Precision Medicine Challenges Deepen in DLBCL As Subtypes Emerge

Grzegorz S. Nowakowski, MD

Despite efforts to advance the precision oncology portfolio for patients with diffuse large B-cell lymphoma (DLBCL) by categorizing subtypes of the molecularly heterogenous disease, developing treatment routes for these alternate forms presents an uphill battle.

“Where the field is going is quite technologically challenging,” said Grzegorz S. Nowakowski, MD during a presentation at the 2nd Annual Precision Medicine Symposium, hosted by Physicians’ Education Resource®, LLC (PER®).¹

Specifically, “progressive technology and the identification of novel clusters based on much deeper molecular translocation, including next-generation sequencing [NGS] and secondary and tertiary genetic analysis of the tumor” represent key focuses of precision medicine efforts in DLBCL, said Nowakowski, director of the Aggressive Lymphoma Program and a consultant in the Division of Hematology in the Department of Internal Medicine at Mayo Clinic in Rochester, Minnesota. The discovery of clusters associated with distinct outcomes, as well as different driver mutations holds the potential to open the door to studying different drugs in this setting.

Since 2002, DLBCL has traditionally been divided into 2 cell of origin (COO) subtypes: activated B-cell (ABC) and germinal center B-cell (GCB).² The former is recognized as a comparatively more aggressive manifestation of DLBCL that is associated with poorer outcomes regardless of the regimen used to treat the disease.^2,3 Molecular variances between ABC-DLBCL and GCB-DLBCL, such as discrepancies in subcellular distribution and doxorubicin’s differing mechanism of action in each subtype, are credited for the disparities in therapeutic efficacy seen with ibrutinib (Imbruvica) and lenalidomide (Revlimid), with both agents demonstrating greater activity in ABC-DLBCL.³

Although these COO subtypes have classically guided the molecular characterization of DLBCL, the recent identification of 5 genetically distinct DLBCL clusters (C1-C5) by Chapuy et al suggests that there is further heterogenicity in this disease setting that can guide treatment decisions and targeted therapy development.^1,2,4 C1, a subtype of ABC-DLBCL, is classified as having a favorable-risk profile, with features of extrafollicular origin and alterations also seen in transformed marginal zone lymphomas. Whereas C5 ABC-DLBCL is an unfavorable-risk subtype marked by 18q/BCL2 copy gain and co-occurring CD79B and MYD88.⁴

Recent data have demonstrated that the C1 and C5 subtypes were responsive to the treatment regimen of rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone, and lenalidomide (R2CHOP), supporting the notion that selecting patients with C1 or C5 ABC-DLBCL could guide the use of R2CHOP in this molecularly specific population.^1,2 The C1 and C5 subtypes’ enrichment for SPEN mutations and MYD88 and PIM1 alterations, respectively, is thought to influence R2CHOP response.²

Molecular clusters are “promising” emerging markers of interest in DLBCL and Nowakowski anticipates that “the future will be cluster-based.” These clusters could be especially instrumental in elucidating effective frontline regimens with a chemotherapy backbone for patients with cluster-selected disease, but investigators must exercise caution when sequencing clusters, to ensure that NGS does not hamper expeditious patient enrollment in clinical trials, Nowakowski said.¹

Although COO classification has been “helpful” in the management of relapsed/refractory disease, distinguishing DLBCL into the ABC and GCB subtypes has not led to an improvement in the upfront setting, where R-CHOP has remained the standard of care for 18 years, Nowakowski said. Thus, therapeutic development in DLBCL can benefit from an increased focus on the paradigm-advancing potential of molecular clusters.

Addressing DHL/THL and DEL

Identifying patients with double hit/triple hit lymphoma (DHL/THL) or double expresser lymphoma (DEL), defined as rearrangement of MYC and BCL2 and/or BCL6 resulting in MYC overexpression,⁵ is another priority in both the precision oncology undertakings in DLBCL, as well as initiatives to improve frontline therapies in this space.¹ In 2016, the revised World Health Organization guidelines formally recognized DHL/THL as a “high-risk” form of B-cell lymphoma.⁵ DHL/THL, which affects 5% to 10% of DLBCL diagnoses and correlates with resistance to standard chemotherapy and suboptimal outcomes, signifies a DLBCL subtype that health care providers should “approach differently apart from just cell of origin,” Nowakowski said. “I like to emphasize that these are rearrangements, so they need to be identified by cytogenetic [modalities] such as FISH [fluorescence in situ hybridization].”

Although R-CHOP could potentially cure as much as 40% of patients with DHL/THL, “there’s no question that the outcomes are more inferior than other subtypes of diffuse large B-cell lymphoma,” Nowakowski added. At present, there is no standard of care for DHL/THL, but data from ongoing or planned randomized studies can be expected to shed light on the treatment strategies that could be of benefit in this patient population.

The phase 1 United States Intergroup trial (NCT03036904) for DH and DEL, organized with the intention of “capturing high-risk patients because those patients have the most to gain,” is one of them, Nowakowski said.¹ “Hopefully the ongoing and planned randomized studies will provide evidence on how to treat these patients,” he said.

DEL, is another form of DLBCL and is defined by the concomitant expression of MYC and BCL2 proteins. In contrast with DHL, which is commonly identified by FISH, immunohistochemistry is used to detect DEL.⁶ Importantly, both FISH and IHC are under investigation in the frontline DHL and DEL settings, respectively, as the value of these diagnostic measures in identifying these types of DLBCL is investigated in step with therapeutic interventions that could confer benefit.¹

Probing for molecular clusters, DHL/THL, and DEL constitutes a key focus in DLBCL in the era of precision medicine, according to Nowakowski, who concluded that these molecularly-focused endeavors are critical to constructing a future of DLBCL therapy as other promising strategies such as combination tafasitamab-cxix (Monjuvi) and lenalidomide; and ibrutinib, lenalidomide, and rituximab (iR2) are concurrently explored.¹

References

1. Nowakowski GS. How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment? Presented at: 2nd Annual Precision Medicine Symposium; September 25-26, 2020.
2. Hartert KT, Wenzl K, Krull JE, et al. Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL. Published online ahead of print March 5, 2020. Leukemia. 2020. doi:10.1038/s41375-020-0766-4
3. Xu-Monette ZY, Zhang H, Zhu F, et al. A refined cell-of-origin classifier with targeted NGS and artificial intelligence shows robust predictive value in DLBCL. Blood Adv. 2020;4(14):3391-3404. doi:10.1182/bloodadvances.2020001949
4. Chapuy B, Stewart C, Wood T, et al. Validation of the genetically-defined DLBCL subtypes and generation of a parsimonious probabilistic classifier. Blood. 2019;134(suppl 1):920. doi:10.1182/blood-2019-131250
5. Li W, Gupta SK, Han W, et al. Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors. J Hematol Oncol. 2019;12(1):73. doi:10.1186/s13045-019-0761-2
6. Kawashima I, Inamoto Y, Maeshima AM, et al. Double-expressor lymphoma is associated with poor outcomes after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;24(2):294-300. doi:10.1016/j.bbmt.2017.10.013