Gy Involved Field Radiotherapy Research Articles

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial

The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Involved-site Radiation Therapy is Equally Effective and Less Toxic Than Involved-field Radiation Therapy in Patients Receiving Combined Modality Treatment for Early-stage Unfavorable Hodgkin Lymphoma—An Analysis of the Randomized Phase 3 HD17 Trial of the German Hodgkin Study Group

PurposeCombined modality treatment (CMT) with chemotherapy followed by consolidation radiotherapy (RT), provides excellent outcomes for patients with early-stage Hodgkin lymphoma (HL). The international standard of care for consolidation RT, involved-site/involved-node radiotherapy (ISRT/INRT), has never been evaluated in a randomized phase III trial against the former standard involved-field radiotherapy (IFRT). Methods and materialsIn the multicenter phase III AnonymizedStudyGroupXXX AnonymizedStudyYYY trial, patients with early stage unfavorable HL were randomized between the standard CMT group and a positron-emission tomography (PET) -guided group. In the standard group, patients received two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gray (Gy) IFRT. In the experimental group patients received no further therapy if post-chemotherapy PET was negative, and 30 Gy AnonymizedStudyGroupXXX -INRT, comparable and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT. Results1,100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival (PFS) were 96.8 % (95% CI: 91.6% – 98.8%) in the IFRT group and 95.4% (95% CI: 89.9% – 97.9%; HR: 1.40, 95% CI: 0.44 – 4.42) in the ISRT group. Pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade III/IV toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (p=0.03). ConclusionsFor the first time, consolidation INRT/ISRT was randomly compared to IFRT in a phase III trial. Regarding PFS, no advantage for IFRT could be demonstrated. In summary, our data confirm the place of INRT/ISRT as the current standard of care.

Early-Stage Follicular Lymphoma: Learnings from the Final Analysis of the Multicenter Phase II FIL (Fondazione Italiana Linfomi) “Miro” Trial, Combining Local Radiotherapy and MRD-Driven Immunotherapy

Introduction. Early-stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing a complete and long-lasting eradication of the disease in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate if a minimal residual disease (MRD)-driven immunotherapy consolidation after IFRT can improve the outcome of pts unlikely to be cured by IFRT only, and to assess the therapeutic effect of IFRT and anti-CD20 consolidation by MRD evaluation. Methods. One hundred and ten pts with stage I/II FL were enrolled; 106 were evaluable and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Fondazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In pts BCL2::IGH+ at baseline by both nested PCR (NEST) and RQ-PCR (RQ) in the BM and/or (a/o) PB, MRD was analyzed after IFRT and every 6 months over a 3-year period. Pts who were MRD+ by both NEST and RQ in the BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 monoclonal antibody ofatumumab (OFA). The primary objective of the study was to define the efficacy of immunotherapy in obtaining a negative MRD. Results. Of the 106 evaluable pts, 50 were males (47%). Median age was 55.5 years (29-83). The FLIPI score was 0 in 60% of pts, 1 in 34%, 2 in 6%; 69% of pts had inguinal site involvement, significantly more frequent in young patients. At baseline, 30.5% of pts had a BCL2::IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in the BM a/o PB; the concordance between compartments was 87%. BCL2::IGH+ and BCL2::IGH- pts were not significantly different, except for a younger age (p 0.009) and a more frequent FLIPI 0 (p 0.052) among marker negative cases. All but 1 pt achieved a clinical response after IFRT; 1 pt died soon after IFRT of unrelated causes. MRD evaluation after IFRT revealed the persistence of BCL2::IGH+ cells in the PB a/o BM in 60% of pts. MRD+ pts, either after IFRT (n=18) or in case of conversion to MRD+ during the follow-up (n=8), received OFA, obtaining a conversion to MRD- in 23/25 evaluable pts (92%, CI 74-99%), significantly superior to the expected 50%. After a median follow-up of 46.3 months (m) (range 11-66), of the 23 pts who achieved a MRD- with OFA, 5 returned MRD+ (4 underwent OFA re-treatment, achieving a second MRD-, 1 relapsed as a transformation), 4 relapsed being MRD-, 14 remain in complete remission and MRD-, with a duration of molecular response at the last molecular assessment of 30 months (range 6-36). Overall, a clinical relapse was observed in 29 pts submitted to IFRT and 1 patient progressed soon after IFRT. A confirmed histologic transformation to DLBCL was observed in 5 of these patients. Among the 73 “marker negative” patients, 20 relapsed (27.4%) over time, whilst among the 32 BCL2::IGH+ at baseline 9 (28.1%) were resistant or relapsed (p=0.939). The administration of OFA was associated to a significantly reduced risk of POD24 (p= 0.035). Overall, the 24-m and 36-m overall survival (OS) were 100% and 98.9%, respectively; the 24-m and 36-m PFS were 83.7% and 77.4%, respectively. PFS was not different according to the presence or absence of BCL2::IGH at enrollment (p=0.820). PFS was significantly different according to the FLIPI score (p=0.041), but not different according to gender (p=0.696), stage I-II (p=0.122), histological grade (p=0.212), inguinal nodal site vs others (p=0.492). The Kaplan Meier landmark analysis, stratified by MRD, at m+6 (p=0.228), m+12 (p=0.003), m+18 (p=0.0002), m+24 (p=0.004) showed that PFS significantly improved from m+12 onwards when a negative MRD was present (Figure 1). Conclusions. IFRT alone is often insufficient to eradicate FL, inducing a MRD- status only in 40% of pts, long-lasting only in a third of them. An immunotherapy consolidation with OFA after IFRT in MRD+ pts was capable of increasing the molecular responses to 92%, allowing to achieve the primary objective of the study, though this effect was not always persistent. The achievement of a molecular remission correlated significantly with a reduction in the incidence of relapse over time, although this strategy was applicable only to 30% BCL2::IGH+ PET/CT staged FL pts. A consolidation strategy with more effective agent should be advisable. With these limits, a clinical advantage of the MRD-driven treatment strategy is suggested, although not largely applicable.

