The Hematologist

September-October 2017, Volume 14, Issue 5

Primary Central Nervous System and Testicular Lymphoma: From Genes to Action in One Year

Caron A. Jacobson, MD Instructor in Medicine
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Published on: August 14, 2017

Chapuy B, Roemer MG, Stewart C, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127:869-881.

Nayak L, Iwamoto FM, LaCasce A PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 2017;129:3071-3073.

Advances in genomic technology have allowed for the more rapid identification of recurrent genetic alterations in tumors, many of which are targetable with existing therapies. As such, the time from discovery of pathologic events to delivering clinical benefit to patients is shortening. Recent advances in the understanding and treatment of primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular lymphoma (PTL) exemplify this remarkable advancement in moving from the laboratory to the bedside at break-neck speed.

PCNSL and relapsed PTL in the brain are associated with relatively high rates of chemotherapy resistance, with up to 33 percent of PCNSL not responding to chemotherapy and up to 50 percent relapsing within two years of their initial therapy. Additional therapies are needed to treat these relapsed and refractory patients. In February 2016, Dr. Bjoern Chapuy and colleagues reported the results of their comprehensive characterization of the genetic features of PCNSL and PTL. They analyzed copy number alterations by single nucleotide polymorphism arrays, transcript abundance by Affymetrix arrays, single nucleotide variants by whole-exome sequencing, and chromosomal rearrangements by DNAseq using a custom bait set in PCNSL, PTL, and primary mediastinal B cell lymphoma, and compared these findings to those observed in a previously analyzed diffuse large B cell lymphoma (DLBCL) cohort. Their analysis revealed genetic similarities between PCNSL and PTL that were distinct from DLBCL. These tumors demonstrated increased genomic instability with recurrent copy number gains in 3q12.3, 18q21.33, and 19q13.42, and copy number loss in 6p21.33, 6q21, and 9p21.3.

Among the candidate driver genes identified to be associated with these chromosomal gains and losses are NFKBIZ on chromosome 3q12.3 and CDKN2A on chromosome 9p21.3. Amplification of 9p24.1, containing the genes for PDL1 and PDL2, was also identified as a recurrent alteration in PTL as well as in the extension cohort of Epstein Barr Virus (EBV) –negative PCNSL. EBV-positive PCNSL was associated with increased expression of PDL1 and/or PDL2 in the absence of any copy number alterations. Inhibition of PD1, then, may be a promising therapy in these patients. Additionally, unique chromosomal rearrangements involving PDL2 were identified in several of these tumors, as well as recurrent rearrangements involving activation of BCL6 and inactivation of ETV6. In both the discovery cohorts and extension cohorts of PCNSL and PTL, mutations in Toll-like receptor (TLR) signaling component genes MYD88 and CD79B occurred at high frequency (>80%), with all CD79B mutations occurring in the context of a coincident MYD88 mutation. Similarly, a vast majority of EBV negative PCNSL and PTL tumors had an activating mutation in MYD88, and/or copy number gain of chromosome 3q12.3 with amplification of NFKBIZ, whose product IĸB-ζ is downstream of TLR activation. This near-uniform activation of TLR signaling suggests that therapies that inhibit IRAK1/4, IRF4, and/or BTK may be active in these diseases. Finally, very few of these tumors harbor mutations in TP53, but instead exhibit copy number loss of CDKN2A on chromosome 9p21.3, which lies upstream in the p53 pathway, thus making these tumors potential candidates for therapy with drugs that inhibit MDM2/4. Thus, out of this comprehensive genetic investigation of these two diseases emerged three potential therapeutic strategies, all of which can be targeted with existing drugs.

By June 2017, and based on these results, Dr. Lakshmi Nayak and colleagues had treated five patients with either multiply recurrent PCNSL (n=4) or with a CNS relapse of PTL following a thiotepa-based autologous stem cell transplant (n=1) with the anti-PD1 antibody nivolumab. They observed an incredible 100 percent response rate in these five heavily chemotherapy refractory patients, with four of five complete responses. Responses were observed within a median of three treatments, and responses have been durable, ranging from 13+ to 17+ months. CNS responses were ongoing in four of five of these patients (although one had relapsed outside of the CNS during therapy), with one patient relapsing at 17 months after having received only three doses of nivolumab. Based on these results, nivolumab is being investigated as a therapy for relapsed/refractory PCNSL and PTL (CheckMate 647, clinicaltrials.gov identifier NCT02857426). This is a remarkable example of the power of our current technologies to identify recurrent and actionable genetic alterations associated with a specific malignancy and to translate these findings into effective clinical strategies with direct patient benefit in an unprecedented timeframe.

Conflict of Interests

Dr. Jacobson indicated no relevant conflicts of interest. back to top