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M.J. Kersten et al.
Figure 1. Consort diagram. Number of patients in the full analysis set going through the protocol treatment including reasons for exclusion. BV: brentuximab vedotin; DHAP: dexamethasone, high-dose cytarabine, cisplatin; C: cycle; N: num- ber; CT: computed tomography; SC: stem cell; PD: progressive disease; VIM: ifosfamide, mitox- antrone, etoposide; PET: positron emission tomography; mCR: metabolic complete response; BEAM: carmustine, etoposide, cytarabine, mel- phalan; auto-PBSCT: autologous peripheral blood stem-cell transplant.
patient developed veno-occlusive disease (VOD) that was fatal. This patient already had elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) during BV-DHAP and very high levels of AST (2400 U/L), ALT (970 U/L), lactate dehydrogenase (LDH; 1,400 U/L), GGT (900 U/L) and direct bilirubin (660 mmol/L) during the VOD after BEAM/auto-PBSCT.
Peripheral neuropathy grade 1/2 was present before study entry in 11 patients (n=1 grade 2) but did not wors- en during BV-DHAP treatment. During BV-DHAP treat- ment, 15 (27%) and three (5%) patients developed novel onset grade 1 and 2 peripheral neuropathy, respectively, but all recovered. Of all patients, regardless of the pres- ence of peripheral neuropathy at baseline, 12 patients reported transient muscle weakness (grade 1/2) in the neu- rotoxicity questionnaire, of whom 11 recovered without sequelae. No grade 3/4 neuropathy has occurred (Online Supplementary Table S4).
In total, seven patients experienced ototoxicity (n=3 grade 1, n=4 grade 2) and switched from cisplatin to car- boplatin in cycle 2 or 3. Three patients recovered without sequelae, and three patients had continuing ototoxicity (hearing loss or tinnitus) 6 months after auto-PBSCT (1 patient unknown).
Serious AE (SAE) grade 3/4 following BV-DHAP treat- ment are described in Table 3. In total, 18 (33%) patients experienced one or more SAE during BV-DHAP. SAE that occurred in more than one patient were febrile neutrope- nia (n=9), infections (n=2), and renal function disorder (n=2). Most SAE recovered, except for the two renal func- tion disorders which recovered with sequelae (persisting grade 1 or 2 nephrotoxicity, e.g., decreased glomerular fil- tration rate or persisting high levels of creatinine). One additional nephrotoxicity grade 3 was not considered an SAE because of rapid recovery without hospitalization.
Survival
After a median follow-up of 27 months, the 2-year PFS by intention-to-treat for all 55 patients was 73.5% (95%CI: 62.6-86.4) (events=14/55) and the 2-year overall survival (OS) was 94.9% (95%CI: 89.5-00.0) (events=3/55) (Figure 2A and B).
Three patients died during the study period: one patient died of encephalitis (exact cause remained unknown despite a brain autopsy, the patient did not recover from
seizures; brain autopsy did not show cerebral localization of lymphoma or infection), and one patient died due to VOD. Both deaths occurred within four months after BEAM/auto-PBSCT. The third patient died of an unrelated head trauma, nine months after BEAM/auto-PBSCT while in mCR. One patient who withdrew consent after cycle 1 went off study and later died from PD; this patient was censored at the time of withdrawal of consent.
Patients with progression after treatment in this study received salvage treatment according to the treating physi- cian’s choice. Four patients received BV monotherapy, two of whom had a complete response, but all progressed again and needed a third salvage regimen.
Exploratory analysis of survival
For an exploratory analysis of PFS, six patients from phase I who were treated at the recommended dose level were added to the analysis, to a total of 61 patients.22
Patients with mPR after three cycles showed a signifi- cantly lower PFS compared to patients with mCR. Two- year PFS rates of patients with mPR (n=5) versus patients with mCR (n=48) were 40% (95%CI: 14-100) versus 87% (95%CI: 78-97): log-rank P=0.004, hazard ratio (HR) 6.02 (95%CI: 1.50-24.2; P=0.011), respectively (Figure 3A and Online Supplementary Table S5). A multivariable Cox analy- sis showed that patients with an mPR had a significantly increased risk of progression, independently of primary refractory status (Online Supplementary Table S5). Patients with relapsed disease (n=37) had a lower risk of progres- sion compared to patients with primary refractory disease (n=24), with 2-year PFS rates of 86% (95%CI: 75-98) versus 63% (95%CI: 46-85): log-rank P=0.036, HR 0.33 (95%CI: 0.11-0.98; P=0.046), respectively (Figure 3B and Online Supplementary Table S5). Univariable analysis did not show significant associations for other baseline risk factors (i.e., B symptoms, age, stage and first-line treat- ment regimen) (Online Supplementary Table S5).
Central pathology review
Based on morphology, immunophenotype, and molecu- lar clonality analysis if needed, central pathology review confirmed cHL (according to the World Health Organization classification 201624) in 59 of all 67 patients (88%) of the complete phase I (cHL confirmed in 10 of 12 patients in total) and phase II (cHL confirmed in 49 of 55 patients in total) part of the study. In all cases with equivo-
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