Splenic irradiation prior to allogeneic transplant conditioning in myelofibrosis: A pilot experience

IntroductionIn the era of JAK inhibitors, allogeneic stem cell transplantation (HSCT) remains the only curative treatment for patients with Myelofibrosis (MF). Splenic irradiation (SI) may be used to reduce spleen size and related symptoms. MethodsWe conducted a retrospective analysis on 14 patients with MF who underwent HSCT with SI from any donor source at our center between June 2016 and March 2021. All patients received a conditioning backbone based on treosulfan and fludarabine, with post-transplant cyclophosphamide (PTCy) and sirolimus as graft-versus-host disease (GvHD) prophylaxis. Patients received SI with 10 Gy involved-field radiotherapy in five 2-Gy fractions over the course of a week prior to the beginning of conditioning. ResultsAt transplant all patients were transfusion-dependent and had splenomegaly (median bipolar diameter by ultrasound: 20.75 cm). Overall, 12 patients had received ruxolitinib prior to transplant. Re-evaluation of spleen dimensions was available for 13 patients: median splenic bipolar diameter after at least 3 months from transplant decreased by a median of 25%. With a median post-transplant follow-up of 25 months, 6 patients remain in CR with full-donor chimerism, 3 patients died due to NRM. Overall, 4 patients relapsed. At last follow-up, nine patients are currently alive and achieved transfusion-independence. ConclusionsIn a small cohort of mostly ruxolitinib pre-treated patients, SI and treosulfan-based conditioning appeared a safe and effective tool to reduce spleen dimensions and ameliorate symptoms. Future prospective studies with adequate sample size are warranted to further investigate the usefulness and safety of this approach in MF.

Positron Emission Tomography-Adapted Therapy in Bulky Stage I/II Classic Hodgkin Lymphoma: CALGB 50801 (Alliance).

Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)-adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET-) disease and intensifying treatment in patients with PET-positive (PET+) disease. Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2-, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation. Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2- and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2- and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2- was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04). Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

PET-Guided Treatment in Patients with Early-Stage Favorable Hodgkin Lymphoma: Follow-up Analysis of the HD16 Trial By the German Hodgkin Study Group

PET-Guided Treatment in Patients with Early-Stage Favorable Hodgkin Lymphoma: Follow-up Analysis of the HD16 Trial By the German Hodgkin Study Group

Involved-Field Radiation Therapy Prevents Recurrences in the Early Stages of Hodgkin Lymphoma in PET-Negative Patients After ABVD Chemotherapy: Relapse Analysis of GHSG Phase 3 HD16 Trial

The HD16 trial of the German Hodgkin Study Group (NCT00736320) demonstrated that radiation therapy in early-stage Hodgkin lymphoma without risk factors cannot be safely omitted, and therefore combined modality therapy (CMT) remains the standard treatment. To demonstrate the local effect of consolidating involved-field radiation therapy (IF-RT), we performed an analysis of the recurrence pattern of positron emission tomography (PET)-negative HD16 patients. Between 2009 and 2015, 1150 patients with early-stage Hodgkin lymphoma without risk factors were randomly assigned to PET guided to 20 Gy IF-RT after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the HD16 study of the German Hodgkin Study Group. The study was designed as a prospective randomized controlled trial. We correlated the localization of recurrence with the panel-based IF-RT plan, which was drawn up for all patients prospectively, blinded to treatment allocation. Accordingly, we were able to identify recurrences that occurred at least in part inside or outside of the (potential) radiation field (in-field and out-field, respectively). There were 328 and 300 PET-negative patients assigned to CMT and PET-guided treatment (ie, chemotherapy alone), respectively. Within a median 47-month follow-up, disease progression or recurrence was documented for 15 and 29 patients treated with and without IF-RT, respectively. Relapse localization was unknown in 1 CMT patient. Without IF-RT, 5-year incidence of in-field relapses was 10.5% (95% confidence interval, 6.5-14.6) compared with 2.4% (0.5-4.3) with CMT (P=.0008). There were no relevant differences in out-field recurrences (5-year incidence 4.1% [1.7-6.6] vs 6.6% [3.0-10.3], P=.54). There was no grade 4 toxicity observed during IF-RT, and incidence of second primary malignancies was similar in both groups. PET-negative patients of the HD16 study showed no significant toxicity after 20 Gy IF-RT, and we demonstrated that omission of IF-RT resulted in more, particularly local, recurrences. Therefore, consolidation IF-RT should still be considered as standard therapy in this setting.

