIV positive, had refractory disease (progression during chemotherapy or at the time of post-treatment imaging) or toxicity that precluded response evaluation, were excluded for this analysis. Since July 2005, all pts in BC with advanced stage HL, including those with bulky disease, were recommended to be treated with 6 cycles of ABVD followed by a PET scan if residual abnormalities > 2 cm were observed on CT imaging.Results: In total, 316 pts with CHL who met the above criteria were identified. Pt characteristics were: 48% females; median age 33 y (16-82 y); stage 1 1.3%; stage 2 47.2%; stage III/IV 51.5%; extranodal disease 40.5%; B symptoms 66%; 13% international prognostic score > 4 13%; bulky disease 62%. At the end of treatment, 264 (83.5%) were PET-neg (indeterminate n=4), none of whom received RT, and 52 (16.5%) were PET-pos, of which 79% (n=41) received consolidative RT (30-35 Gy). With a median follow-up for living pts of 4.6 y (range 0.6 - 13.5 y), the 5-y freedom from treatment failure (FFTF) for the whole cohort was 83% and 5-y overall survival (OS) was 94.5%. Overall, pts with a PET-neg scan post treatment had a superior 5-y FFTF compared to those with a PET-pos scan (89% vs 56%, P < 0.00001) (Figure 1a). In the PET-neg group, there was no difference in outcome comparing the bulky (n=112) and non-bulky (n=152) subgroups (5-y FFTF 89% vs 88.5%, p=0.50, respectively, Figure 1b; 5-y OS 96% vs 94%, P=0.51). Similar survival estimates were observed when the analysis is restricted to PET-neg cases with a bulky mediastinal mass at diagnosis (n=102) (5 y FFTF 89%; 5 y OS 96%). Of the PET-pos pts who were able to receive consolidative RT (PET-pos RT) (n=41), the 5-y FFTF was 60% and the 5 y OS was 94%. For those with mediastinal PET-pos disease who received RT (n=29, 72% bulky at diagnosis), the 5-y FFTF was 69.5%. For all PET-pos RT pts, 13 subsequently relapsed: 1 within the RT field only; 5 outside of the RT field only; and 7 relapsed both within and outside of the RT field.Conclusions: Advanced stageCHL pts, including those with bulky disease, that have a negative PET scan following ABVD chemotherapy have an excellent outcome without additional consolidative RT, thus potentially avoiding long-term effects. Radiotherapy may be useful in select responding patients with PET-pos residual uptake. With a PET-guided approach, we have significantly reduced the need for RT. [Display omitted] [Display omitted] DisclosuresSavage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Seattle Genetics: Research Funding; Roche: Research Funding. Villa:Lundbeck: Honoraria. Gerrie:Janssen: Other: Advisory board; Roche: Honoraria, Other: Advisory board, Research Funding; Lundbeck: Honoraria, Other: Advisory board, Research Funding. Shenkier:Roche: Honoraria, Other: Travel funds. Scott:Celgene: Consultancy, Honoraria. Pickles:Janssen: Honoraria; Oncura: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Other: Advisory board; Astellas: Honoraria, Other: Advisory board.

Clinical Impact of CD8+ Cells in Hodgkin Lymphoma Lymphadenopaties. Contribution of Flow Cytometry

CONTEXT: Microenvironment of Hodgkin and Reed Sternberg(H-RS) cells is a current focus of interest to define risk and predict evolution of Hodgkin′s Lymphoma.OBJECTIVES: To determine the role of infiltrating CD8+ cells, using flow cytometry (FCM), in the evolution of patients with HL.DESIGN: Cell suspensions obtained after mechanical disintegration of ganglion biopsies of patients with newly diagnosed HL were analyzed using FCM. Definitive diagnosis was made by conventional histology and immunohistochemistry. Clinical data were collected from medical records. Statistical analysis was performed using SPSS 20.0 software.SETTING: In the University Hospital of Salamanca, we consecutively analyzed by FCM all lymph nodes with suspected lymphoma at diagnosis. There was no selection bias when collecting patients, except for some cases with inadequate quality(insufficient cells).PATIENTS OR OTHER PARTICIPANTS: From 1996(earliest available FCM data) to 2014, 104 of that samples had a definitive diagnosis of HL. Treatment depended on stage: a)early diagnosis received ABVD(x3) & local radiotherapy(RT) (20-30 Gy), b)advanced: ABVD(x6 to 8), plus RT in selected cases. Median follow-up was 10 years.INTERVENTIONS :This was a retrospective observational study.MAIN OUTCOMES MEASURES: Primary end points were overall survival(OS) and freedom from treatment failure(FFTF), considered from diagnosis to progression or relapse.RESULTS: Most cells obtained were lymphocytes (Median17.1±86.9%) with a T/B/NK distribution of 72%/27%/1.6%(median) and predominance of CD4+ (median CD4:51%-CD8:12%). Median CD8+ cells(12%) was used to divide patients into 2 groups.FFTF was longer in patients with more than 12% of CD8+cells(93% vs. 71%, p=0.01). When analyzed separately patients with early/advanced disease, the clinical benefit remained in the group with advanced disease (p=0.006), whereas the statistical significance was lost in the group with early disease, possibly due to the excellent prognosis for those patients(FFTF 10 years > 95%). No differences were observed in the OS, because second line therapy was highly effective. In the multivariate analysis using Cox regression, advanced stage (HR=9.6 with 95% CI 1.2 to 73.9) and>12% CD8+ tumor infiltrating T-cells were independent variables(HR=0.26, 95% CI 0.07 to 0.9).CONCLUSIONS: Increased number of CD8+ in the H-RSC microenvironment of HL is associated with better FFTF, particularly in the advanced-disease group. This should be considered as a new biomarker to identify high-risk patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ten years’ experience with four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine (BEACOPP)-escalated followed by four cycles of baseline-dose BEACOPP in patients with advanced stage Hodgkin lymphoma: a single-center, retrospective study

The HD-9 trial showed that eight cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine)-escalated led to significant improvements in response rate, progression-free survival and overall survival over COPP/ABVD (cyclophosphamide, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine, dacarbazine) therapy. This monocentric retrospective study was performed to evaluate 10 years of experience with four cycles of BEACOPP-escalated and four cycles of BEACOPP-baseline outside of clinical trials. The outcomes were assessed in 78 patients with newly diagnosed advanced stage Hodgkin lymphoma. A complete response after chemotherapy ± radiotherapy was achieved in 75 patients (96%). At the median follow-up of 74 months, the actuarial 5- and 10-year freedom from treatment failure (FFTF) rates were 91% and 89%, and actuarial 5- and 10-year overall survival rates for the entire group were 93% and 90%, respectively. These results suggest that the combination of escalated and baseline BEACOPP chemotherapy is feasible in routine practice with good efficacy and acceptable toxicity.

Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial

The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma. In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366. Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin. Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT. Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.

Guidelines for the first line management of classical Hodgkin lymphoma

The guideline group was selected to be representative of UK-based medical experts and patients’ representatives. MEDLINE and EMBASE were searched systematically for publications in English from January 1990 to June 2013 using the key words Hodgkin, Lymphoma, Treatment, Chemotherapy and Radiotherapy. References from relevant publications were also searched. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and the BCSH and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with classical Hodgkin Lymphoma (HL). The guidance may not be appropriate for all patients with HL and in all cases individual patient circumstances may dictate an alternative approach.