Abstract 191
PI3Kdelta drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kdelta that has shown considerable monotherapy ...activity when given at dose levels of 3100 mg BID in patients with heavily pretreated CLL.
This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated CLL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/BR regimen). Initial cohorts of patients received a GS-1101 dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Hallek 2008). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays.
The study enrolled a total of 51 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the tableParameterRegimenGS-1101/R N=19GS-1101/B N=17GS-1101/BR N=15Age, median range, years65 40–8459 38–8159 48–76Sex, males/females, %68/3241/5960/40Patients with bulky1 adenopathy, %586567Prior therapiesMedian range, n2 1–83 1–94 1–10Patients with prior R/B, %100/4794/41100/40Pts with refractory disease, %377147GS-1101 dosesPts at 100 mg/dose BID, n44n/aPts at 150 mg/dose BID, n151315GS-1101 minimum follow-up, weeks644048Pts with Grade ≥3 adverse events, %Anemia53520Neutropenia327667Febrile neutropenia11127Thrombocytopenia213527Infections11180Pneumonia/pneumonitis21290Rash5613Diarrhea5127Hepatic transaminase elevation5180Pts with decrease in adenopathy, % (evaluable N)95 (19)93 (15)100 (13)Max. decrease in adenopathy, median range, % (evaluable N)−78 −92 to +33 (19)−74 −92 to +16 (15)−85 −97 to −63 (13)Pts with lymph node response (decrease ≥50%), % (total N)84 (19)82 (17)87 (15)Best on-treatment response rate2, CRu3/PR/SD/PD/NE, %0/78/11/11/00/82/6/0/127/80/0/0/13Intent-to-Treat ORR, %7882871-Year PFS, %7488871, 31 node of 35 cm diameter,2investigator assessment,3unconfirmed CR (no BM Bx).
The majority of patients had bulky adenopathy and had undergone extensive prior therapy, with virtually all patients receiving prior rituximab and many receiving prior bendamustine. Grade 33 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid, and almost all evaluable patients had reductions in lymphadenopathy. As reported by investigators, the overall response rates (ORR) for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens were 78%, 82% and 87%, respectively. With a minimum follow-up of 340 weeks for all regimens, 1-year progression-free survival (PFS) rates were 74%, 88% and 87% in the GS-1101/R, GS-1101/B, and GS-1101/BR treatment groups, respectively. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment.
A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kdelta inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with CLL. GS-1101-based combination therapies with rituximab and/or bendamustine offer major and rapid reductions in lymphadenopathy and durable tumor control. Based on these results, Phase 3 trials evaluating the efficacy of GS-1101 in combination with R or BR have been initiated (NCT01539512 GS-1101/placebo+R, NCT01569295 GS-1101/placebo+BR).
Coutre:Gilead: Consultancy. Off Label Use: Phase 1 trial of GS-1101 (CAL-101)-based combination therapy. Leonard:Gileade: Consultancy. Barrientos:Gilead: Research Funding. de Vos:Gilead: Consultancy. Sharman:Gilead: Honoraria, Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Miller:Gilead: Employment. Jahn:Gilead: Employment.
Highlights • These recommendations re-assess the role of allo-HCT as new therapies emerge • Allo-HCT is now relegated to later stages of relapsed or refractory CLL • Future studies may likely include ...new therapies within the allo-HCT treatment plan
The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free ...survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo
H
O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P<0.001) for unmutated IGHV. The association between elevated birth rate and shorter TFS was observed in subjects with either mutated or unmutated IGHVs, and the use of both markers was a better predictor of TFS than either parameter alone. Thus, an increased CLL birth rate in early stage disease is a strong predictor of disease progression and earlier treatment.
Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib ...is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years range, 42-85 years; median prior therapies, 2 range, 1-13) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.
•At a median follow-up of 41 months, median PFS has not been reached in previously treated CLL patients on the BTK inhibitor acalabrutinib.•Patients with previously treated CLL or SLL had favorable safety, response, and durability of response with acalabrutinib.
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Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone's Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated ...expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9-induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone's BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated anomaly + del13q14) and negatively linked to a very high proportion of CD38(+) cells within the blood-derived B-CLL population. Furthermore, a clone's intrinsic potential for in vitro growth correlated directly with doubling time in blood, in the case of B-CLL with Ig H chain V region-unmutated BCR and <30% CD38(+) cells in blood. Finally, in vitro high-proliferator status was statistically linked to diminished patient survival. These findings, together with immunohistochemical evidence of apoptotic cells and IL-15-producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in vivo B-CLL growth.
Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains ...nonstandard and poorly understood.
To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies.
We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (
= 130), and 81% were idelalisib naïve (
= 263). ORR to BTKi was 84% (
= 44) in BTKi-naïve patients versus 54% (
= 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.
For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.