UPDATED RESULTS OF THE FIL “MIRO” STUDY, A MULTICENTER PHASE II TRIAL COMBINING LOCAL RADIOTHERAPY AND MRD‐DRIVEN IMMUNOTHERAPY IN EARLY‐STAGE FOLLICULAR LYMPHOMA

Background: Early-stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing a complete and long lasting eradication of the disease only in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying pts unlikely to be cured by IFRT, for whom an immunotherapy consolidation could improve outcome. Methods: 110 pts with stage I/II FL were enrolled and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Fondazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In BCL2/IGH+ pts at baseline by both nested PCR (NEST) and RQ-PCR (RQ) in BM a/o PB, MRD was analyzed after IFRT and every 6 months over a 3-year period. Pts with MRD+ by both NEST and RQ in BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab (OFA). The primary objective of the study was to define the efficacy of immunotherapy in obtaining a negative MRD. Results: Of the 106 evaluable pts, 50 were males. Median age was 55 y (29-83). The FLIPI score was 0 in 59% of pts, 1 in 35%, 2 in 6%. 68% of pts had inguinal site involvement. At baseline, 30% of pts had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM a/ o PB;the concordance between compartments was 90%. All but one pt achieved a clinical response after IFRT;one additional pt died soon after IFRT of unrelated causes. MRD evaluation after IFRT revealed the persistence of BCL2/IGH+ cells in PB a/o BM in 60% of pts. MRD + pts, either after IFRT (n = 18) or in case of conversion to MRD+ during the follow-up (n = 6), received OFA, obtaining a conversion to MRD-in 22/24 pts (91.7%-CI 73.0-99.0), significantly superior to the expected 50% (Fig). After a median F-U of 38 m, 17 pts who achieved a MRD-with OFA are still negative;5 converted to MRD+ (2 received OFA retreatment, achieving a second MRD-;2 pts were not re-treated due to Sars-Cov2 pandemic;1 relapsed). A clinical relapse or progression was observed in 23 pts: 18 (24.6%) among the 73 “no marker” pts and 5 (15.6%) among the 32 BCL2/IGH+ at baseline (p = 0.3), with no significant difference in PFS (p = 0.25). Two early relapses were observed among the 12 pts who became MRD-after IFRT and 3 among the 24 treated at least once with OFA (1 MRD+, 1 MRD-, 1 converted from MRD-to MRD+). Only 1 Pt relapsed while MRD-after OFA. Conclusions: MRD data indicate that RT alone is often insufficient to eradicate the disease, inducing a MRD-only in 40% of pts, notably long-lasting only in half of them. The primary objective of this study-MRD conversion after immunotherapy-was largely achieved. The strategy of an immunotherapy consolidation after IFRT in MRD+ pts allowed increasing molecular responses. However, this strategy is applicable only to 30% of enrolled pts. A clinical advantage of the MRD driven treatment strategy is suggested although not significan.

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.

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.

Risk-Adapted Therapy with ABVD for Low- and Intermediate-Risk Patients and Oepa-Copdac for High Risk Patients Plus Involved-Field Radiation Therapy (IFRT) Based on Prognosis at Diagnosis and Early Response: Results from Pediatric Argentinian Collaborative Group Gatla Study for Children and Adolescents with Hodgkin Lymphoma

