Venetoclax (Venclexta) resistance is primarily associated with non-BCL2 gene mutations in patients with mantle cell lymphoma (MCL), according to a study published in American Journal of Hematology. The analysis also demonstrated that venetoclax could play a potential role as salvage therapy among patients with MCL with multiple relapses.

This is the first report on the genomic profile of patients with venetoclax-resistant MCL, demonstrating that the acquisition of BCL2 mutations was infrequent and acquisition of TP53, SMARCA4, CELSR3, CCND1, andKMT2D alterations may play a role in disease progression on venetoclax therapy.

Furthermore, in our cohort of venetoclax combined with other agents, the PFS was longer compared to single-agent (8.3 vs 3.5 months), therefore we hypothesize that combination of venetoclax with other agents are promising compared to single-agent venetoclax, however randomized clinical trials would confirm whether venetoclax should be used as single-agent or in combination with other agents in relapsed patients with MCL, wrote lead author Shuangtao Zhao, MD, PhD, assistant professor, Genomic Medicine, The University of Texas MD Anderson Cancer Center.

The objective response rate (ORR) with venetoclax was 50% (12 of 24), and 21% had a complete response (CR; 5 of 24). Partial responses (PRs) were observed in 29% of patients (7 of 24), and 4 patients were not evaluable for response. Six patients were primary refractory and 2 had stable disease (SD).

The ORR was not significantly different between venetoclax monotherapy (42%) and combination (58%). The median duration of best response was 4 months (range, 1-16).

After a median follow-up of 17 months, the median progression-free survival (PFS) was 8 months, and the median overall survival (OS) was 13.5 months. The duration of response among those who had a CR was 8.6 months versus 4 months in those who had a PR (P =.58).

At the time of the last follow-up, 9 patients remained alive, 15 had died and 16 progressed. The median survival post-venetoclax treatment was 7.3 months.

Nine patients received subsequent therapy, and 4 responded, which included 1 CR after rituximab, mesna, Ifosfamide, mitoxantrone, and etoposide (R-MINE); and 3 PRs, 1 from umbralisib (TGR-1202), 1 from acalabrutinib (Calquence), and 1 from local radiation followed by R-HCVAD chemotherapy. All 4 responders were refractory to the BTK inhibitor (BTKi) ibrutinib (Imbruvica) prior to venetoclax treatment. Additionally, 2 patients had SD, and 3 did not respond to subsequent therapy.

Five patients had paired samples from whole exome sequencing (WES) before and after progression on venetoclax. Two of these patients had a CR (patients 1 and 2), 2 had a PR (patients 4 and 6), and 1 had SD (patient 7). Overall, investigators conducted WES in 12 samples, including these patients.

Patient 1 received single-agent venetoclax following 6 prior lines of therapy, and upon progression on venetoclax, the patient received R-MINE chemoimmunotherapy for 5 cycles and achieved a CR that was lost to follow-up. Patient 2 received venetoclax in combination with acalabrutinib, obinutuzumab (Gazyva), and radiation after 5 prior lines of therapy, which included an allogeneic stem cell transplant and did not receive further therapy after venetoclax.

Patient 4 received venetoclax plus obinutuzumab after 4 prior lines of therapy and received single-agent lenalidomide (Revlimid) plus bortezomib (Velcade) without response. Patient 6 had received venetoclax plus rituximab after 6 prior lines of therapy and received 7 subsequent lines of therapy after progression on the combination regimen. The patient ultimately progressed after receiving an experimental anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, which was rechallenged with venetoclax/obinutuzumab/ibrutinib, obinutuzumab plus MINE, gemcitabine/oxaliplatin/obinutuzumab, acalabrutinib, R-HCVAD, and bendamustine/rituximab. Patient 7, who had 7 prior lines of therapy, received venetoclax in combination with obinutuzumab plus acalabrutinib, and was treated with 2 lines of subsequent therapy following progression on the venetoclax combination, including abemaciclib (Verzenio) and copanlisib (Aliqopa), which induced a PR before subsequently progressing.

All 5 patients had received prior ibrutinib before receiving the venetoclax treatment. Patients 1 and 2 had transformed MCL, and patients 6 and 7 had blastoid morphology MCL.

Alteration frequencies of certain genes increased by > 2-fold at progression, including TP53 (83% vs. 33%), KMT2D (67% vs. 17%), CELSR3 (67% vs. 17%), CCND1 (67% vs. 17%), KMT2C (50% vs. 17%), and ATM(50% vs. 17%). CDKN2A (67%) and NOTCH2 (50%) were increased at progression as well. A BCL2 mutation was observed in 33% of patients at progression. SMARCA4 mutations were only detected after progression.

Predominant genetic alterations at progression were observed in patient 1 (TP52, NOTCH2), patient 2 (CDKN2A, CCND1, KMT2C, and SMARCA4), patient 4 (TP53, NSD2), patient 6 (TP53, KMT2D, ATM, Bcl2,and NOTCH1) and patient 7 (TP53, CDKN2A, KMT2D, CELSR3, SMARCA4, CCND1 and gain of Bcl2). An increase in tumor mutational burden was also observed, as well as predominance of mutation signature 5 at progression.

Clonal and sub-clonal evolution of mutations associated with clinical venetoclax resistance were demonstrated in patients 2 and 7. Investigators also noted a high degree of intra-tumoral heterogeneity and treatment-induced clonal evolution as resistance.

All 5 patients had expanded TP53, SMARCA4, CELSR3, KMT2D, and KMT2C mutations at progression. Acquired DNA copy number changes were also observed in patients 2 and 7 at progression, including loss of 9p (CDKN2A) and 17p (TP53), and gain of 11p (CCND1). In patient 7, investigators noted an alteration in chromosome 18q21 depicting BCL2 mutation at progression.

The degree of aneuploidy was significantly higher among patients at progression and was noteworthy for copy number gain on chromosomes 2, 3, 4, 12, and 18, and deletion was noted at chromosome 15.

For this analysis, data were collected from 24 patients with MCL who were treated with venetoclax salvage therapy, either alone or in combination. Twelve patients received venetoclax as monotherapy, and venetoclax was given in combination with either obinutuzumab in 8 patients, a BTKi with/without obinutuzumab in 3 patients, and chemotherapy in 1 patient. The patients in this study were heavily pretreated.

Our study demonstrates that venetoclax is a potential salvage therapy in multiply relapsed patients with MCL. The majority (92%) patients in this study were exposed to BTKi, 66% were BTKi refractory, and these patients exhibited poor outcomes, wrote Zhao.

Reference

Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) outcomes and mutation profile from venetoclax resistant MCL patients [Published Online April 2, 2020].American Journal of Hematology. DOI: 10.1002/ajh.25796.

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Venetoclax May Play Role as Salvage Therapy in Multiply Relapsed MCL - Targeted Oncology