Salvage Therapy for Hodgkin’s Lymphoma: A Review of Current Regimens and Outcomes

Figures & data

Table 1 Prognostic Factors Identified in the Pre-PET Era

Author	N	Prognostic Factors	End Points
Lohri,^Citation73 1991	71	B symptoms Relapse < 12 m Stage IV dg	5-y FF2F	0= 82% >0= 17%
Reece,^Citation74 1994	58	B symptoms Relapse < 12 m Extranodal disease	3-y PFS	0= 97% 1= 87% 2= 47% 3=1%
Brice,^Citation75 1997	214	Extra-nodal disease Relapse < 12 m	4-y PFS	0= 93% 1= 59% 2= 43%
Horning,^Citation76 1997	119	B symptoms Stage IV (lung/BM) > minimal pre-HDC disease	4-y FFP	0= 85% 1= 57% 2= 41% >3= <20%
Josting,^Citation77 2001	422	Hb levels (< 10, < 12) Stage III–IV Relapse < 12 m	4-y FF2F	0= 100% 1= 70% 2= 55% 3= 50%
Moskowitz,^Citation5 2001	65	B symptoms Extranodal disease Relapse < 12 m/refractory	EFS at 43 months	0–1= 83% 2= 27% 3= 10%

Abbreviations: FF2F, freedom from second failure; PFS, progression-free survival; FFP, freedom from progression; EFS, event-free survival.

Table 2 Studies Evaluating PET Predictive Significance in HL

Author	N	Study	PET+		PET-
			OS	PFS	OS	PFS
Spaepen,^Citation78 2003	60	R	40%	23%	95%	100%
Jabbour,^Citation79 2007	211	R	58%	23%	87%	69%
Schot,^Citation47 2007	23	P	/	37–40%	/	73%
Filmont,^Citation48 2007	60	P	43%	25%	80%	81%
Moskowitz,^Citation49 2010	153	P	/	31%	/	75%

Notes: In Speapen, survival was reported at 2 y. In Jabbour, survival was reported at 3 y. In Schot, survival was reported at 2 y as failure-free survival. In Filmont, the median follow-up was 1510 days. In Moskowitz, survival was reported at 2 y as event-free survival.

Abbreviations: R, retrospective; P, prospective.

Table 3 Clinical Results Obtained in Patients Refractory to First-Line CT

Author	N	Disease at HDC	OS	PFS	TRM	Stem cells
Andre,^Citation80 1999	86	CT S 62%	35% @ 5 y CR= 60% PD= 20%	25% @ 5 y	8%	BM
Sweetenham,^Citation81 1999	175	NS	36% @ 5 y	32% @ 5 y	14%	BM
Josting,^Citation82 2000	206	CT S 43%	43% @ 5 y 0= 55% 3= 0%	31% @ 5 y	10%	BM + PBSC
Constans,^Citation83 2003	62	NS	26% @ 5 y	15% @ 5 y	14%	BM + PBSC
Czyz,^Citation84 2004	76	NS	33% @ 5 y	NS	9%	BM + PBSC

Notes: In Josting et al risk factors were: PS <90%, age >50 y, and chemosensitive disease (CT S) to first-line CT.

Abbreviations: NS, not stated; BM, bone marrow; PBSC, peripheral blood stem cell.

Table 4 Platinum-Based Salvage CT Reported in the Literature

	Author	Regimen	N	Refractory	CT/PET Evaluation	ORR	CR	OS	PFS
Platinum-based	Rodriguez,^Citation81999	ASHAP	56	12%	CT+Gallium	70%	34%	41% @ 4 y	36% @ 4 y
	Aparicio,^Citation85 1999	ESHAP	22	22%	CT	68%	41%	/	/
	Moskowitz,^Citation5 2001	ICE	65	34%	CT	88%	26%	83% @ 43 m	68% @ 43 m
	Josting,^Citation7 2002	DHAP	102	16%	CT	89%	21%	/	/
	Baetz,^Citation6 2003	GDP	23	9%	CT	69%	17%	/	/
	Josting,^Citation1 2010	DHAP	279	/	CT	70%	24%	80% @ 3 y	62% @ 3 y
	Labrador,^Citation14 2014	ESHAP	82	50%	CT	67%	50%	74% @ 5 y	56 months

Note: OS and PFS are reported for patients receiving HDC.