Background: The GATLA Collaborative Group has a 50 year (y) long experience of running cooperative trials for lymphomas in Argentina. Aim: Describe the outcome of pediatric patients(pts) treated according to the international cooperative work with AHOPCA and St. Jude Children's Research Hospital (11-EHP-12) adopting OEPA/COPDAC strategy for High Risk (HR) pts and ABVD for Intermediate (IR) and Low Risk (LR) pts. Methods: 11-EHP-12: Risk assignment according Stanford/Danna Farber/ SJCRH Consortium classification. LR: ABVD x 4± IFRT (20 Gy). IR: ABVD x 6 ± IFRT (20 Gy). HR: OEPA-COPDAC+IFRT (20/25 Gy). Response evaluation: LR after 4th cycle, IR and HR after the 2nd cycle. Complete Remission (CR): response > 80% reduction and PET negative. Partial Remission (PR): response >50% and <80% reduction and/or PET positive. 170 pediatric patients (pts) were enrolled since November 2012. 133 evaluable pts. 37 on treatment and/or a follow up of less than 5 years. Sex: M/F: 85 (63,9%) /48. Median age: 13 y (range 4-18 y). Histology: nodular sclerosis 91 (68,4%), mixed celularity 31 (23.3%), lymphocyte rich 1 (0,7%), lymphocyte depleted 1 (0,7%), nodular lymphocyte predominant 8 (6,9%). Stage: I :16 (12%), II: 51 (38.4%), III: 27 (20.3%), IV: 39 (29.3%). B Symptoms: 66 (49.6%). Interim evaluation: PET/TC: 109/133 (82%), TC: 24. Distribution by risk groups: HR pts.: 77 (57,9%), IR: 35 (26,3%), LR: 21 (15,8%). Results: 5 y OS was 94% (100% for LR and IR, and 91% HR) and 5y EFS was 88% (100% for LR, 91% IR, and 84% HR). 95% of the LR pts and 72% of the IR pts did not undergo radiotherapy. 70% of the HR pts achieved CR after the 2nd OEPA and received 20 Gy IFRT. According PR or CR after 2nd OEPA, the 5y EFS in HR pts was 84% and 90% respectively. Conclusion: Thanks to this international cooperation We could significantly improve the results in Argentina compared to our previous experience (7-PHD-96: COPP-ABV x 6 + IFRT Bulky disease or PR (20/25Gy): 5yOS:85%, 5yEFS:67%), reduce the number of patients who required radiotherapy and reproduce the Euronet experience for HR pts in a different context. Figure Disclosures No relevant conflicts of interest to declare.

“Miro” Study, a FIL multicenter phase II trial combining local radiotherapy and MRD-driven immunotherapy in early-stage follicular lymphoma.

e20073 Background: Early stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing eradication of the disease in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate the role of minimal residual disease (MRD) in identifying pts unlikely to be cured by IFRT, for whom an immunotherapy-based consolidation could improve outcome. Methods: 110 pts with stage I/II FL were enrolled and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Federazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In BCL2/IGH+ pts at baseline, MRD was analyzed by nested PCR (NEST) and RQ-PCR (RQ) in BM and/or PB after IFRT and every 6 months over a 3-year period. Pts with positive MRD by both NEST and RQ in the BM and/or PB after IFRT or who became positive during the follow-up (FU) were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab (OFA). Primary objective: efficacy of immunotherapy in obtaining a negative MRD. Results: 49 of 106 pts were males. Median age was 55 y (29-83). 69% of pts had inguinal involvement. At baseline, 30% of pts had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM and/or PB; the concordance between compartments was 90%. All pts obtained a clinical response after IFRT, with persistence of BCL2/IGH+ cells in PB and/or BM in 60% of cases. MRD-positive pts, either after IFRT (n = 18) or in case of conversion to a positive signal during the FU (n = 7), received OFA, obtaining a conversion to MRD negativity, in 20/22 cases (91% - CI 65.1-97.1), significantly superior to the expected 50%. After a median FU of 25 months, all but 2 pts who achieved a negative MRD with OFA are still negative. A clinical relapse or progression was observed in 17 pts: 13 (18%) among the 73 “no marker” pts; 2 relapses (16%) were observed among the 12 MRD-negative pts after IFRT and 2 among the 25 treated with OFA (8%), 1 having achieved a MRD negativity and 1 not. No significant differences in PFS have so far been observed between the three groups. Conclusions: In early stage FL RT alone is often insufficient to eradicate the disease, inducing a negative MRD only in 40% of pts, long-lasting only in half of them. The primary objective of this study - MRD negativity after immunotherapy - was achieved. The strategy of an immunotherapy consolidation after IFRT in MRD-positive pts allowed to increase molecular responses. A longer FU and further studies will allow to define the impact of this MRD-driven strategy also on clinical outcome. Clinical trial information: EudraCT number: 2012-001676-11 .

PET-Guided Treatment of Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase 3 Trial HD16 by the GHSG

