Young Adults Aged 18 to 30 Years with Hodgkin Lymphoma Can Tolerate a Modified Version of the Combined Modality German Paediatric HD95 Protocol with Minimal Neurotoxicity and Excellent Outcome. Results of the UK NCRN 18–30 Study (CRUK/08/012)
Authors: Ardeshna Kirit M , Hoskin Peter , Smith Paul , Chadwick Nicholas , Braganca Nivette , Wong Wai-Lup , Kayani Irfan , Sanghera Bal , Diez Patricia , Lucraft Helen , Jack Andrew , McNamara Christopher J , Mikhaeel George , Marshall Scott , Pettengell Ruth , Marcus Robert E. , Kruger Anton , Linch David C 
Published: October 2019

Abstract
Abstract 1621
The outcome for children with Hodgkin's Lymphoma treated using the German-Austrian paediatric risk-adapted combined modality regimen appears superior to that of adults treated with ABVD +/− radiotherapy. Whether this is related to the superiority of the therapy or a biological difference in the disease in the different age groups is unclear. As a preliminary step to try and compare these regimens directly we enrolled 47 patients between 18 and 30 years of age (median 23y range 18–30) recruited from 8 centres across the UK onto the 18–30 study which used a modified version of the HD95 protocol. Patients were allocated to one of three treatment groups according to stage TG1=1A, 1B, 2A (n=16), TG2=2AE, 2B, 3A (n=11) TG3=2BE, 3AE, 3BE, 3B, 4A, 4B (n=20). Patients in TG1 received 2 cycles of OEPA (vincristine 1.5mg/m2 iv d1,d8,d15 (capped at 2mg/dose), etoposide 125mg/m2 iv d1–5, adriamycin 40mg/m2 iv d1 & 15, prednisolone 60mg/m2 po d1–15). Patients in TG2 received 2xOEPA and 2 xCOPP (cyclophosphamide 500mg/m2 iv d1 and 8 vincristine 1.5mg/m2 iv d1,8 (capped 2mg/dose) procarbazine 100mg/m2 po d1–15, prednisolone 40mg/m2 po d1–15). Patients in TG3 received OEPAx2 and COPPx4. All patients (except those in TG1 who were in CR by CT and PET criteria) went on to receive involved site radiotherapy to all sites of previous disease. The dose of radiotherapy was 20Gy for patients in CR and VGPR (>75% reduction) by CT criteria with areas of residual abnormality on scan >50ml receiving a 30Gy boost. Patients with a PR (50–75% reduction) received the same doses if they were PET negative however those who were PET positive received 30Gy to all sites of previous disease. The schedule of vinca alkaloids in HD95 is compressed with those in TG3 receiving 16 doses of vincristine 1.5mg/m2 (max 2mg) given over 6 months compared with 16 doses of vinblastine 6mg/m2 given over 8 months in ABVD. In view of this and the increase in vinca alkaloid related neurotoxicity with age the primary endpoint of this study was to establish the level of neurotoxicity using this paediatric regimen in young adults. 45 patients (23 male) completed therapy. 1 patient was withdrawn after a hypersensitivity reaction to etoposide on d1 OEPA1 and 1 patient withdrew consent prior to starting therapy. Worst neurotoxicity grade was recorded as: 0 (n=8), 1 (n=17), 2 (n=16) 3 (n=4 [with 2 motor in TG1 &TG2, 1 sensory inTG2, 1 ileus inTG3). In 3 of the 4 patients with severe neurotoxicity vincristine was converted to vinblastine 6mg/m2 according to protocol. No progression of the neuropathy was seen and patients were able to complete their scheduled therapy. In one case (TG2) vincristine was omitted in the final cycle. Neurotoxicity grade at last FU was 0 (n=34) 1 (n=8) 2 (n=3). All 4 cases of grade 3 neurotoxicity reverted to grade 0. Seven patients with grade 2 neuropathy had adjustments made to the dose or type of vinca alkaloid at the request of the physician. Current grade of neuropathy at last FU in these 7 patients:0 (n=4) 1 (n=2) 2 (n=1). There were 8 episodes of febrile neutropenia. Other grade 3 toxicities included diarrhoea (n=2), vomiting (n=3), mucositis (n=3), abdominal pain (n=3) and thrombosis (n=2). Bone/joint pain was seen in 4 patients. Two patients (both TG3) have developed proven osteonecrosis. All 45 patients who completed the chemotherapy achieved a CR or PR. Four did not require radiotherapy, 36 required 20Gy and 5 required 30Gy as a baseline dose to previously involved sites. The median follow up to date is 18 months. Four patients have progressed (1=TG2, 3=TG3) giving a 2yr PFS of 89%. All patients are currently alive. Quality of life data has been collected and assessments of late effects are ongoing. In conclusion, young adults aged 18–30 can tolerate a modified HD95 protocol with a minority of patients experiencing grade 3 neurotoxicity which is reversible when adjustments are made. Outcome with this regimen (which contains only 160mg/m2of adriamycin and no bleomycin) seems encouraging and this (or a more up to date German Austrian Paediatric protocol e.g.with dacarbazine replacing procarbazine in an attempt to spare fertility and omission of radiotherapy based on PET scan after OEPA) warrants testing against ABVD in this age group.

Disclosures:
No relevant conflicts of interest to declare.