NcXHF

NEW TARGETED THERAPIES FOR iNHL
TABLE 5. Early-Phase Data for Selected Miscellaneous Investigational (Nonmarketed) Agents for iNHL Under
Preliminary Testing
Agent Molecular Target/Pathway Disease(s) Notable Outcomes Reference(s)
ABT-199 BCL-2 FL, MZL 73% RR in FL 81
CAR T cells Multiple, primarily CD19 CLL, FL CRs, PRs; very limited data 77–80
Panobinostat (with everolimus) HDAC FL, CLL 33% RR, high toxicity 71
Pidilizumab PD-1 FL 66% ORR, no grade 3 or higher toxicity 82
Polatuzumab vedotin ADC: CD79b (BCR) and mitotic function FL 67% ORR as single-agent 75
SAR3419 ADC: CD19 and mitotic function FL 29% ORR, 43% SD 74
TRU-016 (with bendamustine and rituximab) SMIP: CD37 FL, SLL 83% ORR 76
Abbreviations: FL, follicular lymphoma; MZL, marginal-zone lymphoma; RR, response rate; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; PR, partial response; HDAC, histone
deacetylase; ORR, overall response rate; ADC, antibody-drug conjugate; SD, stable disease; SMIP, monospecific protein therapeutic; SLL, small lymphocytic lymphoma.
40%. The discontinuation rate was 7%, with grade 1 to 2
neuropathy experienced by 16% of patients. There was no
grade 3 or higher neuropathy. Other grade 3 to 4 adverse
events included neutropenia (5%), fever (5%), and infection
(5%). 67 Bortezomib and rituximab represent a potentially
effıcacious therapy combination. Extrapolating from
the multiple myeloma literature, subcutaneous bortezomib
administration may reduce nonhematologic toxicity
without compromising effıcacy, a key consideration
for older patients.
Bortezomib has not yet been FDA-approved for iNHL, although
in WM bortezomib is a standard agent in both frontline
and relapsed settings; that topic has been reviewed
elsewhere. 60 The second-generation proteasome inhibitor
carfılzomib has been utilized as a neuropathy-sparing approach
in WM. A phase II study of 31 patients of median age
61 evaluated carfılzomib, rituximab, and dexamethasone,
which led to an 87% ORR. Grade 3 or higher toxicities included
hyperglycemia (23%), hyperlipasemia (16%), neutropenia
(10%), and cardiomyopathy (3%). There was no grade
3 or 4 neuropathy. 68 Carfılzomib may also have activity
against other histologies in the relapsed or refractory setting:
a phase I trial of carfılzomib included six patients with FL and
one patient with CLL/SLL; carfılzomib treatment resulted in
stable disease in four of the patients with FL and the patient
with CLL/SLL. 69
FUTURE DIRECTIONS: OTHER AGENTS
Additional classes of agents have shown promise in treating
iNHL, including histone deacetylase inhibitors, 70,71 hypomethylating
agents, 72,73 antibody-drug conjugates (ADCs), 74,75
monospecifıc protein therapeutics 76 ; chimeric antigen receptor
T cells directed against CD19, 77-80 BCL-2 inhibitors, 81 and programmed
cell death (PD)-1 T cell inhibitory receptor antibodies
82,83 (Table 5). Among these, histone deacetylase inhibitors,
ADCs, and PD-1 antagonists have potential for excellent tolerability
in older patients and might prove highly useful in earlyline
combination regimens or as later-line single agents for
patients with advanced age or extensive comorbidities. Hopefully,
further trials that emphasize older patients with the above
investigational therapies and recently approved agents will lead
to more data that can be used to address one of the largest unmet
needs in the treatment of indolent hematologic malignancies:
providing well-tolerated drugs across multiple lines of therapy
for older patients.
ACKNOWLEDGMENT
This work was supported by research funding from NIH
P01CA044991, K24CA184039, and Fred Hutchinson Cancer
Research Center–University of Washington Cancer Consortium
Cancer Center Support Grant of the National Institutes
of Health (P30 CA015704); philanthropic gifts from Frank
and Betty Vandermeer.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Maxwell M. Krem, BMS (I), Celgene (I). Honoraria: Ajay Gopal, Pfizer,
Seattle Genetics, Janssen Oncology, Millennium Takeda, Gilead Sciences. Consulting or Advisory Role: Ajay Gopal, Pfizer, Seattle Genetics, Janssen
Oncology, Millennium Takeda, Gilead Sciences. Speakers’ Bureau: Ajay Gopal, Seattle Genetics. Research Funding: Ajay Gopal, Merck, GSK, Bristol-Myers
Squibb, Gilead Sciences, Seattle Genetics, Teva, Piramal Life Science, Spectrum Pharmaceuticals, Pfizer, Abraxis BioScience, Janssen Oncology, Millennium
Takeda. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other
Relationships: None.
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