Combined modality treatment (CMT) consisting of two cycles of ABVD and 20 Gy of involved-field radiation therapy (IFRT) is widely accepted standard of care for early-stage favorable Hodgkin lymphoma (HL). Recent clinical research suggests that metabolic response assessment after two cycles of chemotherapy using FDG-PET (PET-2) can predict the individual outcome and PET-2 negativity might allow reducing the overall treatment intensity. In this study, we assessed whether omitting consolidating radiation therapy in patients with negative PET-2 is feasible without loss of efficacy as determined by progression-free survival (PFS). Furthermore, we analyzed the prognostic impact of PET-2 among patients receiving CMT. Between November 2009 and December 2015, we recruited patients with newly diagnosed, early-stage favorable HL aged 18–75 years from Germany, Switzerland, Austria, and the Netherlands for this double-blind, randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard CMT with 2x ABVD and 20 Gy IFRT or PET-guided treatment, whereby IFRT was restricted to those patients with a positive PET after 2xABVD. A total of 1150 patients were enrolled; 628 patients with negative PET-2 were eligible for the per-protocol non-inferiority analysis and were treated with CMT (n=328) or ABVD alone (n=300). With a median follow-up of 47 months, the estimated 5-year PFS was 93.4% (90.4–96.5) with CMT and 86.1% (81.4–90.9) with chemotherapy only (difference 7.3%, 95% CI 1.6%–13.0%). The hazard ratio was 1.78 with a 95% CI ranging from 1.02 to 3.12, including the non-inferiority margin of 3.01. The PFS difference primarily resulted from a significant increase in disease recurrences with in-field recurrence rates of 2.1% vs. 8.7% (p=0.0003); there was no relevant difference regarding out-field recurrences (3.7% vs. 4.7%, p=0.55). Estimated 5-year overall survival in the per-protocol population was 98.1% (96.5–99.8) with CMT and 98.4% (96.5–100.0) with ABVD. Six hundred ninety-three patients assigned to receive CMT were eligible for the analysis of the PET objective and had a negative (n=353) or positive (n=340) PET-2. With a median follow-up of 46 months, estimated 5-year PFS was 93.2% (90.2–96.2) among PET-2-negative and 88.1% (83.8–92.3) among PET-2-positive patients (p=0.035). When using the more common liver cutoff (Deauville score 4) for the definition of PET-2 positivity, the difference became was more pronounced (5-year PFS 93.1% [90.7%–95.5%] vs. 80.1% [71.2%–88.9%], p=0.0004). In early-stage favorable HL, radiation therapy cannot be safely omitted from standard CMT without a clinically relevant loss of tumor control in patients with negative PET-2. PET positivity after 2xABVD represents a risk factor for PFS in HL patients treated with standard CMT, particularly when a Deauville score of 4 is considered as cutoff for positivity.

PET-Guided Treatment of Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase 3 Trial HD16 By the German Hodgkin Study Group

Background. Combined modality treatment (CMT) consisting of two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and 20 Gy of involved-field radiotherapy (IFRT) is widely accepted standard of care for early-stage favorable Hodgkin lymphoma (HL). Recent clinical research suggests that metabolic response assessment after two cycles of chemotherapy using FDG-PET (PET-2) can predict the individual outcome and PET-2 negativity might allow reducing the overall treatment intensity.Aims. We assessed whether omitting consolidating radiotherapy in patients with negative PET-2 is feasible without loss of efficacy as determined by progression-free survival (PFS). Furthermore, we analyzed the prognostic impact of PET-2 among patients receiving CMT.Methods. Between November 2009 and December 2015, we recruited patients with newly diagnosed, early-stage favorable HL aged 18-75 years from Germany, Switzerland, Austria, and the Netherlands for this double-blind, randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard CMT with 2x ABVD and 20 Gy IFRT or PET-guided treatment, whereby IFRT was restricted to those patients with a positive PET after 2xABVD. PET-2 was centrally assessed by a panel blinded towards the randomization result, with FDG uptake not higher than the mediastinal blood pool (i.e., Deauville score 1-2) defined as negative. The trial was designed to exclude inferiority of 10% or more in 5-year PFS of ABVD only compared with CMT in a per-protocol analysis among PET-negative patients, corresponding to a non-inferiority margin of 3.01 for the hazard ratio, and to detect a 5-year PFS difference of 5% or more between PET-2-positive and -negative patients receiving CMT, each with 80% power.Results. A total of 1150 patients were enrolled; 628 patients with negative PET-2 were eligible for the per-protocol non-inferiority analysis and were treated with CMT (n=328) or ABVD alone (n=300). With a median follow-up of 47 months, the estimated 5-year PFS was 93.4% (90.4-96.5) with CMT and 86.1% (81.4-90.9) with chemotherapy only (difference 7.3%, 95% CI 1.6%-13.0%). The hazard ratio was 1.78 with a 95% CI ranging from 1.02 to 3.12, including the non-inferiority margin of 3.01. The PFS difference primarily resulted from a significant increase in disease recurrences with in-field recurrence rates of 2.1% vs. 8.7% (p=0.0003); there was no relevant difference regarding out-field recurrences (3.7% vs. 4.7%, p=0.55). Estimated 5-year overall survival in the per-protocol population was 98.1% (96.5-99.8) with CMT and 98.4% (96.5-100.0) with ABVD.693 patients assigned to receive CMT were eligible for the analysis of the PET objective and had a negative (n=353) or positive (n=340) PET-2. With a median follow-up of 46 months, estimated 5-year PFS was 93.2% (90.2-96.2) among PET-2-negative and 88.1% (83.8-92.3) among PET-2-positive patients (p=0.035). When using the more common liver cutoff (Deauville score 4) for the definition of PET-2 positivity, the difference was more pronounced (5-year PFS 93.1% [90.7%-95.5%] vs. 80.1% [71.2%-88.9%], p=0.0004).Conclusion. In early-stage favorable HL, radiotherapy cannot be safely omitted from standard CMT without a clinically relevant loss of tumor control in patients with negative PET-2. PET positivity after 2xABVD represents a risk factor for PFS in HL patients treated with standard CMT, particularly when a Deauville score of 4 is considered as cutoff for positivity. DisclosuresGreil:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Sandoz: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Tresckow:MSD: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

Children and Adolescent Hodgkin Lymphoma in Argentina: Long-term Results After Combined ABVD and Restricted Radiotherapy.

