ABVD Group Research Articles

ESCALATED BEACOPP X 2 + ABVD X 4 IS SUPERIOR TO ABVD X 6 IN ADVANCE STAGE CLASSICAL HODGKIN LYMPHOMA: EXPERIENCE IN A TERTIARY CENTER

Introduction: Classical Hodgkin lymphoma (cHL) is a curable disease but results in advanced stages are suboptimal when treated with standard treatment ABVD with 10%–15% of primary refractoriness and 30% of relapses, although 5 years overall survival (OS) around 88%–90%. First-line treatment with more intensive schemes such as escalated BEACOPP has improved progression-free survival (PFS) in these patients, although associating greater toxicity. However, escalated BEACOPP did not improve OS when compared to ABVD due to the efficacy of rescue treatments, but assuming a high toxic cost. We present our experience to optimize first-line treatment in advanced cHL. Methods: We retrospectively analyzed patients with advanced stage cHL (IIB-IV) treated with curative intent in our center between December 2008 and December 2022 (Table 1). In the period 2008–2011, patients were treated with ABVD x 6. During the period 2011–2022, we implemented a strategy intermediate PET guided (PET2) after escalated BEACOPP (x 2). With PET2 negative, we continued with ABVD/AVD x 4; in PET2 positive patients we continued with escalated BEACOPP x 4. Both groups received radiotherapy on bulky masses. We evaluate the efficacy of this strategy by comparing results and toxicity in the two study periods. Results: In the 2008–11 period, 21 patients received standard treatment with ABVD and during the 2011–22 period, 60 the intensified one (S). In PET2, 55 (91.6%) of patients in the intensified group achieved CR and 5 (8.4%) PR versus 5 (23.8%) CR, 14 (66.7%) PR and 2 (9.52%) refractory patients in the ABVD group. At the end of treatment, 58 patients (96.6%) achieved CR in the intensified treatment group and 15 (71.4%) in the ABVD group. There where 4 (19%) refractory patients in ABVD group versus 2 (3.3%) in the intensified group. PFS for the intensified treatment group was 90.8% at 5 years versus 57.1% for the ABVD group (p = 0.00025). OS for the intensified treatment group was 98.1% versus 85.7% for the ABVD group at 5 years (p = 0.01). The incidence of admissions for febrile neutropenia tended to be higher in the intensified group (15% vs. 4.76%, p = 0.44) and no significant differences were observed in the incidence of secondary malignancies or infertility. There were no toxic deaths in any group. Keywords: Hodkin lymphoma, PET-CT No conflicts of interests pertinent to the abstract.

T082: AVD - a possible golden standard in the first-line treatment of older classical Hodgkin lymphoma patients

Figure 1: 5-year overall survival in cHL patients aged ≥60 years treated with curative intent in Sweden, Denmark and Norway 2000–2021. Limited stage disease (top) and advanced stage disease (bottom) stratified by first-line chemotherapy regimen. Background: First-line treatment in patients ≥60 years with classical Hodgkin lymphoma (cHL) is challenging and less well studied compared to younger patients. Although survival has improved over the past decades, older patients still have an inferior outcome and no golden standard in first-line treatment exists. These patients often have a higher comorbidity-burden and are more susceptible to acute toxicity. In addition, the ageing body and an increased incidence of more advanced disease makes curative treatment challenging. Method: We collected patient and treatment data from Sweden, Denmark and Norway for 1554 patients aged ≥60 years at cHL diagnosis who received treatment with curative intent, diagnosed from January 1st, 2000 to December 30th, 2021 from national registries. Data was also collected from patient records. Survival was estimated using Kaplan-Meyer curves and the risk of death was estimated with both univariable and multivariable Cox regression analysis. Patients were grouped according to first-line chemotherapy regimen; ABVD (n=671), AVD (n=122), CHOP (n=465) or “other” (n=296, single agent or combination chemotherapy). Results: Median age was 70 years (60–94 years) for all patients and stages. In the different treatment groups the median age was 66 years (60–90), 74 years (61–86), 73 years (60–92), 73 years (60–94) for ABVD, AVD, CHOP and “other”, respectively. Overall survival (OS) at 5 years for limited stage patients was 85% for the ABVD group, 94% for AVD, 64% for CHOP and 48% for patients who received “other” chemotherapy. A majority of limited stage patients also received radiotherapy. In patients with advanced stage disease 5-year OS was 63% in the ABVD group, 64% for AVD, 46% for CHOP and 39% in the “other”-group. In multivariable OS analysis patients treated with CHOP had a significantly poorer outcome than those treated with AVD, while there was no significant difference between AVD and ABVD. The majority of patients receiving AVD were treated in Sweden after 2016 and patients in the CHOP and other-group generally had poorer performance status compared to the ABVD-group. PFS data will be presented. Conclusion: AVD is less toxic than ABVD, as bleomycin is omitted, and outcome with respect to OS was equal to ABVD and superior to CHOP in this patient group. Based on our findings AVD is a preferable treatment and should be considered as backbone in prospective studies with novel drugs.

