Introduction: Most therapies for relapsed/refractory (rel/ref) T-cell lymphomas (TCLs) induce responses in about 25%-30% of pts. Phosphoinositide-3-kinase (PI3K) delta has a role in survival and proliferation of malignant T cells as well as T-cell receptor and cytokine signaling in nonmalignant T cells. Inhibition of PI3K gamma can reprogram macrophages and promote tumor phagocytosis. A phase I study of the PI3K-δ/γ inhibitor duvelisib (D) in pts with rel/ref TCLs showed promising activity, but high rates of grade (Gr) 3/4 ALT elevation at the MTD of 75 mg BID (Horwitz et al, Blood 2018). Based on in vitro evidence of synergy, we initiated a phase I/II study of D combined with either romidepsin (R) or bortezomib (B). Methods: Pts were enrolled into parallel phase I dose escalation arms utilizing a 3+3 design to define the maximum tolerated dose (MTD) of D combined with either R (Arm A) or B (Arm B) in cycle 1. D was dosed at 25 mg, 50mg, or 75 mg BID on days 1-28 with either R (10 mg/m2 on days 1, 8, & 15) or B (1 mg/m2 on days 1, 4, 8, & 11) each on 28-day cycles. Once the MTD was established with each combination, preplanned expansion cohorts were enrolled to further characterize safety and describe subtype-specific efficacy (PTCL and CTCL). Based upon promising safety and efficacy, a total of 39 pts were treated on Arm A (33 at the MTD, D 75 mg BID + R 10 mg/m2). All pts received prophylaxis against Varicella and Pneumocystis. Response assessments were performed q2 cycles for 6 months and then q3 cycles. To assess biomarkers of response and resistance to single-agent D, 10 pts in Arm A (75 mg BID) and 10 pts in Arm B (25 mg BID) were each treated with 1 cycle of D alone, with pretreatment and on-treatment biopsies. Pts who did not achieve CR on D alone at the end of cycle 1 proceeded to combination therapy. Results: The MTD was not reached in Arm A (R+D); thus, dose level 3(DL3); (D 75 mg BID + R 10 mg/m2 days 1, 8, & 15) was deemed the MTD and used for expansion. In Arm B there were no cycle 1 DLTs. However, Gr 3 elevations of ALT or AST following cycle 2 were observed in 3 pts at DL2 (D 50mg BID) and 2 pts at DL3 (D 75mg BID) leading to DL1 (D 25mg BID + B 1mg/m2 days 1, 4, 8, & 11) being accepted as MTD for expansion. Of Arm A pts at the MTD, 21/32 (65%) had adverse events (AEs) ≥Gr 3, possibly related to study drug. Events occurring in ≥10% of pts included: increased ALT/AST (n=5, 15%), neutropenia (n=6, 18%), and hyponatremia (n=4, 12%). Three pts had ≥Gr 3 diarrhea. There were no Gr 5 AEs related to protocol therapy. Strikingly, 4 of 5 pts with elevated transaminases (ALT [4], AST [1]) on combination began on the D-only Lead-In Arm at 75 mg BID. In contrast, only 1 of 22 (4%) pts receiving combination R+D in cycle 1 had Gr 3-4 transaminitis (p=.0242). Of the pts with Gr 3-4 diarrhea, 2 of 3 were on Lead-In (p=.0793). In Arm A, 35/39 pts were evaluable for response. Overall response rate (ORR) across all DLs was 51% (18/35) and CR rate (CR) was 17% (6/35). PTCL, ORR and CR rates were 55% (12/22) and 27% (6/22) respectively. Among CTCL, ORR was 46% (6/13), no CR. Reponses by histology are detailed in Table 1. Of these responders, 3 proceeded to allogeneic stem cell transplantation (allo SCT) with curative intent. Of note, 4 pts were not evaluable for response, described in Table 1. Median PFS for Arm A (all DL) was 8.8 m (PTCL) and 5.4 m (CTCL). Median follow up was 5.8 m, and median duration of response was 9.1 m. Of Arm B pts at the MTD, 10/22 (45%) had AEs ≥Gr 3, possibly related to study drug, of these, only neutropenia (n=4, 18%) occurred in ≥10% of pts at the MTD. There was 1 Gr 5 event, Stevens-Johnson syndrome, possibly related to protocol therapy. In Arm B, the ORR across all DLs was 32% (9/28), the CR rate was 11% (3/28). ORR in PTCL was 36% (5/14), 21% (3/14) achieved CR. ORR in CTCL was 28% (4/14), no CR. Responses by histology are detailed in Table 2. Of these responders, 1 proceeded to allo SCT with curative intent. Median PFS for Arm B (all DL) was 3.5 m (PTCL) and 4.6 m (CTCL). Median follow up was 7.2 m, and median duration of response was 9.3 m. Conclusion: Duvelisib in combination with romidepsin is highly active in pts with PTCL with tolerable side effects. Duvelisib can be safely combined with romidepsin at a 3-fold higher