Genomics Help Customize Therapy in Non-Hodgkin Lymphoma

Thomas Habermann, MD

With the R-CHOP chemotherapy regimen considered the backbone of therapy for treatment-naïve patients with non-Hodgkin lymphoma, researchers are now delving further into the genome to pave the way for therapeutic improvements.

The goal of current and novel therapies should be to achieve event-free survival (EFS) in patients at 24 months, particularly in diffuse large B cell lymphoma (DLBCL). Patients who reach that endpoint have a subsequent overall survival equal to that of age- and gender-matched members of the general population.

To help reach that goal, science is moving forward to finding new driver mutations in these heterogeneous diseases, to understand the effects of the microenvironment and of individual patient characteristics on survival, and to identify drugs that can target these factors.

Supporting 24-Month EFS

Thomas Habermann, MD, professor of Medicine at the Mayo Clinic, presented a review of the evidence supporting these principles, during the 2016 International Congress on Hematologic Malignancies.The current standard of care for patients with DLBCL was established in a 2006 study, ECOG 4494,¹ which demonstrated the value of adding rituximab to CHOP (prednisone, cyclophosphamide, vincristine, and doxorubicin), and then using rituximab as a maintenance therapy, in patients with aggressive non-Hodgkin lymphoma, compared with the less effective strategy of CHOP plus observation.

In a 2014 study of patients with DLBCL treated with first-line chemoimmunotherapy,² EFS at 24 months was a predictor of survival rates akin to those in the general population, both in the United States and France. However, 21.7% of patients with this condition relapse before reaching that 2-year endpoint, another study showed. Among 107 patients in that study who underwent autologous stem cell transplant, 39 were alive at 2 years.

In a whole-exome analysis, certain acquired genomic alterations were associated with poor outcome after first-line chemoimmunotherapy in DLBCL.³ Specifically, 77% of patients who will fail to achieve EFS at 24 months can be identified in advance, based on a specific gene signature: a FOX01 mutation and gains in BCL6, CBL, and RELB.

Another gene, SLC22A16, a doxorubicin transporter, was lost in half of those who did not achieve 24 months of EFS, the researchers found. That’s important because doxorubicin, an anthracycline, is considered a vital part of the R-CHOP regimen for patients with this disease, Habermann said.

Seeking Better Treatments for DLBCL

Habermann and his colleagues have created a personalized way to help predict whether patients with these diseases will achieve 24-month EFS, through a nomogram looking at variables including age, performance status and the level of bulky disease. An electronic version of the nomogram is available online at http://www.qxmd.com.Recent clinical trials have generated data demonstrating that a variety of drugs hold promise as potential treatments for non-Hodgkin lymphomas.

The BTK-targeted drug ibrutinib (Imbruvica), a tyrosine kinase inhibitor indicated for the treatment of chronic lymphocytic leukemia and other blood cancers, has shown promise in DLBCL. In a trial that reported results in 2015,⁴ 37% of 80 participating patients with relapsed or refractory DLBCL categorized as activated B cell-like (ABC) experienced a complete or partial response, but only 5% of those with germinal center B cell-like (GCB) disease benefited, Habermann noted. Those with the highest likelihood of response had MYD88 mutations. Ibrutinib is now being tested in the disease in a phase III international trial.

When ibrutinib was combined with R-CHOP in an early trial,⁵ patients with CD20-positive B cell non-Hodgkin lymphoma achieved a 100% overall response rate, but most patients experienced side effects of grade 3 or greater, with neutropenia being the most common. A large phase III study, PHOENIX, launched in 2013 to compare R-CHOP with or without ibrutinib in patients with newly diagnosed non-GCB DLBCL.

R-CHOP is also being studied with the CD30-targeted antibody-drug conjugate brentuximab vedotin as a front-line therapy in patients with high-risk DLBCL.⁶ Results from the ongoing phase II study show a 12-month progression-free survival (PFS) rate of 82% in patients whose cancers are CD30-positive and a 56% PFS rate in those who are CD30-negative tumors.

The immunomodulatory agent lenalidomide affects multiple pathways that are important in B-cell malignancies, discouraging angiogenesis, modulating the tumor microenvironment, and acting directly against the tumor. According to one retrospective analysis,⁷ the drug, when combined with R-CHOP, can overcome the negative prognostic impact of non-GCB DLBCL that newly diagnosed patients in this subgroup face when given R-CHOP alone.

In a phase I trial,⁸ the mTOR inhibitor everolimus plus R-CHOP21 showed extremely promising results in 24 patients with treatment-naïve DLBCL. The patients demonstrated a 96% overall response rate, with 23 in functional complete response, and none have had a relapse of DLBCL, Habermann summarized.

