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

Abstract

Over the last few decades, advances in immunochemotherapy have led to dramatic improvement in the prognosis of non-Hodgkin's lymphoma (NHL). Despite these advances, relapsed and refractory disease represents a major treatment challenge. For both aggressive and indolent subtypes of NHL, there is no standard of care for salvage regimens, with prognosis after relapse remaining relatively poor. Nevertheless, there are multiple emerging classes of targeted therapies for relapsed/refractory disease, including monoclonal antibodies, antibody- drug conjugates, radioimmunotherapy, small-molecule inhibitors of cell-growth pathways, and novel chemotherapy agents. This review will discuss treatment challenges of NHL, current available salvage regimens for relapsed/refractory NHL, and the safety and efficacy of novel emerging therapies.

Keywords: non-Hodgkin’s lymphoma; novel therapies; relapsed/refractory disease.

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. 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.

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.