Abbreviations: CT, CT scan; m, months; ASHAP, adriamycin, cytarabine, cisplatin, methylprednisolone; ESHAP, etoposide, cytarabine, cisplatin, methylprednisolone; ICE, ifosfamide, carboplatin, etoposide; DHAP, dexamethasone, cytarabine, cisplatin; GDP, gemcitabine, dexamethasone, cisplatin.

Table 6 Salvage CT Without Gemcitabine and Platine-Derived Compounds

Author	Regimen	N	Refractory	CT/PET Evaluation	ORR	CR	OS	PFS
Fermé,^Citation86 1995	MINE	100	41%	CT	73%	34%	71% @ 4 y	60% @ 4 y
Proctor,^Citation87 2003	IVE	51	/	CT	84%	61%	/	/

Abbreviations: MINE, mitoguazone, ifosfamide, vinorelbine, etoposide; IVE, ifosfamide, etoposide, epirubicin.

Table 5 Gemcitabine-Based Salvage CT

	Author	Regimen	N	Refractory	CT/PET Evaluation	ORR	CR	OS	PFS
Gemcitabine-based	Bartlett,^Citation9 2007	GVD	91	/	CT	70%	19%	70% @ 4 y	52% @ 4 y
	Santoro,^Citation10 2007	IGEV	91	39%	CT	81%	53%	/	/
	Santoro,^Citation11 2016	BeGEV	59	46%	PET	83%	73%	77% @ 2 y	62% @ 2 y
	Santoro,^Citation12 2020	BeGEV	59	46%	PET	83%	73%	78% @ 5 y	59% @ 5 y
	Cohen,^Citation13 2020	GB	22	/	PET	69%	46%	/	/

Note: In Bartlett et al, 51 patients were transplant naïve.

Abbreviations: IGEV, Ifosfamide, gemcitabine, vinorelbine; GVD, gemcitabine, vinorelbine, pegylated liposomal doxorubicin; BeGEV, Bendamustine, gemcitabine, vinorelbine; GB, gemcitabine, bendamustine.

Table 7 Salvage CT Associating CT and BV and Salvage Therapy with BV Alone

	Author	N	Refr	Rel After HDC	CT/PET Evaluation	ORR	CR	ORR Refr	CR Refr	OS	PFS
BV alone	Younes,^Citation16 2012 §Chen^Citation17 2015	102	/	100%	PET	75%	34%	/	/	/	/
	Rothe,^Citation88 2012	45	64%	87%	PET	60%	22%	/	/	/	/
	Zinzani,^Citation89 2013	65	69%	92%	PET	70%	21%	/	/	/	/
	Gibb,^Citation90 2013	18	71%	33%	PET	72%	17%	/	/	/	/
	Chen,^Citation17 2015	37	65%	/	PET	68%	35%	67%	/	/	/
	¤Moskowitz,^Citation18 2015	47	56%	/	PET	76%	76%	/	/	95% @ 2 y	80% @ 2 y
	^Perrot,^Citation91 2016	240	56%	59%	CT or PET (78%)	64%	33%	58%	/	/	57% @ 2 y
	Eyre,^Citation32 2018	99	/	/	CT or PET	53%	29%	/	/	70% @ 2 y	68% @ 2 y
BV-Benda	LaCasce,^Citation19 2018	55	50%	/	PET	92%	73%	85%	64%	67% @ 3 y	60% @ 3 y
	O’Connor,^Citation20 2018	65	/	63%	PET	71%	32%	/	/	/	/
	Kalac,^Citation21 2018	10	100%	/	PET	100%	90%	/	/	/	/
	Picardi,^Citation22 2019	20	55%	25%	PET	100%	100%	/	/	/	/
	Broccoli,^Citation23 2019	40	50%	/	PET	80%	75%	75%	65%	88% @ 2 y	67% @ 2 y
	Iannitto,^Citation24 2020	47	51%	25%	PET	79%	49%	/	/	72% @ 2 y	60% @ 2 y
BV-CT	Michallet,^Citation28 2015 GVD	11	45%	/	PET	100%	73%	/	/	60% @ 1 y	/
	Abuelgasim,^Citation25 2019 IGEV	28	43%	/	PET	96%	71%	/	/	87% @2 y	73% @ 2 y
	Garcia-Sanz,^Citation27 2019 ESHAP	66	40%	/	PET	91%	70%	/	37%	91% @ 2.5 y	71% @ 2.5 y
	Hagenbeek,^Citation26 2019 DHAP	12	/	/	PET	92%	92%	/	/	/	/
O-CT	Martinez,^Citation15 2016 ESHAP	62	32%	/	PET	73%	44%	50%	/	88% @ 2 y	46% @ 2 y

