A systematic literature review of the epidemiology, quality of life, and economic burden, including disease pathways and treatment patterns of relapsed/refractory classical Hodgkin lymphoma

Figures & data

Figure 1. Proportion of patients* with CHL progressing after treatment in studies with >500 patients.1L, first-line of treatment; 2L/2L+, second-line and/or later line of treatment; 3L, third-line of treatment; classical Hodgkin lymphoma; HL, Hodgkin lymphoma. *Where ranges were reported, the highest value is shown. cHL patients (Farruggia 2019; Myers, 2018); HL patients (Mehta 2012; Josting 2005; Martinez 2017; Sureda 2013).

Table 1. Summary of treatment use in HL/cHL studies with >250 patients.

Reference	Country	Patients (n)	Median age (range), years	Diagnosis	Population	Prior line of systemic therapy, n (%)	Prior use of brentuximab vedotin, n (%)	Prior use of ASCR, n (%)
Dulery 2016	France	1987	34 (18–65)	HL	Relapsed after 2L+	NR	NR	494 (24.9%)
Martinez 2017	Europe	709	32 (18–68)	HL	Relapsed after 2L+	NR	NR	518 (73.2%)
Ramsey 2016	USA, Europe	329	33 (18–76)	cHL	R/R after 1L	1: 90 (54.5%) ≥2: 74.5 (45.5%)	NR	329 (100%)
Chen 2017	USA	795	43 (NR)	cHL	R/R	NR	NR	795% (100%)
Szabo 2017a	USA	990	NR	HL	R/R after 2L+	3: 337 (34%)	67* (20%)	554 (56%)
Szabo 2017b	USA	289	NR	HL	R/R after 2L+	1: 47 (16.2%) 2: 115 (39.7%) 3: 99 (34.2%) 4: 22 (7.6%) 5: 6 (2.0%)	NR	92 (31.8%)
Collins 2018	Europe	509	44 (2–89)	HL	R/R after 2L+	2: 373 (73.3%) 3: 88 (17.3%) 4: 29 (5.7%)	Total: 123 (24.2%) 2L: 36 (9.5%) 3L: 53 (49.1%) 4L: 22 (51.2%)	Total: 226 (44.4%) 2L: 191 (37.5%) 3L: 22 (16.2%) 4L: 5 (10.4%)
Bröckelmann 2018	Germany	352	57 (NR)	cHL	Relapsed after 2L+	NR	105 (30%)	148 (42%)
Byrne 2017	Germany	351**	54 (NR)	cHL	R/R after 2L+	NR	286 (30%)**	197 (59%)**

Abbreviations: 2L+: second line and/or later line of treatment; 3L: third line of treatment; 4L: fourth line of treatment; ASCR: autologous stem cell transplantation; cHL: classical Hodgkin lymphoma; HL: Hodgkin lymphoma; NR: not reported; R/R, Relapsed/Refractory.

*Based on 337 patients.

**Study was based on 959 patients from four countries, percentages are based on overall population as per original publication statistics.

Table 2. Summary of QoL data in HL/cHL studies with >75 patients.

Reference	Region/Country	Population/Median age (range), years	Patients (n)	Study design	Median (range) Follow up	Questionnaire(s)	QoL results
Ruffer 2003	Austria, Germany, Switzerland	Relapsed HL 31^* (15–72)	94	Survey	5.2 years	EORTC QLQ-C30 MFI	Relapse was significantly associated with the occurrence of fatigue in patients with HL
Goodman 2008	USA	R/R HL 25 (5–47)	218	Retrospective observational	11.5 (3–18) years	EORTC QLQ-C30	HDT with ASCR was associated with reduced social and cognitive functioning and worsening of some symptoms
Magagnoli 2010	Italy	R/R HL 31 (NR)	81	Retrospective observational	NR	Psychosocial dysfunction	19% of patients reported psychosocial dysfunctions and >70% of patients had high fear of recurrence after ASCR
Minn 2012	USA	R/R HL 26 (10–63)	154	Retrospective observational	10.2 (2–20) years	EORTC QLQ-C30	ASCR was associated with reduced functioning and worsening of some symptoms
Ramsey 2016	Europe, USA	R/R cHL 32.5 (18–76)	329	Randomized (brentuximab vedotin versus placebo)	NR^**	EQ-5D	Brentuximab vedotin was associated with decreased QoL, but no significant difference versus placebo
Younes 2016	Canada, Europe, USA	R/R cHL 37 (28–48)	80	Single-arm (nivolumab)	8.9 (7.8–9.9) months	EORTC QLQ-C30 EQ-5D	Nivolumab was associated with improved QoL and symptoms
von Tresckow 2019	Australia, Canada, France, Germany, Greece, Hungary, Israel, Italy, Japan, Norway, Russia, Spain, Sweden, UK, USA	R/R cHL 35 (18–76)	206	Single-arm (pembrolizumab)	8.3 (0.03–14.99) months	EORTC QLQ-C30 EQ-5D	Pembrolizumab was associated with improvements in most functional and symptom scores
Lepik 2019	NR	R/R cHL 31 (19–62)	101	Retrospective observational	25 (3–31) months	SF-36 EQ-5D	Nivolumab was associated with QoL improvement and decreased symptom burden in responders and nonresponders
Kreissl 2019	Germany	Relapsed HL 36^* (18–60)	97	Survey	106 months	Patient-reported survey	40% of relapse-free and over 60% of relapsed patients reported fears of late effects and relapse. Most physical, psychological, and socio-economic sequelae were significantly more frequent among relapsed than relapse-free patients
Shi 2019	China	R/R cHL 33 (28–43)	96	Single arm (sintilimab)	10.5 (9.2–11.1) months	EORTC QLQ-C30 EQ-5D	Sintilimab was associated with improved QoL, with greater improvement in responders than nonresponders