Prospective analysis of clinical characteristics and long-term treatment results of a pediatric cohort with Hodgkin lymphoma (HL) treated in a single institution with ABVD and restricted radiotherapy (RT). Between September 2000 and December 2015, 165 new consecutive assessable patients with HL were registered at our institution. Lymphocyte predominant nodular HL was excluded. Low risk (LR) patients were stage I and IIA (no bulky disease, <4 involved ganglionar areas and no lung hilar nodes), high risk (HR) was assigned to stage IV and any other stage with bulky mediastinum. The rest of the cohort was treated as intermediate risk (IR). Chemotherapy for LR and IR patients was 4 and 6 courses of ABVD regimen, respectively. These subsets received Low-dose involved field radiotherapy only in case of partial remission at the end of chemotherapy (21 Gy in initially involved areas, plus 14 Gy boost on residual disease). The HR group was treated with 6 courses of ABVD followed always with 21 Gy involved field radiotherapy if complete remission (CR) was achieved. A boost of 14 Gy was added to residual disease in case of partial remission. Median age was 10.6 years (range, 2.7 to 17 y). Males: 117 (71%); females: 48 (29%). Eighteen (11%) patients were stage I, 76 (46%) stage II, 35 (21%) stage III, and 35 (21%) stage IV. Forty-nine (30%) patients were assigned to LR, 49 (30%) to IR, and 67 (40%) to HR. Forty-three patients (26%) had "bulky" mediastinum involvement. One hundred thirty (79%) patients achieved CR after chemotherapy and 161 (98%) after RT. Four patients (all HR), did not respond to initial therapy and died of disease. One patient died in first CR due to adenovirus infection on previously therapy-related damaged lungs. Seventeen (10%) patients relapsed and 13 of them remained in second CR after further therapy. Seventy-six (46%) patients could be spared from RT and cured of disease (88% of LR patients and 67% of IR patients). With a median follow-up of 5 years, event free and overall survival were 0.84 (SE: 0.03) and 0.95 (SE: 0.02), respectively. Overall survival according to risk group was 1 for LR, 0.93 for IR, and 0.85 for HR. Acute toxicity and late effects due to therapy were not significant. The strategy of avoiding RT for LR and IR patients that responded completely to ABVD chemotherapy achieved very good results. For the HR group, the combination of 6 cycles of ABVD and Low-dose involved field radiotherapy was efficacious with similar good results. Nearly half of the patients could be cured without RT.

Intermediate-Risk Lymphocyte-Predominant Hodgkin Lymphoma: AHOD0031: A Report from the Children's Oncology Group

Background: Children's Oncology Group (COG) AHOD0031 demonstrated that early response assessment in pediatric intermediate-risk Hodgkin lymphoma (HL) permits reduction or augmentation in therapy with maintenance of excellent event-free (EFS) and overall survival (OS). While the majority of patients on this trial had classical HL (cHL), patients with lymphocyte-predominant HL (LPHL) were included. Pediatric patients with LPHL typically present with localized disease and such low risk patients have excellent outcomes with surgical resection alone or minimal chemotherapy. However, management of patients with intermediate-risk LPHL is less clear due to their small number in most clinical trials. We report the outcomes of these patients on AHOD0031 and present directions for future therapeutic strategies.Methods: Eligible patients had clinical stage I-IIA with bulk, I-IIAE, I-II B, IIIA-IVA with or without bulk. Patients initially received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC), followed by a response evaluation of rapid early (RER) versus slow early responder (SER) status. All SER patients were randomized to an additional two cycles of ABVE-PC +/- 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA). All SER patients received 21 Gy involved field radiotherapy (IFRT) following completion of chemotherapy. RER patients received 2 additional cycles of ABVE-PC. RER with complete responder (CR) status (RER/CR) patients were randomized to involved field radiotherapy (IFRT) or no further therapy. RER/non-CR patients were non-randomly assigned to IFRT.Results: Ninety-seven (5.7%) of the 1712 eligible patients on AHOD0031 had LPHL, with the remainder cHL. Compared to patients with cHL, patients with LPHL were younger (p=0.0001), more often male (p<0.0001), and less likely to have B symptoms (p=0.0006), bulk (p<0.0001) or stage IV disease (p<0.0001). Five-year event-free survival (EFS) was marginally superior in patients with LPHL (91.2%) compared with cHL (83.2%) (p = 0.08) (Figure 1), without difference in overall survival (OS) (p = 0.21). LPHL patients treated with chemotherapy alone (N = 33) had a 5-year EFS of 93.4% and OS of 100%. Stage and presence of bulk disease, RER or SER status and use of IFRT did not impact EFS or OS in LPHL patients. The proportion of patients who were RER was higher in LPHL compared with cHL (93.7% vs. 81.0%). Furthermore, LPHL patients were more likely to achieve a CR compared to cHL patients (68% vs. 45%; p=0.00003). There was only one reported subsequent malignant neoplasm among the LPHL patients, a non-Hodgkin lymphoma one year after treatment in a patient who received IFRT.Discussion: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes as demonstrated in this analysis. The majority of patients treated with the ABVE-PC backbone achieve RER/CR status and can be successfully treated without radiation therapy. Future therapeutic strategies should focus on further reduction in cytotoxic therapy for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Subsequent Malignant Neoplasms Among Children and Adolescents with Hodgkin Lymphoma Treated with Response-Adapted Therapy: A Report from the Children's Oncology Group Study AHOD0031

