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Deep clinical responses and limited inflammatory toxicity in patients with relapsed/refractory T-cell lymphomas receiving Duvelisib and Romidepsin

ABSTRACT: PI3K-d inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities leading to market withdrawals. We previously demonstrated single-agent activity of the PI3K-dg duvelisib in T-cell lymphomas that was associated with inflammatory adverse events. We conducted a phase Ib/IIa study of duvelisib in combination with either romidepsin or bortezomib in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. Among those with peripheral T-cell lymphomas (PTCL), secondary endpoings of overall and complete response rates of duvelisib and romidepsin were 56% and 44% respectively with less grade 3/4 hepatotoxicity (14%) compared to the 40% rate of grade 3/4 transaminase elevation seen in our prior study with duvelisib monotherapy. Correlative analyses demonstrated enhanced response rates in patients with a follicular helper T-cell subtype. Finally, the attenuated hepatotoxicity seen in this study was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. These findings support further development of combined PI3K and HDAC inhibition in T-cell lymphomas and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266760 | GEO | 2024/05/06

REPOSITORIES: GEO

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Project description:Performing GWAS on multiple myeloma in relation to the development of the toxicity neuropathy. This set was used as validation set. We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell transplantation and conducted validation in an independent cohort of 116 MM patients. We identified one previously unreported BiPN risk locus at 21q22.3 (rs2839629, PKNOX1; OR = 0.53, 95% CI: [0.40-0.69]). PKNOX1 is known to regulate MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium ( r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment. Each patient of both IFM and HOVON cohorts was genotyped using the Affymetrix SNP6.0 Human DNA chip (Affymetrix, Santa Clara, CA) according to manufacturerâs instructions (Affymetrix, Santa Clara, CA). The HOVON65 samples were genotyped using CRLMM v2 resulting in a call rate higher than 95%. Unannotated SNPs according to the hg19 na32 SNP6 Affymetrix annotations (n= 130) along with SNPs from MT and sexual chromosomes (n= 37,326) were not considered in the study. To perform GWAS in the IFM cohort, we used stringent criteria to select a total of 370,605 SNPs from the 872,166 SNPs available onto the array. A SNP was analysed if an AA or BB genotype was present in more than 5% of patients, if its genotype was determined in at least 95% of the patients and if the Hardy-Weinberg rule was not rejected. Statistical analyses were performed using SNPTEST v2.5.11. Firstly, we compared 370,605 genotypes from 155 IFM patients with neuropathy (grade >= 2) after bortezomib exposure to 314 control patients treated with bortezomib who did not develop neuropathy (grade 0-1). Secondly, we performed a validation in the HOVON 65/GMMG-HD4cohort for the highest associated SNPs as identified in the discovery cohort. We compared 41 bortezomib-treated patients with neuropathy (grade >= 2) with 75 bortezomib-treated controls who did not develop neuropathy. We applied a one-sided logistic regression with 10,000 label swapping permutations to correct for multiple testing in order to confirm BiPN association in this independent cohort. This set was used as a validation set. An independent dataset was used for discovery [GSE65777].

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Deep clinical responses and limited inflammatory toxicity in patients with relapsed/refractory T-cell lymphomas receiving Duvelisib and Romidepsin

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