New Treatments Emerge for Non-Hodgkin’s Lymphoma

The non-Hodgkin’s lymphomas are a diverse and heterogeneous group of neoplasms most commonly originating in B lymphocytes (80%-85%), but also in T lymphocytes (15%-20%), and, rarely, in natural killer cells.

The non-Hodgkin’s lymphomas (NHLs) are a diverse and heterogeneous group of neoplasms most commonly originating in B lymphocytes (80%-85%), but also in T lymphocytes (15%-20%), and, rarely, in natural killer (NK) cells.¹Among cancers, the NHLs constitute the seventh leading site (4% of new cancer cases), with 3% cancer-related deaths.¹The different subtypes of NHL display variable responses to standard chemotherapies.²A number of novel therapies with differing mechanisms of action are under investigation for NHL, with the goal of developing therapeutic combinations.²Although it is unclear how best to use these agents as a treatment, the most effective approach will likely be based on a scientific rationale that targets a specific pathway or pathways; this contrasts with an older, less productive approach of simply adding new agents to existing ones.²

Anas Younes, MD

Anas Younes, MD

Ibrutinib and R-CHOP

Here is a summary, from the 55th American Society of Hematology meeting in December, 2013, of some of the experimental drugs now being investigated for the treatment of NHL.The combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been a standard of care for multiple B-cell malignancies, including NHL, but relapse or failure to respond occurs in a proportion of these patients.³For example, in patients with NHL and prior rituximab therapy, the rate of response to retreatment with rituximab was only 40%⁴; other studies show lower rates of 3-year progression-free (17% vs 57%) and overall (38% vs 67%) survival after salvage chemotherapy in patients with prior rituximab therapy versus those who were rituximab naïve.⁵The Bruton’s tyrosine kinase inhibitor ibrutinib has demonstrated activity as a single agent in B-cell malignancies with good tolerability.³

