Treatment challenges in the management of relapsed or refractory non-Hodgkin’s lymphoma – novel and emerging therapies

Figures & data

Figure 1 Examples of salvage therapy regimens for refractory NHL.

Notes:¹Radiommunotherapy options include ¹³¹I-tositumomab and ⁹⁰Y-ibritumomab tiuxetan; ²therapy for systemic ALCL, excluding primary cutaneous ALCL. Treatment options, stratification, and abbreviations are based on NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.1.2013. Not all treatment options included in the NCCN Guidelines are shown above. Reproduced/Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.1.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.¹³¹

Abbreviations: CEOP, cyclophosphamide, etoposide, vincristine, prednisone; CEPP, cyclophosphamide, etoposide, prednisone, procarbazine; CFAR, cyclophosphamide, fludarabine, alemtuzumab, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; DA-EPOCH, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; DHAP, dexamethasone, cisplastine, cytarabine; DLBCL, diffuse large b-cell lymphoma; ESHAP, etoposide, methylprednisolone, cytarabine, cisplatin; FCR, fludarabine, cyclophosphamide, rituximab; FCMR, fludarabine, cyclophosphamide, mitoxantrone, rituximab; FL, follicular lymphoma; FMR, fludarabine, mitoxantrone, rituximab; GDP, gemcitabine, dexamethasone, cisplatin; GemOx, gemcitabine, oxaliplatin; HyperCVAD, fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; ICE, ifosphamide, carboplatin, etoposide; MCL, mantle cell lymphoma; OFAR, oxaliplatin, fludarabine, cytarabine, rituximab; PCR, pentostatin, cyclophosphamide, rituximab; PTCL, peripheral T-cell lymphoma; R, rituximab; RFND, rituximab, fludarabine, mitoxantrone, dexamethasone; SCT, stem cell transplant.

Figure 2 Emerging therapeutic options in relapsed/refractory NHL. Numerous novel classes of drugs are emerging as therapeutic options in relapsed or refractory NHL. These classes include monoclonal antibodies (both next-generation anti-CD20 and non-anti-CD20 antibodies), antibody–drug conjugates, antibodies conjugated to radioactive isotopes, small-molecule inhibitors of key cell-signaling and apoptotic pathways, HDAC inhibitors, and toxicity-reducing chemotherapies.

Abbreviations: abs, antibodies; Bcl-2, B-cell lymphoma 2; BTK, Bruton tyrosine kinase; HDAC, histone deacetylase; mTOR, mammalian target of rapamycin; NHL, non-Hodgkin’s lymphoma; Syk, spleen tyrosine kinase; PI3K, phosphoinositide 3-kinase.

Table 1 Emerging antibody therapies in non-Hodgkin’s lymphoma

Monoclonal Ab	Ab type	Phase	Patients	Disease	Regimen	Response	Ref	Current use
Anti-CD20 antibodies
Ocrelizumab	Humanized, IgG	I/II	47	R/RFL	Ocrelizumab	ORR 38%, PFS 11.4 mo	^Citation33	Phase III
Ofatumumab	Humanized, IgG	II	138	FA-ref, BF-ref CLL1	Ofatumumab	ORR: FA-ref 58%, BF-ref 47%	^Citation29	FDA-/EMA-approved for R/R CLL
		II	61	Untreated CLL	O-FC	ORR 75%, CR 41%	^Citation30
		II	116	Rituximab R/R FL	Ofatumumab	ORR 11%	^Citation31
		II	59	Untreated FL	O-CHOP
Veltuzumab	Humanized, IgG120	I/II	82	R/R NHL	Veltuzumab	ORR 41%, CR 21%	^Citation35	Early phase
Other antibodies
Blinatumomab	Anti-CD3/CDI9 Bispecific	I	62	R/R NHL	Blinatumomab	ORR 82%, all subtypes	^Citation53	Phase II
Epratuzumab	Humanized, IgG1	II	63	R/R NHL	E+R	ORR 47%, all subtypes, 64% = FL, DLBCL = 47%	^Citation38	Phase III
		II	107	Untreated DLBCL	ER-CHOP	ORR 96%, CR 74%, OS (3-yr) 80%	^Citation128
Galiximab	Chimerized, IgG1	I/II	35	R/R FL	Galiximab	ORR 11%, stable disease 34%	^Citation41	Phase III
		II	61	Untreated FL	Galiximab+R	ORR 72%, CR 48%	^Citation42
Mogamulizumab	Humanized, IgG1	II	27	CCR4+ATL	Mogamulizumab	ORR 50%	^Citation45	Phase II, approved in Japan for ATL
Antibody-drug conjugates
Brentuximab	Anti-CD30, chimeric	II	58	R/R CD30+ALCL	Brentuximab vedotin	ORR 86%, CR 57%	^Citation52	2 FDA-approved for R/R ALCL
Vedotin	MMAE-conjugated
Inotuzumab	Anti-CD22, humanized	I	79	R/R FL, DLBCL	Inotuzumab-Ozo	ORR: FL 68%, DLBCL 15%	^Citation46	Phase III
Ozogamicin	IgG4, calicheamicin-conjugated	I/II	61	R/R Fl, DLBCL	Inotuzumab-Ozo+R	ORR: FL 88%, DLBCL 71%	^Citation47
Radioimmunotherapy
^131I-tositumomab	anti-CD20 mouse IgG2a, ^131Iodine-conjugated	I/II2	250	R/R low grade,	^131I-tositumomab transformed NHL	ORR 47%–68%, CR 20%–38%	^Citation55	FDA-approved for R/RFL
		III	532	Untreated FL	R-CHOP vs CHOP + ^131I-tositumomab	2-yr PFS: RCHOP 76%, CHOP + ^131I-tositumomab 80%	^Citation59
^90Y-ibritumomab Tiutexan	anti-CD20 mouse IgG1, ^90Yttrium-conjugated	III	143	R/R FL (R-naïve)	^90Y-ibritumomab vs R	ORR: ^90Y-ibritumomab 80%, R = 56%	^Citation57	FDA-approved for untreated FL