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The recent generation of mice lacking functional SOCS3 in hepatocytes, macrophages, and neutrophils reveals SOCS3 to be an essential regulator of IL-6 signaling via mediation of gp130-related ...cellular complexes, as well as a negative regulator of G-CSF signaling in myeloid cells. Although SOCS3 would appear to be a critical physiologic regulator of inflammatory responses, its possible role in hematologic malignancies and the underlying mechanisms which regulate its expression in B cells remain to be clearly defined. We previously showed that CD19+ B cells isolated from Eμ-Bcl-2 transgenic mice express high levels of SOCS3 in addition to overexpression of Bcl-2. Moreover, hematopoietic cell lines transduced to stably overexpress Bcl-2 exhibited marked induction of SOCS3 compared to controls, suggesting Bcl-2-associated pathways may play a role in the induction of SOCS3. In the current study, we describe SOCS3 overexpression limited to neoplastic follicular lymphoma (FL) cells in Bcl-2-associated human de novo FL and show that overexpression of SOCS3 is capable of stimulating cytokine-independent cellular proliferation of the BaF3 pro-B cell line. We measured SOCS3 protein levels by immunohistochemistry in paraffin-embedded biopsies from twelve patients diagnosed with de novo, untreated histologic grade I or II FL which harbored t(14;18) and Bcl-2 overexpression. In 9/12 de novo FL cases examined, immunostaining with two distinct antibodies to SOCS3 revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic FL cells and co-localized with Bcl-2 primarily in the nucleus of positive cells. In contrast, SOCS3 protein was not detected by immunostaining in germinal center follicular B cells from benign hyperplastic tonsil tissue. To further evaluate the role of SOCS3 in B cell biology, the IL-3-dependent BaF3 pro-B cell line was stably transduced with either a retroviral expression construct containing a 675bp human SOCS3 cDNA (BaF3SOCS3) or with vector only control (BaF3Δ). Whereas no SOCS3 protein was detected in control cells, high level expression of SOCS3 in transduced BaF3SOCS3 cells was confirmed by Western analysis using SOCS3 anti-sera. Furthermore, Bcl-2 protein was not detected in either BaF3SOCS3 or control cell lines. 2 x 105 BaF3SOCS3, BaF3Δ, and non-transduced BaF3 cell lines were initially grown in the presence 10% fetal bovine serum (FBS) and 5% WEHI 3B cell-conditioned medium as a source of IL-3. IL-3 was then removed by washing with DMEM/10% FBS. Cell viability was then measured by recording absorbance at 490nm using incorporation of the MTS tetrazolium compound. Interestingly, BaF3SOCS3 cells overexpressing SOCS3 did not undergo apoptosis but were able to proliferate in the absence of IL-3, with percent viable cells approaching 400% at > 96 hours, which represented the final time-point measured. In contrast, BaF3Δ and non-transduced BaF3 cells underwent apoptotic cell death between 8 and 36 hours in response to IL-3 withdrawal. Thus, SOCS3 overexpression confers IL-3-independent cell proliferation to the BaF3 cell line. These data indicate that unlike its negative regulatory effect on G-CSF signaling in myeloid cells, overexpression of SOCS3 in B cells may promote B cell proliferation rather than growth suppression and may play an important role in the pathogenesis of de novo FL in humans.
Clonal evolution occurs during the course of chronic lymphocytic leukemia (CLL) and activation-induced deaminase (AID) could influence this process. However, this possibility has been questioned in ...CLL because the number of circulating AID mRNA+ cells is exceedingly low; synthesis of AID protein by blood CLL cells has not been demonstrated; the full range of AID functions is lacking in unmutated CLL (U-CLL), and no prospective analysis linking AID expression and disease severity has been reported. The results of the present study show that circulating CLL cells and those within secondary lymphoid tissues can make AID mRNA and protein. This production is related to cell division because more AID mRNA was detected in recently divided cells and AID protein was limited to the dividing fraction and was up-regulated on induction of cell division. AID protein was functional because AID+ dividing cells exhibited more double-stranded DNA breaks, IGH class switching, and new IGHV-D-J mutations. Each of these actions was documented in U-CLL and mutated CLL (M-CLL). Furthermore, AID protein was associated with worse patient outcome and adverse cytogenetics. We conclude that the production of fully functional AID protein by U-CLL and M-CLL cells could be involved in clonal evolution of the disease.
Théâtre et pouvoir Adde, Amélie; Adler, Heidrun; Alcántara Mejía, José Ramón ...
2002
eBook, Book
Odprti dostop
Actes du IVe Colloque International sur le théâtre, domaines hispanique, hispano-américain et mexicain, en France, organisé les 8, 9 et 10 octobre 1998 à l’Université de Perpignan, par le Centre de ...Recherches Ibériques et Latino-américaines de l’Université de Perpignan.
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