Effectiveness of brentuximab vedotin monotherapy in relapsed or refractory Hodgkin lymphoma: a systematic review and meta-analysis

Figures & data

Figure 1. PRISMA flowchart of search results. DEF: data extraction form; WoS: Web of Science.

Table 1. Characteristics of studies included in the systematic review on the effectiveness and safety of BV in R/R cHL patients (N = 32).

Study authors	Country	Year	Design	Study period	Data source	Sample size	Response assessment	Effectiveness and safety parameter(s)
Europe (n = 24)
Angelopoulou et al. [14]	Greece	2018	CS	June 2011–April 2015	Medical chart review	95	International Working Group Criteria (2007) – as reported by treating physicians	ORR, CR, OS, PFS
Bazarbachi et al. [15]	Multinational	2019	RC	2010–2014	Registry (disease)	80	International Working Group Criteria (2007) – assessed retrospectively	ORR, CR, OS
Brockelmann et al. [16]	Germany, United Kingdom	2017	CS	January 2008–June 2014	Medical chart review	136	NR	ORR, CR, OS, PFS, AEs
Chavda et al. [17]	Multinational	2019	CS	2012–2019	Registry (disease)	101	NR	ORR, CR, AEs
Czyz et al. [18]	Poland	2018	RC	2018^a	Medical chart review	57	PET scan – assessed retrospectively	ORR, CR, OS, PFS, AEs
Czyz et al. [19]	Poland	2019	RC	2012–2018	Medical chart review	44	CT or PET scan	ORR, OS, PFS
Gandolfi et al. [20]	Italy	2016	CS	2016^a	EMRs	43	International Working Group Criteria (2007) and Lugano Classification (2014) – assessed retrospectively	ORR, CR, OS, PFS
Garciaz et al. [21]	France	2014	CS	July 2009–November 2012	Medical chart review	24	International Working Group Criteria (2007) – assessed retrospectively	ORR, CR, OS, PFS, AEs
Gibb et al. [22]	United Kingdom	2013	CS	December 2010–August 2011	Medical chart review	18	International Working Group Criteria (2007) – as reported by treating physicians	ORR, CR
Goranova-Marinova et al. [23]	Bulgaria	2019	CS	2019^a	Medical chart review	64	NR	ORR, CR, PFS
Ionova et al. [24]	Russia	2019	CS	2019^a	Ad hoc data collection	55	RECIST Criteria v1.0 – as reported by treating physicians	ORR, CR, AEs
Jansson et al. [25]	Sweden	2018	CS	2011–2017	Medical chart review	39	NR	ORR, CR, OS, PFS
Král et al. [26]	Czech Republic, Slovakia	2019	CS	2012–2016	Registry (disease)	58	International Working Group Criteria (2007) – assessed retrospectively	ORR, CR, OS, PFS, AEs
Ladicka et al. [7]	Slovakia	2018	CS	July 2012–February 2017	Medical chart review	51	NR	NR
Monjanel et al. [27]	France	2014	CS	June 2009–October 2012	Medical chart review	32	International Working Group Criteria (2007) – assessed retrospectively	ORR, CR, PFS
Pellegrini et al. [28]	Italy	2017	CS	November 2012–July 2014	Medical chart review	234	International Working Group Criteria (2007) – assessed retrospectively	ORR, CR, OS, PFS, AEs
Perrot et al. [29]	France	2014	CS	2011–2014	Medical chart review	241	International Working Group Criteria (2007) – assessed retrospectively	ORR, CR, OS, PFS
Piddock et al. [30]	United Kingdom	2017	CS	2017^a	Medical chart review	24	International Working Group Criteria (2007) – as reported by treating physicians	ORR, CR
Pierdomenico et al. [31]	Portugal	2016	CS	September 2011–February 2016	Medical chart review	34	PET-CT scan – assessed retrospectively	ORR, CR, OS, PFS, AEs
Sarma et al. [32]	United Kingdom	2016	CS	2013–2015	Medical chart review	26	FDG-PET/CT scan – assessed retrospectively	ORR, CR
Tsirigotis et al. [33]	Greece	2018	RC	1995–2015	Registry (disease)	68	NA	OS
Viviani et al. [34]	Italy	2015	RC	January 2011–April 2014	Medical chart review	45	PET scan – assessed retrospectively	ORR, CR, OS, PFS, AEs
Zagadailov et al. [8]	Germany, United Kingdom	2018	RC	January 2008–June 2014	Medical chart review	196	NR	ORR, CR, PFS, AEs
Zinzani et al. [35]	Italy	2015	CS	2011–2014	Medical chart review	30	International Working Group Criteria (2007) – assessed retrospectively	ORR, CR, AEs
North America (n = 4)
Badar et al. [36]	United States	2020	RC	2005–2016	Medical chart review	98	PET scan – assessed retrospectively	ORR, CR, PFS
Houk et al. [37]	United States	2014	RC	2009–2014	Medical chart review	43	NA	PFS
Rajeeve et al. [38]	United States	2018	CS	2008–2015	Medical chart review	21	NR	ORR, CR
Svoboda et al. [39]	United States	2019	RC	2013–2018	Medical chart review	21	Lugano Classification (2014) – as reported by treating physicians	ORR, CR
Asia-Pacific (n = 2)
NCT02139592 [40]	Japan	NA	PC	April 2014–June 2017	Ad hoc data collection	182	PET scan – as reported by treating physicians	ORR, OS
Tien et al. [41]	Taiwan	2019	CS	May 2016–October 2018	Medical chart review	20	PET scan – assessed retrospectively	ORR, CR, OS, PFS, AEs
Central Asia (n = 1)
Jazyltayeva et al. [42]	Kazakhstan	2019	CS	2015–2018	Medical chart review	21	NR	ORR, CR, OS
Multi-regions (n = 1)
Karuturi et al. [43]	Multinational	2012	RC	1996–2009	Medical chart review	102	NA	OS