Notes: ^§Long-term follow-up of Younes 2012. ^15% of the patients received allogeneic stem cell transplantation. ¤In this study, after BV alone, the CR rate was 27%. Seventy-three percent of non-responding patients received CT, and 73% obtained CR. Overall, after BV and CT, 76% obtained PET negativity.

Abbreviations: O, ofatumumab; Rel, relapse; Refr, refractory; CT, chemotherapy; IGEV, Ifosfamide, gemcitabine, vinorelbine; GVD, gemcitabine, vinorelbine, pegylated liposomal doxorubicin; DHAP, dexamethasone, cytarabine, cisplatin; ESHAP, etoposide, cytarabine, cisplatin, methylprednisolone.

Table 8 Results from Clinical Trials Using CPIs in R/R HL

	N	Study	CPI	ORR	CR Rate
Ansell,^Citation34 2014	23	P	Nivo	87%	17%
*Younes,^Citation35 2016	80	P	Nivo	66%	9%
Beköz,^Citation39 2017	82	R	Nivo	64%	21%
Armand,^Citation36 2018	243	P	Nivo	69%	16%
Chen,^Citation42 2019	210	P	Pembro	69%	22%
Manson,^Citation38 2109	78	R	Nivo	65%	38%
Bair,^Citation37 2019	53	R	Nivo	68%	45%
Shi,^Citation43 2019	96	P	Sintilimab	80%

Notes: *In this study, there was an important difference in terms of ORR and CR rate between investigators and independent reviewers (66% vs 78% and 9% vs 28%, respectively).

Abbreviations: P, prospective; R, retrospective.