Notes:

1 FA-ref, fludarabine/alemtuzumab-refractory; BF-ref, fludarabine-refractory with bulky lymphadenopathy (>5 cm);

2 integrated efficacy analysis of five clinical trials resulting in FDA approval of ¹³¹I-tositumomab; clinical trial data are presented for select antibody-based therapies.

Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; E, epratuzumab; O-FC, ofatumumab + fludarabine/cyclophosphamide; O-CHOP, ofatumumab + cyclophosphamide, doxorubicin, vincristine, prednisone; R, rituximab; MMAE, monomethyl auristatin E; R/R, relapsed/refractory; ORR, overall response rate; CR, complete remission; FL, follicular lymphoma; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin’s lymphoma; ALCL, anaplastic large cell lymphoma; DLBCL, diffuse large B-ceII lymphoma.

Figure 3 Targeting the PI3K and BTK pathways in NHL. The B-cell receptor-signaling pathway (purple) is initiated through phosphorylation of coreceptors that recruit spleen tyrosine kinase (SYK), which then phosphorylates downstream kinases, including PLCγ, leading to activation of Bruton tyrosine kinase (BTK). BTK then binds phosphatidylinositol (3,4,5)-triphosphate (PIP₃), which in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) into two second messengers – inositol triphosphate (IP3) and diacylglycerol (DAG) – that ultimately activate downstream proteins involved in B-cell signaling. In the PI3K pathway (orange), activation of receptor tyrosine kinases (RTKs) through adaptor proteins phosphorylate subunits of PI3K, leading to conversion of PIP₂ to PIP₃. Phosphorylation of the tumor suppressor PTEN terminates PI3K. Accumulation of PIP₃ leads to phosphorylation of AKT, which further activates downstream pathways, including mTOR (through the tuberous sclerosis complex 1/2 (TSC1/2)) and other essential pathways. Therapeutic inhibition of select pathway components that have been investigated in clinical trials for NHL are shown.

Abbreviations: 4EBP-1, 4E-binding protein 1; GSK3, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; MDM2, mouse double minute 2 homolog; P, phosphorylation site; PI3K, phosphoinositide 3-kinase; PLC, phospholipase C gamma; PTEN, phosphatase and tensin homolog; RHEB, Ras homolog enriched in brain; S6K, S6 kinase.