▪Background:Survivors of childhood Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMN). Response-adapted treatment for HL may decrease the SMN risk by reducing therapy in patients who have a good initial response to treatment. The Children's Oncology Group Study AHOD0031, which enrolled patients from 2002 - 2009, evaluated the role of early treatment response in directing therapy for children and adolescents with intermediate-risk Hodgkin lymphoma. We report the incidence and risk factors for SMN among 1,711 eligible patients enrolled on AHOD0031.Methods:Eligible patients had clinical stage I-IIA with bulk, I-IIAE, I-II B, IIIA-IVA with or without bulk. Patients initially received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC), followed by a response evaluation of rapid early (RER) versus slow early responder (SER) status. All SER patients were randomized to an additional two cycles of ABVE-PC +/- 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA). All SER patients received 21 Gy involved field radiotherapy (IFRT) following completion of chemotherapy. RER patients received 2 additional cycles of ABVE-PC. RER with complete responder (CR) status (RER/CR) patients were randomized to involved field radiotherapy (IFRT) or no further therapy. RER/non-CR patients were non-randomly assigned to IFRT. At a median follow-up of 6.2 years, an analysis of SMN was undertaken. The cumulative incidence of SMNs as a first event was calculated from the time of diagnosis adjusted for competing events due to relapse or death. Comparisons of the cumulative incidence among treatment groups were made using the K-sample test. A multivariable analysis using the Cox proportional hazard model assessed risk conferred by age, gender, race, disease stage, B symptoms, bulk disease, and IFRT.Results:Among 1,711 patients with a median follow up of 6.2 years, excluding non-melanoma skin cancer, 16 SMNs occurred, 13 as a first event. SMNs included seven hematologic malignancies and nine solid tumors. No subsequent breast cancer has been reported to date. Patients who experienced a SMN did not differ from those who did not with respect to age, gender, race, disease stage, B symptoms, or bulk disease. The median time to SMN as a first event was 4.1 years (range 1.1-9.5 years). The 5-year cumulative incidence of SMN as a first event was 0.53% (95% CI 0.16 to 0.90) (Figure 1A). A comparison of the cumulative incidence of SMN in patients who received IFRT and those who did not demonstrated an increased incidence of SMN in the IFRT group (p = 0.03) (Figure 1B). In fact, to date, all SMNs have occurred in patients who received IFRT. Therefore, a multivariate analysis was conducted among patients who received IFRT, which included age, gender, race, disease stage, B symptoms, and bulk disease. The presence of B symptoms was independently associated with increased risk for SMN with a hazard ratio of 15.24 (95% CI 1.73-134.04, p=0.01). Among the 13 patients with a SMN as first event, there were 4 deaths.Conclusions:With a median follow up of 6.2 years, the 5-year cumulative incidence of SMN in patients treated with response-adapted treatment on AHOD0031 is very low. It is likely that we have captured the cases of secondary leukemia related to etoposide exposure, as these generally occur within five years of treatment. Longer follow-up will be needed to assess the risk of solid tumors, which are generally known to have longer latencies without plateau in incidence over time. Evaluation of the location of secondary solid tumors relative to the IFRT fields is in progress. As AHOD0031 demonstrated no benefit in event-free or overall survival for RER/CR patients treated with IFRT, future intermediate risk patients treated according to this treatment strategy will be less likely to receive IFRT and can be expected to be at lower risk of SMN. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Patterns of Relapse From a Phase 3 Study of Response-Based Therapy for Intermediate-Risk Hodgkin Lymphoma (AHOD0031): A Report From the Children's Oncology Group

The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy field (in-field, out-of-field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. At 4-year median follow-up, 244 patients had experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. Although response-based therapy has helped define treatment for selected RER patients, it has not improved outcome for SER patients or facilitated refinement of IFRT volumes or doses.

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.