Table 9 Clinical Results After Allo-SCT from MRD and MUD

Author	N	CTX	MRD/MUD	Disease Status CR/PR	Grade 2–4 aGVHD	cGVHD Overall	OS	PFS	Relapse Rate	NRM
Robinson^Citation72 2002	52	RIC	NR	67%	27%	16%	56% @ 2 yr	42% @ 2 yr	45% @ 2 yr	17% @ 2 yr
Peggs^Citation92 2005	49	RIC	63%/37%	67%	16%	14%	55% @ 4 yr	39% @ 4 yr	33% @ 4 yr	15% @ 2 yr
Alvarez^Citation93 2006	40	RIC	93%/5%	50%	45%	45%	48% @ 2 yr	32% @ 2 yr	NR	25% @ 1 yr
Corradini^Citation94 2007	32	RIC	NR	62%	35%	49%	32% @ 3 yr	NR	81% @ 3 yr	3% @ 3 yr
Anderlini^Citation95 2008	58	RIC	43%/57%	52%	28%	73%	48% @ 2 yr	20% @ 2 yr	61% @ 2 yr	15% @ 2 yr
Devetten^Citation96 2009	143	RIC	MUD 100%	44%	60%	66%	37% @ 2 yr	20% @ 2 yr	47% @ 2 yr	33% @ 2 yr
Robinson^Citation97 2009	285	RIC	63%/37%	59%	30%	42%	25% @ 4 yr	29% @ 4 yr	53% @ 4 yr	19% @ 1 yr
Sureda^Citation98 2012	92	RIC	70%/30%	67%	32%	44%	43% @ 4 yr	24% @ 4 yr	59% @ 4 yr	15% @ 1 yr
Kanate^Citation99 2016	236	RIC-ATG	MUD 100%	81%	49%	37%	50% @ 3 yr	38%@ 3 yr	36% @ 3 yr	26% @ 2 yr
Ghosh^Citation100 2016	807	RIC	MRD 100%	86%	25%	52%	62% @ 3 yr	48%@ 3 yr	40% @ 3 yr	13% @ 2 yr
Anderlini^Citation101 2016	40	RIC	52%/48%	92%	26%	36%	75% @ 3 yr	54% @ 3 yr	28% @ 3 yr	17% @ 3 yr
Martinez^Citation102 2017	338	RIC	MRD 100%	78%	18%	25%	71% @ 2 yr	38% @ 2 yr	49% @ 2 yr	13% @ 1 yr
Martinez^Citation102 2017	273	RIC	MUD 100%	84%	30%	41%	62% @ 2 yr	45% @ 2 yr	32% @ 2 yr	21% @ 1 yr
Gauthier^Citation103 2018	90	RIC	MRD 100%	86%	22%	37%	82% @ 2 yr	NR	15% @ 2 yr	12% @ 2 yr

Abbreviations: NR, not reported; CTX, conditioning regimens; RIC, reduced intensity conditioning; ATG, anti-thymocyte globulin.

Table 10 Clinical Results After Allo-SCT from Haploidentical Donors

Author	N	CTX	Disease Status CR/PR	Grade 2–4 aGVHD	cGVHD Overall	OS	PFS	Relapse Rate	NRM
Burroughs^Citation104 2008	28	NMAC	75%	43%	35%	58% @ 2 yr	51%@2 yr	40% @ 2 y	9% @2 yr
Raiola^Citation105 2014	26	NMAC	92%	24%	9%	77% @ 4 yr	63% @ 4 yr	31% @ 4 y	4% @ 3 yr
Kanate^Citation99 2016	199	NMAC	93%	27%	13%	68% @ 3 yr	42% @ 3 yr	36% @ 3 y	11% @ 1 yr
Gayoso^Citation106 2016	43	RIC	32%/NR	39%	19%	58% @ 2 yr	48% @ 2 yr	24% @ 2 y	21% @ 2 yr
Martinez^Citation102 2017	98	RIC/NMAC	85%	33%	26%	67% @ 2 yr	43% @ 2 yr	39% @ 2 yr	17% @ 1 yr
Castagna^Citation107 2017	62	RIC/NMAC	55%/32%	24%	16%	63% @ 3 yr	59% @ 3 yr	21% @ 3 y	20% @ 1 yr
Gauthier^Citation108 2017	34	RIC/NMAC	44%/38%	28%	15%	75% @ 3 yr	66% @ 3 yr	25% @ 3 y	9% @ 1 yr
Gauthier^Citation103 2018	61	RIC/NMAC	70%	29%	15%	81% @ 3 yr	NR	15%	12% @ 1 yr
Marani^Citation109 2018	41	RIC	47%	20%	11%	75% @ 3 yr	43% @ 3 yr	55% @ 3 yr	7% @ 3 yr

Abbreviations: NR, not reported; CTX, conditioning regimens; RIC, reduced intensity conditioning; ATG, anti-thymocyte globulin; NMAC, nonmyeloablative conditioning regimen.

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