T065: Reproduction patterns among Classical Hodgkin Lymphoma Survivors Treated with BEACOPP and ABVD in Sweden, Denmark, and Norway

Figure 1: Aalen-Johansen estimates of the cause-specific cumulative incidence (CIF) of childbirth estimated in the presence of competing risks of death. Background: Reproduction in classical Hodgkin lymphoma (cHL) survivors has been shown to be reduced compared to the general population, likely due to multi-agent chemotherapy. Understanding if contemporary treatment protocols are associated with reduced reproduction is important as treatment guidelines shift towards more liberal use of more intensive chemotherapy. Methods: We identified 2,937 individuals aged 18–40 years with cHL in Swedish and Danish lymphoma registers, and in the clinical database at Oslo University Hospital (OUH) between 1995 and 2019, who were linked to national medical birth registers in each country. Cox regression adjusted for stage, performance status, year and age at diagnosis was used to estimate hazard ratios (HRs) contrasting time to first childbirth by treatment groups (ABVD, 2–4 BEACOPP, 6–8 BEACOPP) up to ten years after diagnosis. Cause-specific cumulative incidence (CIF) of childbirths was further estimated using flexible parametric survival models. All analyses included an interaction between cHL treatment and sex. Results: Overall, 71.4% of patients were treated with ABVD, 3.6% with 2–4 BEACOPP, and 10.3% with 6–8 BEACOPP. The reproduction rates (per 1,000 person-years) were 45.5 (males) and 48.2 (females) in the ABVD group, and 23.8 (males) and 39.9 (females) in the 6–8 BEACOPP group. The adjusted HR comparing reproduction rates in individuals treated with 6–8 BEACOPP to ABVD was 0.51 (95% CI 0.35–0.73) for males and 0.82 (95% CI 0.57–1.19) for females. The CIF after 10 years was 20.0% (CI: 14.7%–27.2%) for males and 33.0% (CI: 24.6%–44.3%) for females treated with 6–8 BEACOPP. Conclusion: We found that BEACOPP treatment is associated with decreased reproduction rates compared to ABVD in male cHL patients. Infertility counselling should be prioritized for this group. This abstract has been accepted and presented at the EHA 2022 congress.

Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma

BackgroundFive-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin’s lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody–drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.MethodsWe randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed.ResultsA total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P=0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up.ConclusionsPatients who received A+AVD for the treatment of stage III or IV Hodgkin’s lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.)

Treatment outcomes and relative dose intensity of chemotherapy in patients with advanced Hodgkin lymphoma.

The present retrospective study was undertaken to investigate the association of relative dose intensity (RDI) with the outcome of patients with advanced stage Hodgkin lymphoma (HL) receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP regimens (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). A total of 114 patients with HL treated between 2004 and 2013 were enrolled for evaluation. The association of variables with overall survival (OS) and progression-free survival (PFS) was analysed using univariate and multivariate Cox proportional hazards models. The median age of patients was 39 years, and the majority were male and had stage IV disease. A total of 54 patients received ABVD and 60 received BEACOPP chemotherapy with 24 and four deaths, respectively. Patients in the BEACOPP group were significantly younger with lower Charlson comorbidity index (CCI) and better performance status in comparison with the ABVD group, making the comparison of groups not possible. In the ABVD group, RDI was not significantly associated with OS (P=0.590) or PFS (P=0.354) in a multivariate model where age was controlled. The low number of events prevented this analysis in the BEACOPP group. The age of patients was strongly associated with both OS and PFS; all statistically significant predictors for OS and PFS from univariate analyses (chemotherapy regimen, CCI, RDI, performance status) lost their effect in multivariate analyses where age was controlled. Based on these observations, it was concluded that RDI was not associated with OS or PFS after age is controlled, neither in all patients combined nor in the ABVD group.