AEs: adverse events; CS: case series; CR: complete response; CT: computed tomography; EMRs: electronic medical records; FDG: fluorodeoxyglucose; NA: not applicable; NR: not reported; ORR: overall response rate; OS: overall survival; PC: prospective cohort; PET: positron emission tomography; PFS: progression-free survival; RC: retrospective cohort.

a Year of publication.

Table 2. Patient characteristics in studies included in the systematic review on the effectiveness and safety of BV in R/R cHL patients (N = 32).

Study reference	Age distribution	Comorbidities	ECOG PS	Prior SCT
Europe (n = 24)
Angelopoulou et al. [14]	Median: 33 years	NR	NR	ASCT: 70% (n = 67)
				Allo-SCT: 2.1% (n = 2)
Bazarbachi et al. [15]	Median: 30 years (19–59)	NR	NR	ASCT: 77.2% (n = 142)
Brockelmann et al. [16]	Mean: 66.7 ± 11.7 years	Mean Charlson Comorbidity Index: 2.3 ± 2.0	0: 2.2% (n = 3)	NR
			1: 35.3% (n = 48)
			2: 51.5% (n = 70)
			3: 8.8% (n = 12)
			4: 0.7% (n = 1)
Chavda et al. [17]	Median: 34 years (range, 19–65)	NR	NR	ASCT: 100%
Czyz et al. [18]	Median: 33 years (range, 18–68)	NR	NR	ASCT: 36.2% (n = 34)
Czyz et al. [19]	NR	NR	NR	ASCT: 100%
Gandolfi et al. [20]	Median: 33.4 years (range, 18.2–79.4)	NR	0: 60.5% (n = 26	ASCT: 60.5% (n = 26)
			1: 39.5% (n = 17)
Garciaz et al. [21]	Median: 35 years (range, 20–60)	NR	0–1: 95.8% (n = 23)	ASCT: 41.7% (n = 10)
				Allo-SCT: 16.7%
Gibb et al. [22]	NR	NR	NR	ASCT: 33% (n = 6)
Goranova-Marinova et al. [23]	Mean: 40.7 ± 13.1 years	NR	NR	ASCT: 70.3% (n = 45)
Ionova et al. [24]	Median: 28 years (range, 18–67)	NR	0–1: 82% (n = 45)	ASCT: 25.5% (n = 14)
Jansson et al. [25]	Median: 41 years (range, 17–78)	NR	NR	ASCT: 43.6% (n = 17)
				ASCT + allo-SCT: 7.7% (n = 3)
Král et al. [26]	Median: 30.5 years (range, 20.0–53.0)	NR	NR	ASCT: 91.4% (n = 53)
				1 ASCT: 79.3% (n = 46)
				2 ASCT: 12.1% (n = 7)
				Allo-SCT: 12.1% (n = 7)
Ladicka et al. [7]	Median: 38.8 years	NR	NR	NR
Monjanel et al. [27]	Median: 35 years (range, 20–69)	NR	NR	ASCT: 87.5% (n = 28)