GS-9973

CC-122

IPI-145

Anas Younes, MD, Memorial Sloan Kettering Cancer Center in New York City, reported on the results of a phase Ib study that added ibrutinib to R-CHOP in patients with CD20-positive, previously untreated B-cell NHLs (follicular, mantle cell, and diffuse large B-cell [DLBCL] lymphomas).³The primary end point was determination of the recommended phase II dose (RP2D) of ibrutinib in combination with R-CHOP; secondary endpoints included safety and overall response rate (ORR). In part 1 of the study, standard doses of R-CHOP were combined with 280 mg/day, 420 mg/day, or 560 mg/day ibrutinib; part 2 of the study evaluated ibrutinib at the RP2D with standard R-CHOP doses in eligible patients with newly diagnosed DLBCL. Twenty-nine of 33 patients completed six cycles of therapy; a RP2D of 560 mg/day ibrutinib was established. For all evaluable patients, the ORR was 100%, with 73% complete responses (CRs) and 27% partial responses (PRs); for patients with DLBCL in part 2, respective CR and PR rates were 64% and 36%. All-grade adverse events (AEs) observed across parts 1 and 2 (25% or greater) included neutropenia, nausea, thrombocytopenia, and vomiting. Most common grade 3 or higher AEs included neutropenia (61%), thrombocytopenia (21%), and anemia (18%). This trial noted no new toxicities with the combination of ibrutinib with R-CHOP in treatment-na&iuml;ve patients with NHL. A randomized phase III trial of R-CHOP +/- ibrutinib is underway based on these results. Commenting on these data, Marcel van den Brink, MD, PhD, Memorial Sloan Kettering Cancer Center, noted that the &ldquo;response rates were actually higher than we would normally see with these first-line therapies,&rdquo; and that such an approach could constitute a &ldquo;new standard of care&rdquo; for untreated NHL.⁴Jeff P. Sharman, MD, Stanford University School of Medicine, and coworkers reported on the use of GS-9973, a small-molecule, selective inhibitor of the spleen tyrosine kinase (Syk) in CLL and NHL; Syk is believed to be an important mediator of the B-cell receptor cell signaling pathway in both normal and transformed B cells.⁶Included in this phase III trial were four cohorts of NHL patients with 40 subjects each. At the time of report, a total of 16 subjects with NHL had completed 4 weeks of treatment (800 mg GS-9973, twice a day) and were included in the safety analysis. Patients in the trial had received a median of five prior treatments. Investigator-assessed reduced tumor bulk was observed in all patients by the 8-week evaluation (data available for 22 of 54 patients overall, 9 patients with NHL); measurable lymph node disease was reduced by >50% in 4 subjects and <50% in 8 subjects. Results of the study showed GS-9973 to be generally well tolerated, with 30 of 34 patients (88%) experiencing an AE; grade 1 and 2 nausea, diarrhea, and fatigue were the most common treatment-emergent AEs. Reversible grade 3 or 4 transaminase elevations also occurred in 4 patients.⁶CC-122 is a new first-in-class pleiotropic pathway modulator, or PPM, that is also under investigation for patients with NHL; compounds of this class have multiple biologic effects, including anti-angiogenic, antiproliferative, and immunomodulatory activity.⁷Results of a dose-escalation study that included patients with NHL (n = 5), with multiple myeloma (n = 2), as well as with other solid tumors were reported at ASH 2013 by Drew W. Rasco, MD, and coworkers. Daily oral dosages of CC-122 from 0.5 mg/day to 3.5 mg/day were administered in 28-day, continuous-dose cycles. Promising activity in the NHL cohort was observed, with one partial and one complete response observed in 2 patients with DLBCL; another partial response was seen in a patient with mantle cell lymphoma. Fatigue and neutropenia were the principal drug-related AEs, but were uncommon as a cause of discontinuation; a 3-mg daily dosage is being investigated. Exposure-dependent, immunomodulatory pharmacodynamic effects of CC-122 were observed in this study, including decreases in peripheral B-cell count and enhanced T-cell activation.⁷Diffuse large B-cell lymphoma is the most common form of NHL, and heterogeneity in the response to therapy may be attributable, in part, to molecular differences in the tumor genome; phosphatidyl inositol 3 kinase (PI3K), including the delta and gamma isoforms, an essential signaling molecule involved in leukocyte proliferation, differentiation, and migration, as well as in B-cell receptor signaling, which is believed to play a role in DLBCL.⁸