dose than with bortezomib (75 mg BID vs 25 mg BID) with much lower rate of Gr 3-4 transaminitis than single-agent duvelisib at the same dose. The high response rates and safety of Arm A (Duvelisib + Romidepsin) in PTCL appears to be a potential therapeutic advance and warrants further evaluation in a larger study. Disclosures Horwitz: Portola: Consultancy; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Corvus: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Trillium: Consultancy. Moskowitz:Takeda: Honoraria; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Research Funding. Jacobsen:Seattle Genetics: Consultancy; Merck: Consultancy. Mehta-Shah:Spectrum: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Verastem: Research Funding. Khodadoust:Innate Pharma: Research Funding. Fisher:Seattle Genetics Inc.: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Kim:Medivir: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; miRagen: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Merck: Research Funding; Galderma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weinstock:Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis: Consultancy, Research Funding; Genentech/Roche, Monsanto: Consultancy.
There remains a need to identify new sensitive diagnostic and predictive blood-based platforms in lymphoma. We previously discovered a novel circulating microRNA (miRNA) signature in a Smurf2-deficient mouse model that spontaneously develops diffuse large B-cell lymphoma (DLBCL). Herein, we investigated this 10-miRNA signature (miR-15a, let-7c, let-7b, miR-27a, miR-10b, miR-18a, miR-497, miR-130a, miR24, and miR-155) in human lymphoma cell lines, mice engrafted with patient-derived xenografts (PDXs), and DLBCL patient serum samples leveraging systems biology analyses and droplet digital PCR (ddPCR) technology. Overall, 90% of the miRNAs were enriched in PDX DLBCL models and human lymphoma cell lines. Circulating miRNAs from the serum of 86 DLBCL patients were significantly increased compared with healthy controls and had similar patterns to the murine models. Strikingly, miRNAs were identified up to 27-fold higher levels in the serum of PDX-bearing mice and human patients compared with lymphoma cell lysates, suggesting a concentration of these factors over time within sera. Using cut-points from recursive partitioning analysis, we derived a 5-miRNA signature (let-7b, let-7c, miR-18a, miR-24, and miR-15a) with a classification rate of 91% for serum from patients with DLBCL versus normal controls. In addition, higher levels of circulating let-7b miRNA were associated with more advanced stage disease (i.e., III-IV vs. I-II) in DLBCL patients and higher levels of miR-27a and miR-24 were associated with MYC rearrangement. Taken together, circulating multi-miRNAs were readily detectable in pre-clinical cell line and human lymphoma models as well as in DLBCL patients where they appeared to distinguish clinico-pathologic subtypes and disease features.
A delicate relationship exists between reef-building corals and their photosynthetic endosymbionts. Unfortunately, this relationship can be disrupted, with corals expelling these algae when temperatures rise even marginally above the average summer maximum. Interestingly, several studies indicate that failure of corals to regulate symbiont cell divisions at high temperatures may underlie this disruption; increased proliferation of symbionts may stress host cells by over-production of reactive oxygen species or by disrupting the flow of nutrients. This needs to be further investigated, so to begin deciphering the molecular mechanisms controlling the cell cycle in these organisms, we used a computational approach to identify putative cell cycle-regulating genes in the genome of the dinoflagellate Breviolum minutum. This species is important as an endosymbiont of Aiptasia pallida—an anemone that is used as a model for studying coral biology. We then correlated expression of these putative cell cycle genes with cell cycle phase in diurnally growing B. minutum in culture. This approach allowed us to identify a cyclin/cyclin-dependent kinase pair that may function in the G1/S transition—a likely point for coral cells to exert control over algal cell divisions.
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