Table 2 Emerging non-antibody therapies in non-Hodgkin’s lymphoma

Agent	Drug class	Phase	Patients	Disease	Regimen	Response	Ref	Current use
Perifosine	AKT inhibitor	II	40	R/R DLBCL, FL, CLL WM, HL	Perifosine (+sorafenib if failed PR on perifosine)	PR in combination group 22%, stable disease 42%, PD36%	^Citation74	Phase III (non-NHL)
Pixantrone	Aza-anthracenedione	III	140	Relapsed NHL	Pixantrone vs single agent3	CR 20% vs 5.7%	^Citation113	EMA conditional approval (relapsed/refractory NHL) FDA-rejected
Navitoclax	Bcl-2 inhibitor	I	55	R/R NHL	Navitoclax	ORR 21%, PFS14.9mo	^Citation101	Early phase trials
		I	12	R/R NHL	Navitoclax+R	ORR 67%, CR 33%	^Citation102
Oblimersen	Bcl-2 inhibitor	II	43	R/R NHL	Oblimersen+R	ORR 42%, CR 23%	^Citation99	Phase III
		III	241	R/R CLL	F/C ± OBL	CR: OBL-FC 17%, FC 7% 5 year OS: no difference between groups	^Citation100
AVL-292	BTK inhibitor	Ib	18	R/R NHL	AVL-2929	Dose escalation ongoing	^Citation83	Phase I
Ibrutinib	BTK inhibitor	I	56	R/R CLL, MCL, FL, DLBCL, MZL	Ibrutinib	ORR: CLL 79%, MCL 75%, FL 23%, DLBCL 17%	77	Fast-track status by FDA
		Ib/II		Untreated CLL	Ibrutinib	ORR 74%, CR 10%, 15-mo PFS 96%	^Citation79
		Ib/II		R/R CLL	Ibrutinib+BR	ORR 93%, CR 13%, 11-mo PFS 90%	^Citation80
		Ib/II	27	R/R CLL	Ibrutinib+ofatumumab	ORR 100%, CR 4%	^Citation81
Vorinostat	HDAC inhibitor	II	35	R/R FL, MZL, MCL	Vorinostat	ORR: FL 47%, MZL 22%, MCL 0% CR: FL 15%, MZL 11%, MCL 0%	^Citation104	FDA-approved for CTCL
		I	29	R/R NHL	Vorinostat+RlCE	ORR 70%, CR 28%	^Citation105
Romidepsin	HDAC inhibitor	II	47	R/R PTCL	Romidepsin	ORR 38%, CR 18%	^Citation107	FDA-approved for CTCL and PTCL
		II	130	R/R PTCL	Romidepsin	ORR 25%, CR 15%	^Citation129
Lenalidomide	Immunomodulant	II	49	R/R NHL	Lenalidomide	ORR 35%, CR 12%	^Citation123	Phase llI
		II	217	R/R NHL	Lenalidomide	ORR: DLBCL 28%, MCL 42%, FL 42%	^Citation124
		I/II	52	R/R MCL	Lenalidomide+R	ORR 57%, CR 36%, median OS 24 mo	^Citation126
		II	23	R/R DLBCL	Lenalidomide+R	ORR 35%	^Citation125
Everolimus	mTOR inhibitor	II	77	R/R DLBCL, FL	Everolimus	ORR: DLBCL 30%, MCL 32%, FL 38%	^Citation89	FDA/EMEA approval for non-NHL cancers
Temsirolimus	mTOR inhibitor	II	89	R/R DLBCL, FL, CLL, WM	Temsirolimus	ORR: DLBCL 28%, FL 54%, CLL 11% PFS (mo): DLBCL 2.6, FL 12.7	^Citation88	EMEA-approved for MCL; FDA approval for non-NHL cancers
		III	161	R/R MCL	Temsirolimus hi/lo^2 vs investigator’s choice	PFS (mo): hi 4.8, lo 3.4, investigator’s choice 1.9	^Citation87
		II	22	R/R CLL	Everolimus	Partial response 18%	^Citation90
GS-1101 (CAL-101)	PI3K inhibitor	I	55	R/R indolent and aggressive NHL1	GS-1101	ORR: indolent and aggressive NHL 62%	^Citation68	Planned phase III
		I	51	R/R CLL	GS-1101+B and/or R	ORR: CAL-101+R 78%, +B 82%, +B^4R 87%	^Citation70
		I/II	21	R/R CLL	GS-1101+ofatumumab	ORR 80%, CR 10%, nodal response 85%	^Citation71
Bortezomib	Proteasome inhibitor	II	155	Prior treated MCL	Bortezomib	ORR 31%, CR 8%	^Citation119	FDA approval for MCL
		III	201	R-naïve/sensitive FL	Bortezomib+R vs R	ORR: bortezomib+R 59%; ^4R 37% PFS (mo): bortezomib+R 9.5; R 6.7	^Citation130
		III	676	R-naïve/sensitive FL	Bortezomib+R vs R	PFS (mo): bortezomib+R 12.8; ^4R 11	^Citation121
Fostamatinib	Syk inhibitor	I/II	91	R/R NHL	Fostamatinib	ORR 10%—55% based on subtype	^Citation92	Phase II

Notes:

1 Indolent NHL included FL, SLL, and MZL; aggressive NHL included MCL and DLBCL;

2 high-dose temsirolimus, 175 mg IV weekly × 3 cycles followed by 75 mg weekly; low-dose, 175 mg IV weekly × 3 cycles followed by 25 mg weekly;

3 single agents chosen based on investigator’s choice included vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, or gemcitabine; select clinical trials are reported for the above nonantibody-based therapies.

Abbreviations: B, bendamustine; CR, complete response; CTCL, cutaneous T-cell lymphoma; CTX, cyclophosphamide; EMA, European Medicines Agency; F/C, fludarabine/cyclophosphamide; HL, Hodgkin’s lymphoma; MM, multiple myeloma; Mo, months; OBL, oblimersen; PD, progressive disease; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma; PR, partial response; R/R, relapsed/refractory; R, rituximab; WM, Waldenstrom’s macroglobulinemia.

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