S202: CHILDBEARING AMONG CLASSICAL HODGKIN LYMPHOMA SURVIVORS TREATED WITH BEACOPP AND ABVD IN SWEDEN, DENMARK, AND NORWAY

Background: Recent studies have shown decreased childbearing rates in some classical Hodgkin lymphoma (cHL) survivors compared to the general population. This decrease is hypothesized to be caused by administered intensive chemotherapy. Understanding if currently used treatment protocols lead to reduced post-treatment childbirth potential is important as differential impact on childbearing may influence treatment decisions for younger patients. Firm conclusions from previous population-based studies have been hampered by low power for specific treatment contrasts. Aims: To increase understanding of differences in childbearing patterns among male and female HL survivors treated with ABVD and BEACOPP in a study combining population-based register data from Sweden, Denmark, and Norway. Methods: In this cohort study 2,937 individuals aged 18-40 years with a recorded diagnosis of cHL in the Swedish lymphoma register (SLR), the Danish lymphoma registry (LYFO), or the clinical database at Oslo University Hospital (OUH) between 1995 and 2019 were included. Information on first-line chemotherapy treatment was available in the registers. Treatment regimens were classified as ABVD, 6-8 BEACOPP, or other. The SLR, LYFO, and OUH databases were linked to national medical birth registers to obtain information on childbirths. Follow-up started 9 months after cHL diagnosis and was accrued until date of first childbirth, death, or administrative censoring (December 2017, 2018, or 2019 for Norway, Sweden, and Denmark, respectively) or after 10 years. Females were additionally censored at date of relapse or stem cell transplantation due to the limited accessibility of assisted reproductive techniques for female patients experiencing one of those events. Stratified Cox models allowing for effect modification between sex and treatment and adjusted for stage, age at diagnosis, year of diagnosis, parity, and performance status were used to estimate hazard ratios (HRs). Flexible parametric survival models were used to estimate marginal childbirth rates and standardized cumulative incidence of childbirth across treatment groups. A comprehensive study analysis plan been published and pre-registered on the Open Science Framework (https://osf.io/eumy5/). Results: In summary, 75% of HL patients were treated with ABVD and 10.8% with 6-8 BEACOPP. An additional 14.2% received other treatments or had missing treatment information and were excluded from further analyses. The rate of first childbirth per 1,000 person-years for males and females was 45.5 and 50.0 respectively in the ABVD group, and 23.8 and 43.5 in the 6-8 BEACOPP group. The adjusted HR of first childbirths for males and females, comparing patients treated with 6-8 BEACOPP to ABVD were 0.54 (95% CI 0.37-0.79) and 0.92 (95% CI 0.61-1.39) respectively. Plots of the cause-specific cumulative incidence functions (CIF) of childbirth show a constantly lower proportion of male patients with childbirths over time since HL diagnosis comparing patients treated with 6-8 BEACOPP and ABVD. However, this difference was not present among female patients. Adjusted marginal estimates of the cause-specific CIF of childbirth showed the same pattern. Image:Summary/Conclusion: BEACOPP treatment is associated with decreased childbearing rates in male but not female HL patients. Infertility counselling for this group is advisable.

Longitudinal study of AMH variations in 122 Adolescents and Young Adults (AYA) and non-AYA lymphoma patients to evaluate the chemo-induced ovarian toxicity to further personalise fertility preservation counselling.