Ajay Gopal, MD

Ajay Gopal, MD

Idelalisib

ABT-199

IPI-145 is a PI3K-delta, gamma inhibitor that has shown clinical activity in phase I trials of patients with hematologic malignancies. A preclinical study from Campbell and coworkers investigated the activity of IPI-145 in a series of DLBCL cell lines. These investigators found evidence for the role of an intact B-cell receptor signaling pathway in the sensitivity of cell lines to IPI-145, and efforts are under way to define specific biomarkers that identify patients with DLBCL who are sensitive to the drug. In addition, IPI-145 was investigated in combination with the Bruton&rsquo;s tyrosine kinase (BTK) inhibitor ibrutinib, and preliminary evidence was found for a combination effect of these drugs, such that targeted therapy with IPI-145 in specific patients with DLBCL could potentially be improved by adding ibrutinib.⁸Idelalisib is another PI3K inhibitor that is selective for the delta isoform, and has shown activity in phase I trials of recurrent indolent NHL (iNHL).⁹The results of a phase II trial of patients with double refractory (rituximab and alkylating agent) iNHL were reported by Ajay Gopal, MD, University of Washington, and coworkers. Enrolled patients (N = 125) with refractory iNHL and a median of four prior therapies were continuously treated twice a day with oral idelalisib at a dosage of 150 mg until progressive disease or no longer tolerated. Results of the study showed that 90% of patients experienced some reduction in tumor burden; the ORR was 57%, with 6% CR, 50% PR, and one minor response observed. Median duration of response was 12.5 months. Common AEs (grade 3 or higher) included diarrhea (13%), fatigue (2%), nausea (2%), pyrexia (2%), dyspnea (3%), rash (2%), and pneumonia (7%), and 20% of patients discontinued because of AEs. In addition, 13% of patients had grade 3 or higher transaminase elevations. Taken together, the results of this trial demonstrated idelalisib to be well tolerated and active in this population of double-refractory iNHL patients, a finding that constitutes a significant unmet need.⁹Curative treatment options are currently not available for mantle cell lymphoma (MCL).¹⁰Dysregulation of Bcl-2, an anti-apoptosis protein, may mediate resistance to chemotherapies, and this is a characteristic feature of NHLs.¹⁰Matthew S. Davids, MD (Dana-Farber Cancer Institute, Boston, MA) and coworkers presented results from a phase I, dose-escalation study examining the use of ABT-199, an orally administered, small-molecule inhibitor of Bcl-2 for patients with NHL (N = 32), including 8 patients (25%) with MCL. Continuous, once-daily monotherapy with ABT-199 was examined at dosages from 200 mg to 900 mg; AEs, pharmacokinetics, and disease responses were assessed.¹⁰A total of 22 patients discontinued therapy, mostly due to progressive disease (n = 18). Anemia, neutropenia, and thrombocytopenia were the principle grade 3/4 AEs. A T_maxand T^1/2of approximately 8 and 15 hours, respectively, was observed following a single dose with food, and bioavailability was increased 3- to 4-fold with food. Anti-tumor activity of ABT-199 was also observed in this study, particularly among patients with MCL, in whom the ORR was 100% (8/8, all PR); in the overall population, the ORR was 53%, with 2 CR and 15 PR. The dose escalation for this study is ongoing in order to define maximum tolerated dose and RP2D; efforts will also continue to evaluate biomarkers associated with response for the different NHL subtypes examined.¹⁰

References

1. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Non-Hodgkin&rsquo;s lymphomas. Version I. 2014.
2. Mahadevan D, Fisher RI. Novel therapeutics for aggressive non-Hodgkin&rsquo;s lymphoma.J Clin Oncol. 2011;29(14):1876-1884.
3. Younes A, Flinn I, Berdeja J, et al. Combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP): Updated results from a phase Ib study in treatment-na&iuml;ve patients with CD20-positive B-cell non-Hodgkin&rsquo;s lymphoma (NHL). 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 852.
4. Davis TA, Grillo-L&oacute;pez AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin&rsquo;s lymphoma: safety and efficacy of re-treatment.J Clin Oncol. 2000; 18(17):3135-43.
5. Mart&iacute;n A, Conde E, Arnan M, et al; Grupo Espa&ntilde;ol de Linfomas/Trasplante Aut&oacute;logo de M&eacute;dula Osea (GEL/TAMO Cooperative Group). R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study.Haematologica. 2008 Dec;93(12):1829-36.
6. Sharman JP, Klein L, Boxer M, et al. Phase II trial of GS-9973, a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 1634.
7. Rasco DW, Gandhi AK, James A, et al. A first in human dose escalation study of CC-122, a first-in-class pleiotropic pathway modulator&trade; (PPM) compound in subjects with relapsed or refractory solid tumors, multiple myeloma and non-Hodgkin&rsquo;s lymphoma. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 2905.
8. Campbell V, Thompson R, Villegas V, et al. The potent PI3K-&delta;,&gamma; inhibitor IPI-145 exhibits differential activity in diffuse large B-cell lymphoma (DLBCL) cell Lines. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 1832.
9. Gopal A, Kahl BS, De Vos S, et al. Mature response data from a phase II study of PI3K-delta inhibitor idelalisib in patients with double -refractory (rituximab and alkylating agent) indolent B-cell non-Hodgkin lymphoma (iNHL). 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 85.
10. Davids MS, Seymour JF, Gerecitano JF, et al. The Single-Agent Bcl-2 Inhibitor ABT-199 (GDC-0199) In Patients With Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL): Responses Observed In All Mantle Cell Lymphoma (MCL) Patients. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 1789.