Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitor may address some limitations

Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma

Bruton tyrosine kinase (BTK) inhibitors have greatly improved the spectrum of treatment options in mantle cell lymphoma (MCL) [1–4]. Acalabrutinib is a highly selective, orally administered, and potent BTK inhibitor with limited off-target activity [5]. Acalabrutinib was approved in 2017 by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data from the open-label, multicenter, phase 2 ACE-LY-004 study of acalabrutinib 100 mg twice daily [1]. Here, we present updated results from the ACE-LY-004 study after a median 26-month follow-up. Eligibility criteria and study design were published previously (Supplementary methods) [1]. Analysis of minimal residual disease (MRD) was conducted after complete response (CR) or partial response (PR) was achieved using the quantitative ClonoSEQ next-generation sequencing (5 × 10−6 ) assay (Adpative Biotechnologies, Seattle, WA, USA) in consenting patients with available paired archival tumor and whole blood samples. Data are updated as of February 12, 2018

Long-term follow-up of patients with mantle cell lymphoma (MCL) treated with the selective Bruton’s tyrosine kinase inhibitor tirabrutinib (GS/ONO-4059)

International audienceRecent therapeutic advances for mantle cell lymphoma (MCL) include inhibitors of Bruton’s tyrosine kinase (BTK), a critical component in the B-cell receptor signaling pathway [1, 2]. Remarkably, approximately two thirds of patients with relapsed/refractory (R/R) MCL treated with ibrutinib, the first-in-class BTK inhibitor, achieve a durable response [3–5]. However, ibrutinib treatment also commonly produces off-target adverse events (AEs) such as bleeding, atrial fibrillation, diarrhea, and infection

Prospective subgroup analyses of the randomized MCL-002 (SPRINT) study : lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

International audienceIn the mantle cell lymphoma (MCL)-002 study, lenalidomide demonstrated significantly improved median progression-free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long-term follow-up data and results of preplanned subgroup exploratory analyses from MCL-002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL-002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1-21; 28-day cycles) or single-agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent-to-treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single-agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history

Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation

A prospective, multicenter, nonrandomized phase 2 trial was conducted to evaluate the efficacy and safety of a single dose of yttrium-90 (90Y) ibritumomab tiuxetan in elderly patients in first relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem-cell transplantation. Patients had been previously treated with chemotherapy (group A, n = 76) or chemotherapy plus rituximab (group B, n = 28). Patients in group A were further divided into patients in whom induction therapy had failed (stratum AI, n = 33) and patients who had relapsed after achieving complete response (CR; stratum AII, n = 43). The overall response rate (ORR) was 52% and 53% in strata AI and AII, respectively, and 19% in group B, with CR/CRu rates of 24%, 39.5%, and 12%, respectively. Median progression-free survival was 5.9 months and 3.5 months in strata AI and AII, respectively, and 1.6 months in group B. Median overall survival was 21.4, 22.4, and 4.6 months in stratum AI, stratum AII, and group B, respectively. Two patients died from thrombocytopenic cerebral bleeding following administration of therapy. Nonhematologic adverse events were mild to moderate. 90Y-ibritumomab is active in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) and its further evaluation in phase 3 studies is ongoing. © 2007 by The American Society of Hematology

Ibrutinib, Obinutuzumab And Venetoclax In Relapsed and Untreated Patients with Mantle-Cell Lymphoma, a phase I/II trial

International audienceIbrutinib, obinutuzumab plus venetoclax demonstrate synergy in pre-clinical models of mantle-cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multi-center prospective phase I/II trial, aimed to determine the maximum tolerated dose (MTD) of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR). Between Oct 14, 2015 to May 29, 2018, forty-eight patients were enrolled. No dose limiting toxicity (DLT) was reported, and venetoclax at 400mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events (AEs). The complete response rate assessed by positron-emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10 out of 14) and 100% of untreated MRD-evaluable patients (n=12), at the end of three cycles. The median follow-up (mFU) for relapsed patients was 17 months (range, 10 to 35). The 2-years PFS was 69.5% (95% CI, 52.9-91.4%) and 68.6% (95% CI, 49.5-95.1%) for OS. The mFU was 14 months (range, 5 to 19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5-100%). Obinutuzimab, ibrutinib and venetoclax combination is well tolerated and provides high response rates including at the molecular level in relapsed and untreated MCL patients