What is the influence of age and chemotherapy regimen on the longitudinal blood anti-Müllerian hormone (AMH) variations in a large series of adolescents and young adult (AYA) (15-24 years old) and non-AYA (25-35 years old) lymphoma patients? In case of alkylating regimen treatment, there was a deep and sustained follicular depletion in AYA as well as non-AYA patients; however in both groups, the ovarian toxicity was extremely low in cases of non-alkylating treatments. AMH is now well-recognised to be a real-time indicator of ovarian follicular depletion and recovery in women treated by chemotherapy. Its longitudinal variations may discriminate between highly and minimally toxic protocols regarding ovarian function. It has been shown, in different cancer types, that age, type of chemotherapy regimen and pre-treatment AMH levels are the main predictors of ovarian recovery. Large studies on longitudinal AMH variations under chemotherapy in lymphoma patients are few but can provide the opportunity to assess the degree of follicle loss at a young age. This prospective cohort study was conducted in the Fertility Observatory of the Lille University Hospital. Data were collected between 2007 and 2016. Non-Hodgkin or Hodgkin lymphoma patients (n = 122) between 15 and 35 years old were prospectively recruited before commencing chemotherapy. Patients were treated either by a non-alkylating protocol (ABVD group; n = 67) or by an alkylating regimen (alkylating group; n = 55). Serial AMH measurements were performed at baseline (AMH0), 15 days after the start of chemotherapy (AMH1), 15 days before the last chemotherapy cycle (AMH2), and at time 3, 6, 9, 12, 18 and 24 months from the end of chemotherapy. The whole study population was divided into two groups according to age: AYA (15-24; n = 65) and non-AYA (25-35; n = 57). All patients received a once monthly GnRH agonist injection during the whole treatment period. A linear mixed model was used to account for the repeated measures of single patients. At baseline, non-AYA patients had higher BMI and lower AMH levels than AYA patients. All AYA and non-AYA patients having received ABVD protocols had regular cycles at 12 months of follow-up. In case of alkylating regimens, amenorrhoea was more frequent in non-AYA patients than in AYA patients at 12 months (37% vs 4%, P = 0.011) and at 24 months (24% vs 4%, P = 0.045). We distinguished a similar depletion phase from AMH0 to AMH2 between ABVD and alkylating groups but significantly different recovery phases from AMH2 to AMH + 24 months. AMH recovery was fast and complete in case of ABVD protocols whatever the age: AMH reached pre-treatment values as soon as the 6th month of follow-up in the AYA group (mean (95% CI) in log AMH M0 vs M6: 3.07 (2.86 to 3.27) vs 3.05 (2.78 to 3.31), P = 1.00) and in the non-AYA group (mean (95% CI) in log AMH M0 vs M6: 2.73 (2.40 to 3.05) vs 2.47 (2.21 to 2.74), P = 1.00). In contrast, no patients from the alkylating group returned to pre-treatment AMH values whatever the age of patients (AYA or non-AYA). Moreover, none of the AMH values post-chemotherapy in the non-AYA group were significantly different from AMH2. Conversely in the AYA group, AMH levels from 6 months (mean (95% CI) in log AMH: 1.79 (1.47 to 2.11), P < 0.001) to 24 months (mean (95% CI) in log AMH: 2.16 (1.80 to 2.52), P ≤ 0.001) were significantly higher than AMH2 (mean (95% CI) in log AMH: 1.13 (0.89 to 1.38)). Considering the whole study population (AYA and non-AYA), pre-treatment AMH levels influenced the pattern of the AMH variation both in alkylating and ABVD protocols (interaction P-value = 0.005 and 0.043, respectively). Likewise, age was significantly associated with the pattern of the recovery phase but only in the alkylating group (interaction P-value =0.001). BMI had no influence on the AMH recovery phase whatever the protocol (interaction P-value = 0.98 in alkylating group, 0.72 in ABVD group). There was a large disparity in subtypes of protocols in the alkylating group. The average duration of chemotherapy for patients treated with alkylating protocols was longer than that for patients treated with ABVD. These results make it possible to develop strategies for fertility preservation according to age and type of protocol in a large series of young lymphoma patients. In addition, it was confirmed that young age does not protect against ovarian damage caused by alkylating agents. This work was supported by Agence Régionale de Santé Hauts de France and Agence Onco Hauts-de-France who provided finances for AMH dosages (n° DOS/SDES/AR/FIR/2019/282). There are no competing interests. DC-2008-642 and CNIL DEC2015-112.

Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial

Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population. ECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing. Between Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50). With 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma. Millennium Pharmaceuticals (a wholly owned subsidiary of Takeda Pharmaceutical Company), and Seagen.

Intensified treatment of patients with early stage, unfavourable Hodgkin lymphoma: long-term follow-up of a randomised, international phase 3 trial of the German Hodgkin Study Group (GHSG HD14)

To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8-10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis. Patients aged 18-60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m2 (days 1 and 15), bleomycin 10 mg/m2 (days 1 and 15), vinblastine 6 mg/m2 (days 1 and 15), and dacarbazine 375 mg/m2 (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m2 (day 1), doxorubicin 35 mg/m2 (day 1), etoposide 200 mg/m2 (days 1-3), procarbazine 100 mg/m2 (days 1-7), prednisone 40 mg/m2 (days 1-14), vincristine 1·4 mg/m2 (day 8; maximum 2 mg), and bleomycin 10 mg/m2 (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296. Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80-132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58-100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0-95·7) for the ABVD group and 94·1% (91·8-95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6-1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6-97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6-88·1) for the ABVD group and 91·2% (88·4-93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4-0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9-9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1-96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6-3·1]) and the 2 + 2 group (2·5 [1·8-3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7-5·0) in the non-randomised 2 + 2 group. This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity. Deutsche Krebshilfe eV and Swiss Federal Government.

2 + 2 in the long term: informing a new standard of care in 2021 for early stage, unfavourable Hodgkin lymphoma

Early stage, unfavourable Hodgkin lymphoma is associated with a progression-free survival of up to 89% following combined modality therapy.1 A 9-year follow-up of the HD14 randomised trial, published in The Lancet Haematology, by Sarah Gillessen and colleagues2 updates the comparison of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 2 + 2 group) plus 30 Gy involved field radiotherapy with four cycles of ABVD (ABVD group) plus 30 Gy involved field radiotherapy.

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial

Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma

BackgroundBrentuximab vedotin is an anti-CD30 antibody–drug conjugate that has been approved for relapsed and refractory Hodgkin’s lymphoma.MethodsWe conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin’s lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival.ResultsAt a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20). All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity.ConclusionsA+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.)

The IVDG Regimen is the Possible Treatment of Choice as First Line Therapy For Hodgkin’s Lymphoma in Elderly Patients with Cardiovascular and Pulmonary Comorbidity

Background. Among the newly diagnosed patients with Hodgkin's lymphoma (HL), the proportion of elderly patients account for 15-35 %. In &gt; 60 age group the choice of antitumor treatment requires an more individualised approach compared to a younger population. The ABVD regimen is acceptable in terms of efficiency and hematological toxicity, but is associated with a high risk of bleomycine-induced pulmonary complications. In &gt; 60 age group the morbitity and mortality of pulmonary complications account for 24 % and 18 %, respectively. Aim. We aimed to evaluate the efficacy of the IVDG regimen in comparison with ABVD by the principle of “non-inferiority”. Materials &amp; Methods. This single centre, prospective, controlled, randomised study was started in 2009. The study included all primary patients aged &gt; 60 years with verified HL, regardless of the number and severity of comorbidities. The ABVD regimen was administered in 17 patients, and 20 patients received IVDG. The median age in the ABVD and IVDG groups was 67 and 70 years, respectively. The advanced stages of HL were reported in 13 (65 %) patients on IVDG, and in 12 (71 %) patients on ABVD (p = 0.9). Both of the groups were comparable in terms of the prevalence of chronic heart failure and chronic obstructive pulmonary disease. The prevalence of ischemic heart disease was higher in the IVDG group (n = 16) compared to ABVD (n = 8) (p = 0.04). Results. IVDG and ABVD groups did not differ in the frequency of complete (14 and 10) and partial (3 and 4) remissions. Differences in 5-year overall survival were insignificant: 49 % in the IVDG group, vs 22 % in ABVD group (p = 0.41). No infectious or hemorrhagic complications were observed in both groups. The incidence of drug-induced pulmonary fibrosis after treatment was significantly lower in the IVDG group (n = 0) vs ABVD group (n = 4; 24 %) (p = 0.004). Conclusion. The IVDG regimen may be used as first line treatment for HL in the elderly patients, especially in those having cardiac or pulmonary comorbidities. Compared to ABVD the IVDG regimen had similar efficacy and more beneficial safety profile in terms of cardiovascular and pulmonary toxicity.

Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma

BackgroundWe tested interim positron-emission tomography–computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin’s lymphoma.MethodsPatients with newly diagnosed advanced classic Hodgkin’s lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points.ResultsA total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, −3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin’s lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%.ConclusionsAlthough the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.)

Comparison of dose-dense ABVD and standard ABVD in the treatment of early unfavorable and advanced Hodgkin’s lymphoma: A retrospective analysis

This retrospective analysis compared standard regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with the dose-dense ABVD regimen (ABVD-21) in terms of efficacy and toxicity. Patients who had early-stage unfavorable or advanced Hodgkin's lymphoma (HL) according to German Hodgkin Study Group criteria from March 1999 to February 2011 were analyzed for treatment response, long-term survival and hematological toxicity. There were 85 patients in the ABVD-21 group and 118 patients in the ABVD group respectively. The complete remission rates after completion of treatment were 92.9% and 90.7% for ABVD-21 and ABVD, respectively. During a median follow-up period of 62 months, no significant difference was found in projected 10-year progression-free survival (PFS) and overall survival (OS) rates (84.7% and 94.1% respectively for ABVD-21; 81.4% and 91.5% for ABVD). Subgroup analyses showed that ABVD-21 was significantly better than ABVD for patients with IPS≥3 in terms of PFS and OS rates. Grade 3 to 4 leukopenia (51.8% vs. 28.8%, P=0.001) and neutropenia (57.6% vs. 39.0%, P=0.009) were more common with ABVD-21. We were led to conclude that dose-dense ABVD did not result in better tumor control and overall survival than did ABVD for early-stage unfavorable HL. However, patients at high risk, for example, with IPS≥3, may benefit from dose-dense ABVD.

Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study

Roughly 70-80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma. We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB-IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m(2) doxorubicin, 10 units/m(2) bleomycin, 6 mg/m(2) vinblastine, and 375 mg/m(2) dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904. Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]). Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma. Seattle Genetics Inc and Takeda Pharmaceuticals International Co.

Risk and response adapted therapy for early stage Hodgkin lymphoma: a prospective multicenter study of the Australasian Leukaemia and Lymphoma Group/Trans-Tasman Radiation Oncology Group

In this prospective, multicenter, non-randomized study for patients with stage I–II Hodgkin lymphoma, group 1 (without risk-factors [RF]) had three cycles of ABVD chemotherapy (adriamycin, bleomycin, vinblastine, and dacarbazine) and group 2 (any of bulk, extranodal site, >3 regions, raised erythrocyte sedimentation rate [ESR]) and group 3 (B-symptoms) received four cycles. Involved field radiotherapy (IFRT) 30 Gy was given after adequate chemotherapy response. Five-year overall survival and freedom from progression (FFP) were 96% (95% confidence interval [CI] 91–98%) and 90% (84–94%), respectively. Five-year FFP was 97% (90–99%), 89% (75–95%), and 73% (52–86%) for groups 1, 2, and 3, respectively. In patients with RF, chemotherapy responses of complete response unconfirmed (CRu), partial response (PR), and stable disease (SD) were associated with FFP of 90%, 86%, and 62% (p=0.17), and CR/no CR on functional imaging with FFP of 90%/67%, respectively (p=0.05). The 97% FFP in group 1 compares favorably with previously reported results from cooperative trial groups. Intensification of therapy warrants study in patients with RF and a poor chemotherapy response.