				Allo-SCT: 15.6% (n = 5)
Pellegrini et al. [28]	Median: 35.4 years (range, 18.0–79.0)	NR	0: 60.5% (n = 26)	ASCT: 69.8% (n = 163)
			1: 39.5% (n = 17)
Perrot et al. [29]	Median: 34 years (range, 17–79)	Pre-existent peripheral neuropathy: 8% (n = 20)	0–1: 81% (n = 196)	At least 1 SCT: 61% (n = 147)
				2 SCT: 36% (n = 87)
				Allo-SCT: 16% (n = 39)
Piddock et al. [30]	Median: 40 years (range, 21–77)	NR	NR	ASCT: 27.3% (n = 9)
Pierdomenico et al. [31]	Median: 34.5 years (range, 23–69)	NR	NR	SCT: 64% (n = 22)
Sarma et al. [32]	Median: 36 years (range, 23–63)	NR	NR	ASCT: 11.5% (n = 3)
Tsirigotis et al. [33]	Median: 31 years (range, 19–68)	NR	NR	ASCT: 100%
Viviani et al. [34]	Median:	NR	NR	ASCT: 55.6% (n = 25)
	ASCT-ineligible: 38 years (range, 20–76)
	Failed ASCT: 39 years (range, 16–64)
Zagadailov et al. [8]	Mean: 45.7 ± 15.4 years	NR	>1: 75.5% (n = 148)	ASCT: 100%
Zinzani et al. [35]	Median: 27 years	NR	NR	0%
North America (n = 4)
Badar et al. [36]	Median at time of ASCT: 35 years (range, 19–73)	NR	NR	ASCT: 100%
Houk et al. [37]	Median: 34 years (range, 17–80)	NR	NR	ASCT: 72.1% (n = 31)
				Allo-SCT: 23.3% (n = 10)
Rajeeve et al. [38]	Median: 40 years (range, 21–66)	NR	NR	ASCT: 100%
Svoboda et al. [39]	Median: 31 years (range, 18–76)	NR	NR	0%
Asia-Pacific (n = 2)
NCT02139592 [40]	Mean: 56.7 ± 19.8 years	Hepatic disorder: 8.8% (n = 25)	0: 40.1% (n = 114)	ASCT: 15.1% (n = 43)
		Renal disorder: 7.0% (n = 20)	1: 36.6% (n = 104)	Allo-SCT: 3.2% (n = 9)
			2: 11.3% (n = 32)	ASCT + allo-SCT: 4.2% (n = 12)
			3: 6.7% (n = 19)
			4: 5.3% (n = 15)
Tien et al. [41]	Median: 28 years (range, 18–85)	NR	NR	ASCT: 60.0% (n = 12)
Central Asia (n = 1)
Jazyltayeva et al. [42]	Mean: 34.5 years (range, 20–69)	NR	NR	NR
Multi-regions (n = 1)
Karuturi et al. [43]	NR	NR	NR	ASCT: 100%

Allo-SCT: allogeneic stem cell transplant; ASCT: autologous stem cell transplant; ECOG PS: Eastern Cooperative Oncology Group Performance Status; NR: not reported; SCT: stem cell transplant.