Abbreviations: ASCR: autologous stem cell transplantation; cHL: classical Hodgkin lymphoma; EORTC-QLQ C30: European Organization for Research and Treatment-Quality of Life Questionnaire; EQ-5D: EuroQol-5 dimension; HDT: high-dose chemotherapy; HL: Hodgkin lymphoma; MFI: Multidimensional Fatigue Inventory; NR: not reported; QoL: quality of life; R/R: relapsed/refractory; SF-36: 36-Item Short Form Survey. ^*Median age reported for the overall cohort (not specific to relapsed/refractory population). ^**During follow-up until 24 months.

Table 3. Summary of results from cost-effectiveness studies in patients with HL/cHL.

Reference	Country	Population	Intervention	Comparator	Cost-effectiveness results
Large 2018	USA	R/R cHL	Pembrolizumab	Brentuximab vedotin	Pembrolizumab is a cost-effective alternative to brentuximab vedotin
Hui 2017	USA	HL	Brentuximab vedotin (consolidation)	Brentuximab vedotin (active surveillance)	Brentuximab vedotin (consolidation) at current US pricing is unlikely to be cost-effective
Parker 2017	Scotland	R/R cHL	Brentuximab vedotin	Chemotherapy + radiotherapy	Base case ICER is relatively low compared with other orphan drugs, and lower than the ICER generated that informed positive recommendation from the Scottish Medicine Consortium
		R/R cHL	Brentuximab vedotin	Chemotherapy + radiotherapy with intent to alloSCT	Chemotherapy + radiotherapy with intent to alloSCT was dominated by brentuximab vedotin
Babashov 2017	Canada	R/R HL	Brentuximab vedotin	BSC	Brentuximab vedotin had an ICER exceeding $100,000 per QALY gained, which is a level often classified as having ‘weak evidence for adoption and appropriate utilization’ in Canada
Tan 2017	Australia	R/R cHL	Nivolumab	SoC	Nivolumab represents a cost-effective alternative to current SoC, with the potential to improve QoL and survival for patients treated for R/R cHL after the failure of ASCR and brentuximab vedotin in Australia
Jones 2017	UK	R/R cHL	Nivolumab	SoC	Nivolumab is estimated to offer significant benefit in terms of improved survival and QoL while offering a cost-effective alternative to SoC, addressing a significant unmet need in people with R/R cHL
Patidar 2017	USA	R/R HL	Brentuximab vedotin	SoC	The brentuximab vedotin cost-effectiveness findings appear to be in line with or more favorable than many other newly approved anti-cancer therapies. At a willingness-to-pay of $100,000/QALY, brentuximab vedotin was found to be cost-effective, more than 50% of the time
Romero Prada 2016	Colombia	R/R HL	Brentuximab vedotin	Palliative care	Brentuximab vedotin is cost-effective compared to palliative care
Khachatryan 2016	Russia	R/R HL	Brentuximab vedotin	Chemotherapy +/– radiotherapy	Brentuximab vedotin is an appropriate alternative as ICER per life-year is lower than chemotherapy +/– radiotherapy + alloSCT versus chemotherapy +/– radiotherapy. Also, ICER is lower than for other oncologic drugs included in Russian essential drug list
		R/R HL	Brentuximab vedotin	Chemotherapy +/– radiotherapy + alloSCT
Ringkvist 2017	Sweden	HL	Brentuximab vedotin (consolidation)	BSC	Consolidation treatment with brentuximab vedotin following an ASCR is cost-effective for patients diagnosed with HL when compared to BSC in the Swedish health care setting

Abbreviations: alloSCT, allogenic stem cell transplantation; ASCR: autologous stem cell transplantation; BSC: best supportive care; cHL: classical Hodgkin lymphoma; HL: Hodgkin lymphoma; ICER: incremental cost-effectiveness ratio; QALY: quality-adjusted life year; QoL: quality of life; R/R: relapsed/refractory; SoC: standard of care; US: United States.

Table 4. Real-world treatment patterns reported in HL/cHL studies with >200 patients.