Randomized Phase III Trial Comparing ABVD + Radiotherapy and the Stanford V Regimen In Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the US Intergroup Trial E2496

AbstractAbstract 416 Background:Standard therapy for locally extensive Hodgkin Lymphoma (HL) defined as stage I/II with bulky mediastinal disease [mediastinal mass ratio (MMR) > than 1/3 of the chest diameter on standing postero-anterior chest x-ray or 10 cm on computerized tomography] is combined modality therapy (CMT). E2496 was a North American intergroup, randomized phase III study comparing ABVD versus the Stanford V regimen for patients with locally extensive and advanced stage HL. In this subgroup analysis we compare two CMT approaches, ABVD + radiotherapy (RT) and the Stanford V regimen, in patients with stage I/II bulky mediastinal HL. Methods:Patients with stage I/II HL bulky mediastinal disease were randomized to receive chemotherapy (CT) on either Arm A (ABVD × 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V, administered weekly). Two-3 weeks after completion of chemotherapy, modified involved field RT was delivered at 36 Gy to the mediastinum to patients on ABVD as well as Stanford V. Patients on Stanford V also received involved field RT to any other sites >5 cm at diagnosis. The primary endpoint was failure free survival (FFS) defined as the time to either progression/relapse or death. The log-rank test was used to compare FFS and OS (overall survival) for all eligible patients. Results:Of the 812 eligible patients with advanced HL enrolled on the study 267 had locally advanced bulky mediastinal disease: 136 on ABVD and 131 on Stanford V. Patient characteristics between the two randomized groups were well matched with a median age of 30 years and 86% had stage II disease. On ABVD 61% of patients received 6 cycles, 29% 8 cycles of CT and 77% required some dose modification. In Stanford V 97% completed the assigned 12 weeks of CT and 76% required some dose modification. 82% received RT per protocol in ABVD versus 88% in Stanford V. The overall response (CR+PR) was 82% in ABVD and 86% in Stanford V. At a median follow-up of 5.47 years, there are 19 failures and 6 deaths in the ABVD group and 25 failures with 9 deaths in the Stanford V group. We failed to detect statistically significant differences between ABVD +RT and Stanford V for FFS (5y 85% versus 77% p=0.13, HR=1.56 95% CI (0.87, 2.88) and OS (5y 95% versus 92% p=0.31, HR=1.69 95% CI (0.60, 4.75). No difference in hematologic toxicity was observed between the two arms. Evaluation of pulmonary function and patterns of failure are pending. Conclusions:For stage I/II patients with bulky mediastinal disease, CMT with either ABVD +RT or the Stanford V regimen results in high cure rates and is highly effective. ABVD for 6–8 cycles plus 36 Gy RT remains the US standard of care. Longer follow up is required to assess RT related late effects. Future research efforts should focus on risk stratification to identify; a) the 15–20% of patients destined to relapse after standard therapy and evaluate treatment intensification strategies and b) the 80–85% of patients who are cured with standard therapy and determine whether a subset can achieve the same excellent outcomes with a reduction or elimination of radiation. Planned US cooperative group trials will address these questions, using ABVD as the chemotherapy backbone in conjunction with interim PET imaging for risk stratification. Disclosures: Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

A Comparison of Effects of ABVD and ChlVPP Chemotherapeutic Protocols for Hodgkin's Disease on Rats’ Epididiymal and Testicular Tissues

The goal of this study was to determine the effects of ABVD and ChlVPP chemotherapeutic protocols for Hodgkin's disease on the structure of testis and epididymis of male rat. After determining tolerance dose of drugs in pilot study, 24 male rats were divided to four groups: ABVD (doxorubicin, bleomycine, vinblastin, dacarbazine) group, ChlVPP (chlorambucil, vinblastin, procarbazine, prednisolone) group and two control groups one for each treatment group. One half of the lethal dose for 50% of population (LD50) was used for treatment of animals in each protocol. Testes and epididymis tissues were examined for structural changes and serum testosterone level was measured by Lission (chemiluminescence method). Body weight, testis and epididymis weights, in treated rats were significantly less than their control groups specifically in ABVD group was less than ChlVPP group. Decreasing of mean diameter of seminiferous tubules, height of spermatogenic cells and diameter of epididymis in caput, corpus and cauda in ABVD group were significantly more than ChlVPP and control group. The serum testosterone level in ABVD group was significantly less than ChlVPP and control group. According to this study results, the ChlVPP had fewer impairment effects than ABVD on testis and epididymis tissue in tolerance doses on male rats' reproductive system. More clinical trial studies are suggested on Hodgkin's patients. With equal treatment effectiveness, it will be better to use the most reliable and safe treatment especially in young patients.