SWOG S0410/BMT CTN 0703: A Phase II Trial of Tandem Autologous Stem Cell Transplantation (AHCT) for Patients with Primary Progressive or Recurrent Hodgkin Lymphoma (HL) (ClinicalTrials.gov Identifier: NCT00233987)

Background: The SWOG 9011 trial of augmented conditioning regimens (12 Gy TBI or BCNU 15mg/kg with both etoposide 60 mg/kg and cyclophosphamide 100 mg/kg) prior to single AHCT for pts with relapsed or refractory HL demonstrated 5-yr PFS and OS of 41% and 54% respectively in 74 treated pts. Among 46 previously irradiated pts with 2-3 high risk features, the 5-yr OS was 38% compared with 60% for pts with 0-1 risk features. Post-AHCT relapse was the major cause of failure (Stiff et al. BBMT 2003; 9:529). The strategy of sequential high-dose (HD) chemotherapy + tandem AHCT for poor prognosis HL patients was investigated in a City of Hope (COH) & Loyola University (LU) pilot trial of tandem AHCT in 46 HL pts with primary progressive or relapsed HL with at least 1 poor-risk feature. Trial results were promising, with 5-yr OS, EFS and FFP of 54%, 49% and 55% respectively and 100-day TRM of 4% (Fung et al. BBMT 2007;13:594). The purpose of the SWOG led trial S0410 was to evaluate the COH/LU regimen in a phase II cooperative group setting, with the primary endpoint of 2-yr PFS.Methods: Pts with refractory/relapsed HL, eligible ages 15 -70, were enrolled after salvage therapy & stem cell collection (minimum 3.5 X 10.6 CD34/kg). Pts with relapse after prior CR received minimum of 2 cycles salvage chemotherapy or minimum of 25 Gy involved field radiation therapy (IFRT) to determine if they had sensitive or resistant HL. Pts with late relapse (> 12 months after 1st CR) responsive to salvage therapy were excluded. Pts with > 5cm bulk disease after salvage had to agree to 18 Gy IFRT pre-AHCT. A designed sample size of 85 pts over 2-yrs with 18 months follow-up was chosen to have 86% power by 0.025 one-sided alpha test to detect a 15% increase in 2-yr PFS as compared to the historical 2-yr PFS of 45% in S9011. After IFRT to bulk disease pre-AHCT, pts were treated with cycle 1 HD-Melphalan (150 mg/m2) + AHCT. If response after cycle 1 AHCT was SD or better, pts had 2nd AHCT with one of the two HD regimens used in SWOG 9011. Interval between day zero of 1st and 2nd AHCT had to be at least 28 days & not greater than 60 days.Results: 98 patients enrolled from 10 institutions including the BMT CTN. Six ineligible pts had inadequate PFTs (1), incomplete baseline testing (3) or failure to confirm pathology by central review (2). Median age was 34 yrs (range 18-60), 45% had refractory disease, 42% had B symptoms, and 24% had extranodal disease at transplant. Of the 92 eligible pts, 89 were treated, 82 completed both cycles of AHCT and 7 pts did not have 2nd AHCT (1 progressed, 1 declined TBI, 4 with > 60 days since 1st AHCT, 1 poor graft after C1.) Of 89 pts assessed for toxicities, 70 had grade 4 AEs, primarily hematologic and 14 of those pts had grade 4 non-hematologic AEs. Treatment-related mortality was 0%. With median follow-up of 5.4 yrs (range 2 -7.6 yrs), the 2-yr PFS was 63% (95% CI: 52%, 72%) and 2-yr OS was 91% (95% CI 83, 95%), as shown in figures 1 and 2 respectively. There were 15 deaths in eligible pts, 2 deaths in ineligible pts, and 3 deaths in inevaluable pts who did not receive protocol therapy. Of the 15 deaths in eligible and evaluable patients, there were 11 deaths due to progressive HL, 1 death due to non-treatment related respiratory failure, 1 death due to disseminated CMV infection and 2 deaths with primary cause not reported. Late malignancies were mylelodysplasia in 2 pts, thyroid cancer in 1 pt, and 2 pts with non-melanoma skin cancer.Conclusions: The 2-yr PFS of 63% in pts treated with tandem AHCT on S0410 met the predicted study endpoint of at least 15% improvement compared with the 2-yr PFS of 45% in the S9011 trial of augmented HCT conditioning prior to single AHCT. The better-than-expected OS of 91% in S0410 is attributed to the current treatment strategies for progressive or relapsed HL after AHCT, including brentuximab vedotin (BV) salvage and allogeneic HCT, which can lead to a significant percentage of long term survivors. Analysis of prognostic features will be conducted to ascertain if a model can be developed to identify a very high-risk group of HL pts who should be considered for early allogeneic HCT. Next steps will need to take into consideration results of the recently completed trial of BV consolidation after single AHCT; however, the S0410 results are very promising considering the patients had poor-risk relapsed and refractory HL.Support: CA32102, CA38926 [Display omitted] [Display omitted] DisclosuresFisher:Johnson & Johnson : Consultancy; MorphoSys AG: Consultancy.