Reference	Region/Country	Population/Median age (range), years	Patients (n)	Patients in different line-of-therapies in real-world settings
				2L	3L	4L
Badar 2020	USA	R/R cHL 32 (19–72)	215	2L+ Anthracycline based: 31/133 (23%) Gemcitabine based: 53/145 (37%) Brentuximab vedotin: 98/157 (62%) PD-1 inhibitors: 39/215 (18%)	–	–
Laliberté 2019	USA	R/R cHL 59.0 (NR) 53.0 (NR)	317	2L+ Pembrolizumab: 92/317 (29%) Nivolumab: 225/317 (71%)	–	–
Shao 2019	USA	R/R HL 47.0 (NR)	219	2L+ Brentuximab vedotin: 28/219 (13%) Gemcitabine + vinorelbine +/– PeD: 23/219 (11%) Bendamustine: 15/219 (7%) Gemcitabine: 10/219 (5%) Fludarabine: 4/219 (2%)	–	–
Gajra 2019	USA	R/R cHL 18–80 (NR)	338	2L PD-1 inhibitors: 169/338 (50%) 2L+ Nivolumab: 247/338 (73%) Pembrolizumab: 91/338 (27%)	3L PD-1 inhibitors: 105/338 (31%)	–
Feliciano 2018	USA	R/R cHL 51.3 (NR)	293	2L Brentuximab vedotin +/– bendamustine: 101/293 (35%) ICE, DHAP, ESHAP, or gemcitabine: 97/293 (33%) Re-challenge with previous 1L agents: 57/293 (19%) PD-1 inhibitors: 32/293 (11%) Systemic therapy + radiotherapy: 20/293(7%)	3L Brentuximab vedotin: 84/293 (29%) PD-1 inhibitors: 98/293 (33%)	–
Szabo 2017a	USA	R/R HL 42.5 (NR)	990	2L ASCR: 554/990 (56%) Rituximab: 178/990 (18%) ICE: 129/990 (13%)	3L Brentuximab vedotin: 67/337 (20%) Rituximab: 37/337 (11%)	4L Bendamustine: 28/189 (15%)
Szabo 2017b	USA	R/R cHL 40.0 (NR)	289	2L Brentuximab vedotin: 115/289 (40%)	3L Brentuximab vedotin: 99/289 (34%)	4L Brentuximab vedotin: 22/289 (8%)
Gerrie 2014	Canada	R/R HL 28.5 (16–59)	256	2L MVPP: 69/256 (27%) COP/COPP: 51/256 (20%) GDP: 83/256 (32%) Cyclophosphamide: 17/256 (7%) Radiotherapy + chemotherapy: 34/256 (13%)	–	–
Collins 2018	Europe	R/R HL 44 (2–89)	383	2L after ABVD Chemotherapy: 170/383 (44%) Chemotherapy + stem cell transplant: 111/383 (29%) Stem cell transplant: 35/383 (9%) 2L+ after ABVD DHAP: 104/383 (27%) IGEV: 44/383 (11%) BEACOPP: 21/383 (5%) Brentuximab vedotin: 17/383 (4%) ICE: 12/383 (3%)	3L after ABVD Brentuximab vedotin: 41/383 (11%) DHAP: 3/383 (1%) IGEV: 9/383 (2%)	–
Bröckelmann 2018	Germany	R/R cHL 57 (NR)	352	2L DHAP + BEAM: 18% ICE + BEAM: 14% DHAP: 10%	3L Brentuximab vedotin based: 30% BEAM: 13% DHAP: 9% Bendamustine: 7%	4L Brentuximab vedotin: 23% PD-1 inhibitors: 22% Bendamustine: 13% Gemcitabine based: 12%
Byrne 2017	France	R/R cHL 54.0 (NR)	243*	–	3L Brentuximab vedotin: 35%*	4L Brentuximab vedotin: 38%*
Byrne 2017	Germany	R/R cHL 54.0 (NR)	351*	–	3L Brentuximab vedotin: 30%*	4L Brentuximab vedotin: 23%*
Byrne 2017	UK	R/R cHL 54.0 (NR)	237*	–	3L Brentuximab vedotin: 44%*	4L Brentuximab vedotin: 36%*

Abbreviations: 1L: first line of treatment; 2L/2L+: second line and/or later line of treatment; 3L: third line of treatment; 4L: fourth line of treatment; ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine; ASCR: autologous stem cell rescue; BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone escalated; BEAM: carmustine, etoposide, cytarabine, melphalan: cHL, classical Hodgkin lymphoma; COP: cyclophosphamide, vincristine, prednisone; COPP: cyclophosphamide, vincristine, procarbazine, prednisone; DHAP: dexamethasone, cisplatin, high-dose cytarabine; ESHAP: etoposide, methylprednisolone, high-dose cytarabine, cisplatin; GDP: gemcitabine, dexamethasone, cisplatin; HL: Hodgkin lymphoma; ICE: ifosfamide, carboplatin, etoposide; IGEV: Ifosfamide, gemcitabine, and vinorelbine; MVPP: mechlorethamine, vincristine, procarbazine, prednisone; NR: not reported; PD-1: programmed cell death protein-1; PeD: pegylated doxorubicin; R/R: relapsed/refractory.

*Study was based on 959 patients from four countries, percentages are based on overall population as per original publication statistics.

Data availability statement

Data can be obtained via a written request to the corresponding author.