Immunotherapy of Lymphoma

Habermann and his colleagues are testing the possibility of using a nanoparticle to deliver R-CHOP into patients. That trial will open this year.In the immunotherapy realm, patients with relapsed or refractory CD19-positive lymphomas have experienced sustained remissions after treatment with chimeric antigen receptor (CAR) T cells directed against CD19. About half of patients in a very small study responded, and the PFS rate at nearly a year was 43%.⁹ Adverse events included cytokine release syndrome in more than half of patients and neurologic toxicity in a minority of patients.

The PD-1 inhibitor nivolumab (Opvido) showed a mild benefit in DLBCL and follicular lymphoma (FL), but not in multiple myeloma.¹⁰ In a DLBCL group (n = 11) and a FL group (n = 10), one patient in each group had a complete response and three a partial response; PFS was 24 weeks in the DLBCL group and 68 weeks in the FL group.

Lifestyle Factors

PD-1 inhibitor pembrolizumab (Keytruda) showed a hint of efficacy in an early study¹¹ of patients with relapsed or refractory chronic lymphocytic leukemia with Richter transformation, which Habermann described as “very intriguing.”Based on evidence that vitamin D deficiency is associated with inferior event-free and overall survival, Habermann suggested that treating for this deficiency might someday be able to help patients with either recovery or prevention.

He added that data from the Iowa Women’s Health study shows that the consumption of fruits, vegetables, n-3 fatty acids and seafood reduces the risk of getting lymphoma, and intake of trans-fatty acids increases the risk.

Genomic Signature of DLBCL

Finally, among survivors of aggressive lymphoma, meeting exercise recommendations and increasing exercise levels were associated with a quality of life better than that of the general population of the United States.Further understanding the drivers of DLBCL is expected to help pave the way for additional effective therapies that can get patients to the 2-year mark without relapse, and that area is being investigated.

DLBCL may be marked by a loss of p53 and perturbed cell cycle deregulation,¹² which puts patients at higher risk of a poor outcome; however, this pattern is targetable, Habermann said.

Additional driver genes in DLBCL are MYC (up to 15% of patients) and BCL2, and whole-exome sequencing has found that patients with DLBCL may also have mutations in the following genes, among others: PBIM1, CD78B, MYD88, CARD-1, E2H2, MLL2, MLL3, MLL4, and PCL0. Involved pathways include JAK-STAT, B cell receptor signaling/NJkB, G13D, KRAS, BRAF, NOTCH1, SOCS1, and PTEN, Habermann summarized.

So far, Habermann said, researchers are not certain about the functionality of many of these glitches, so this knowledge is not yet actionable in DLBCL; however, studies hope to put these findings into action soon.

References

1. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP Versus CHOP Alone or With Maintenance Rituximab in Older Patients With Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2006;24(19):3121-3127.
2. Maurer MJ, Ghesquieres H. Jais JP, et al. EFS at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014;32(10):1066-1073.
3. Novak AJ, Asmann YW, Maurer MJ, et al. Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma. Blood Cancer J. 2015;5:3346.
4. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21(8):922-926.
5. Younes A, Flinn I, Berdega J, et al. Phase Ib study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-positive B-cell non-Hodgkin lymphoma (NHL). J Clin Oncol. 2013;31(suppl;abstract 8502).
6. Yasenchak CA, Halwani A, Advani R. Brentuximab Vedotin with RCHOP As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL): Results from an Ongoing Phase 2 Study. Reported at the Annual Meeting of the American Society of Hematology; December 5-8, 2015; Orlando, FL. Abstract 814.
7. Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J Clin Oncol. 2015;33(3):251-257.
8. Johnston PB, Laplant BR, McPhail ED, et al. Everolimus Plus RCHOP-21 Is Safe and Highly Effective for New Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of the Phase I Trial NCCTG1085 (Alliance). Presented at the Annual Meeting of the American Society of Hematology. December 5-8, 2015; Orlando, FL. Abstract 813.
9. Schuster SJ, Svoboda J, Dwivedy S, et al. Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas. Presented at the Annual Meeting of the American Society of Hematology. December 5-8, 2015; Orlando, FL. Abstract 183.
10. Lesokhin AM, Ansell SM, Armand P, et al. Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. Presented at the Annual Meeting of the American Society of Hematology; December 6-9, 2014; Abstract 291.
11. Ding W, Dong H, Call TG. PD-1 Blockade with Pembrolizumab (MK-3475) in Relapsed/Refractory CLL Including Richter Transformation: An Early Efficacy Report from a Phase 2 Trial (MC1485). Presented at the Annual Meeting of the American Society of Hematology. December 5-8, 2015; Orlando, FL. Abstract 834.
12. Monti S, Chapuy B, Takeyama K, et al. Integrative Analysis Reveals an Outcome-associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B-cell Lymphoma. Cancer Cell. 2012;22(3):359-372.

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