Higher TMB, PD-L1 Expression Correlate With Shorter Survival in Hematologic Malignancies

Data recently published in Therapeutic Advances in Medical Oncology suggest that tumor mutation burden (TMB) and PD-L1 expression could be notable biomarkers in assessing the prognosis of patients with hematologic malignancies, including non-Hodgkin lymphoma, just as they are in those with solid tumors.^1,2 These biomarkers are known to be predictive of response to immune checkpoint inhibitor (ICI) therapy, but they have previously been insufficiently studied in hematologic malignancies, opined the authors.

Their real-world analysis, utilizing electronic medical records from 388 patients with hematologic malignancies, found that higher TMB and PD-L1 expression correlate with shorter survival. Checkpoint inhibitors are currently approved by the FDA for 2 hematologic indications: relapsed/refractory classical Hodgkin lymphoma and relapsed/refractory primary mediastinal B-cell lymphoma.³

The patients all had undergone next-generation sequencing at the University of California San Diego Moores Cancer Center between 2014 and 2018. While TMB was measured by PD-L1 expression, tumor proportion score (TPS) was measured by immunohistochemistry; it was classified as high (≥50%), low (1%-49%), and negative (<1%).

Higher TMB and PD-L1 expression can correlate with shorter progression-free survival in non-hodgkin lymphoma | Image credit: Saiful52 - stock.adobe.com

Among the 388 patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome–negative myeloproliferative disorders (16%). The TMB in hematologic malignancies tended to be low (median TMB, 1.6 mutations/Mb; range, 0-46.83), especially among the acute leukemias and myeloid malignancies. Median TMB was higher in B- and T-cell NHL, and a subset of lymphomas had higher TMB and/or positive PD-L1 expression.

Significant findings.

TMB of 4 or more mutations/Mb and PD-L1 score of 1% or more were significantly associated with shorter overall survival from diagnosis, the authors reported. Specifically, the HR was 1.46 for the former (95% CI, 1.05-2.03; P = .02) and 2.11 (95% CI, 1.04-4.30; P = .04) for the latter. The relationship to shorter overall survival was even more pronounced when PD-L1 of 50% or higher was used vs PD-L1 of less than 50%, even though the number of patients in this group was small (HR, 2.80; 95% CI, 1.19-6.59; P = .02). Additionally, higher TMB and higher PD-L1 positivity correlations were significant but weak (Pearson correlation coefficient R² = 0.04; P = .04), they wrote.

The TMB cutoff of 4 or more mutations/Mb is lower than the conventional 10 or more mutations/Mb. Utilizing the lower cutoff demonstrated that patients with higher TMB had shorter survival from diagnosis across hematologic malignancies, which is similar to results seen in solid tumors. For instance, a TMB of more than 5 mutations/Mb in solid malignancies has been shown to be associated with worse prognosis than a TMB of 5 or less mutations/Mb.

Overall, 48 patients (12%) had a TMB of 10 or more mutations/Mb; of these, 90% had B-cell or T-cell NHL. In the 85 samples that had available PD-L1 scores, 11 were high, 26 were low, and 48 had no tumor cell expression. Seven of 9 cases (77%) of T-cell NHL PD-L1 cases were TPS positive (≥1%), as were 21 of 51 (41%) of B-cell NHL cases.

Real-World Outcomes

A total of 17 patients in the panel with positive biomarkers—either high TMB and/or positive PD-L1 expression—were treated with ICI-based therapy, with all but 1 patient receiving combination therapy with other agents. Just 4 of the 17 achieved an objective response, declared the authors; these were 3 patients with B-cell NHLs—Richter transformation to diffuse large B-cell lymphoma, primary central nervous system lymphoma (PCNSL), and gray zone lymphoma (GZL)—and 1 with peripheral T-cell lymphoma. The progression-free survival values of those 4 patients ranged from 193 to 951 days. The patient with GZL received brentuximab vedotin and the patient with PCNSL received temozolomide, which are active agents in their respective diseases, so “it appears that a select group of patients derive benefit from ICI combination therapy,” the authors said.

References

1. Jeong A-R, Trando AH, Thomas SD, et al. Higher tumor mutational burden and PD-L1 expression correlate with shorter survival in hematologic malignancies. Ther Adv Med Oncol. Published online August 28, 2024. doi:10.1177/17588359241273053

2. Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598-2608. doi:10.1158/1535-7163.MCT-17-0386

3. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel). 2020;12(3):738. doi:10.3390/cancers12030738