Figure 2. Meta-analysis of overall response rates. (A) Forest plot of estimates of overall response rates after 4 cycles of treatment with BV (1st subgroup); (B) forest plot of estimates of overall response rates after 4–6 cycles of treatment with BV (2nd subgroup); (C) forest plot of estimates of overall response rates after 6 or more cycles of treatment with BV (3rd subgroup); (D) funnel plot of full-text publications reporting overall response rate estimates (n = 12 publications).

Figure 3. Meta-analysis of complete response rates. (A) Forest plot of estimates of complete response after 4 cycles of treatment with BV (1st subgroup); (B) forest plot of estimates of complete response after 4–6 cycles of treatment with BV (2nd subgroup); (C) forest plot of estimates of complete response after 6 or more cycles of treatment with BV (3rd subgroup); (D) funnel plot of full-text publications reporting complete response estimates (n = 12 publications).

Table 3. Pooled estimates of complete response.

Subgroups	Primary analysis (full-text publications of good methodological quality)
	Number of studies (R/R cHL patients treated with BV)	Pooled CR (95% CI)	Heterogeneity statistics
1st subgroup (CR after 4 cycles)	3 (n = 295)	32.9% (20.8–46.3)	I^2=64.8% (95% CI: 0–89.9)
			Cochran’s Q = 5.7; p=.05
2nd subgroup (CR after 4–6 cycles)	4 (n = 353)	32.4% (24.3–41.1)	I^2=49.3% (95% CI: 0–83.2)
			Cochran’s Q = 5.9; p=.12
3rd subgroup (CR after 6 or more cycles)	2 (n = 291)	33.4% (13.0–57.3)	I^2=92.9% (95% CI: 76.4–97.9)
			Cochran’s Q = 14.1; p=.0002

BV: brentuximab vedotin; CI: confidence interval; CR: complete response; R/R cHL: relapsed/refractory classical Hodgkin lymphoma.

Table 4. Sensitivity analysis of pooled estimates of complete response.

Subgroup	Sensitivity analysis 1 (original articles of good or moderate quality)			Sensitivity analysis 2 (original articles of good or moderate quality + conference proceedings)
	Number of studies (patients treated with BV)	Pooled CR (95% CI)	Heterogeneity statistics	Number of studies (patients treated with BV)	Pooled CR (95% CI)	Heterogeneity statistics
1st subgroup (CR after 4 cycles)	4 (n = 319)	35.5% (24.8–46.9)	I^2=59.0% (95% CI: 0–86.3)	5 (n = 542)	34.1% (27.7–40.8)	I^2=47.0% (95% CI: 0–80.6)
			Cochran’s Q = 7.3; p=.06			Cochran’s Q = 7.5; p=.11
2nd subgroup (CR after 4–6 cycles)	6 (n = 396)	32.9% (25.7–40.5)	I^2=43.2% (95% CI: 0–77.5)	13 (n = 831)	32.4% (26.6–38.5)	I^2=63.3% (95% CI: 33.4–79.8)
			Cochran’s Q = 8.8; p=.12			Cochran’s Q = 32.7; p=.001
3rd subgroup (CR after 6 or more cycles)	5 (n = 517)	34.3% (26.1–43.0)	I^2=73.1% (95% CI: 32.8–89.3)	NA	NA	NA
			Cochran’s Q = 14.9; p=.005

BV: brentuximab vedotin; CI: confidence interval; CR: complete response.

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