Recent advances in post autologous transplantation maintenance therapies in B-cell non-Hodgkin lymphomas

Table 1 Studies evaluating the role of antibody based maintenance therapy post autologous hematopoietic cell transplantation in diffuse large B cell lymphoma

Ref.	Study design	Maintenance schedule	n	% CS at HCT	PFS/EFS (%)	OS (%)	Comments
Lim et al[21]	Retrospective	Rituximab 375 mg/m2 (q 3 mo for a total of 8 doses)	15	100	-	80	Relapse free survival 100% (5.5 yr)
						(5.5 yr)
Zhang et al[22]	Single arm prospective	Rituximab 375 mg/m2 (q 3 mo for 2 yr)	12	100	83	100	Prolonged hypogammaglobinemia in 2 patients
					(3 yr)	(3 yr)
Tsirigotis et al[23]	Retrospective	Rituximab 375 mg/m2 (80% q wk and 20% q mo)	19	79	NR	NR	Compared to controls, maintenance improves PFS and OS
Haioun et al[24]	Randomized prospective	Rituximab 375 mg/m2 (weekly for 4 doses)	269	84.5	80 (R) vs 71 (O)	-	Patients underwent autoHCT upfront in first remission
			R = 139, O = 130		(4 yr)
Gisselbrecht et al[25]	Randomized prospective	Rituximab 375 mg/m2 (q 8 wk for 1 yr)	242	100	52 (R) vs 56 (O)	61 (R) vs 65 (O)	4 yr EFS was 52% for Rituximab arm while 53% for observation arm
			R = 122,		(4 yr)	(4 yr)
			O = 120
Armand et al[26]	Prospective phase II	Pidilizumab 1.5 mg/kg (q 42 d for 3 cycles)	66	91	72	85	ORR was 51% (CR of 34%) in pts with measurable disease after autoHCT
					(16 mo)	(16 mo)

CS: Chemo-sensitive; PFS: Progression free survival; OS: Overall survival; NR: Not reached; R: Rituximab arm; O: Observation arm; EFS: Event free survival; ORR: Overall response rate; CR: Complete remission; HCT: Hematopoietic cell transplantation.

Table 2 Studies evaluating the role of rituximab maintenance after autologous hematopoietic cell transplantation in mantle cell lymphoma

Ref.	Design	Maintenance	n	% CS at HCT	PFS/EFS (%)	OS (%)	Comments
Lim et al[46]	Retrospective	Rituximab 375 mg/m2 (q 3 mo for 2 yr starting day + 100)	8	100	57	67	Delayed immunoglobulin reconstitution was seen in all patients and persisted beyond the rituximab maintenance period
Graf et al[47]	Retrospective	Rituximab 375 mg/m2 (variable dosing schedule but median doses = 8)	157	Almost all the patients who received MR	HR of 0.33	HR of 0.40	In the landmark analysis at D 100 after auto-HCT 3 yr PFS and OS were statistically better in the MR compared to the no MR group
			R = 50, O = 107
Dietrich et al[48]	Retrospective	Rituximab 375 mg/m2 (every 3 mo for 2 yr)	72 R = 22, O = 50		90 (R) vs 65 (O)	90 (R) vs 84 (O)	Patients in both the arms were well matched. The median observation time was 56 mo
Gouill et al[49]	Prospective phase III	Rituximab 375 mg/m2 IV (every 2 mo for 3 yr)	238 R = 119, O = 119	81.4	93.2 (R) vs 81.5 (O) (2 yr)	93.4 (R) vs 93.9 (O) (2 yr)	All patients received 4 courses of R-DHAP followed by auto-HCT. The conditioning regimen of auto-HCT was R-BEAM (R=500 mg/m2)

CS: Chemo-sensitive; PFS: Progression free survival; EFS: Event free survival; OS: Overall survival; MR: Maintenance rituximab; HR: Hazard ratio; R: Rituximab arm; O: Observation arm; R-DHAP: Rituximab, dexamethasone, cytarabine and cisplatin; R-BEAM: Rituximab, carmustine, etoposide, cytarabine and melphalan; HCT: Hematopoietic cell transplantation.

Table 3 Future directions - drugs that are currently studied in relapsed/refractory aggressive and indolent B cell lymphomas that can potentially be studied in the post autologous hematopoietic cell transplantation setting

Drug	Mechanism of action	Ongoing trials in relapsed/refractory aggressive and indolent B cell lymphomas (not in post auto-HCT setting)
CD-19 antibodies (MEDI-551)	IgG1k antibody-dependent cellular cytotoxicity enhanced anti-CD19 mAb	Phase I (NCT00983619)
		Phase II (with ICE/DHAP NCT01453205)
		Phase II (with PD-1 inhibitor NCT02271945)
MPDL3280A	Targets PD-L1 expressed on tumor cells and tumor-infiltrating immune cells	Phase I (with Obinutuzumab NCT02220842)
Polatuzumab vedotin	Antibody-drug conjugate that targets CD 79b on the B cell receptor complex	Phase II (with Rituximab or Obinutuzumab and Bendamustine NCT02257567)
Obinutuzumab (GA101)	Fully humanized IgG1 mAb that selectivity binds to the extracellular domain of the human CD20 antigen on malignant human B cells	Phase Ib/II (with lenalidomide NCT01582776) Phase Ib/II (with lenalidomide NCT01995669)
Veltuzumab	A fully humanized mAb directed against the CD20 antigen.	Phase I/II (NCT01147393)
ABT-199	Oral selective small molecule inhibitor of the anti-apoptotic protein Bcl-2	Phase I (NCT02055820)
		Phase I (with BR NCT01594229)
		Phase II (with BR vs BR alone NCT02187861)
Alisertib	Oral selective small molecule inhibitor of the serine/threonine protein kinase Aurora A kinase	Phase  I (with Romidepsin NCT01897012)
		Phase I (with Vorinostat NCT01567709)
		Phase I (with Bortezomib and Rituximab NCT01695941) Phase II (with +/- Rituximab NCT01812005)
SAR245409	Oral small molecule targeting the PI3K and mTOR kinases.	Phase I/II (NCT01587040)
Belinostat	HDAC inhibitor	Phase I (with Carfilzomib NCT02142530)
		Phase II (with Ibritumomab Tiuxetan NCT01686165)

ICE: Ifosfamide, carboplatin and etoposide; DHAP: Dexamethasone, high dose cytarabine, cisplatin; PD-1: Programmed death-1; BR: Bendamustine, rituximab; mAb: Monoclonal antibody; PI3K: Phosphatidylinositol 3 kinase; mTOR: Mammalian target of rapamycin.