Ibrutinib Plus Bendamustine/Rituximab (BR) Is Associated with Greater Reductions in Fatigue Than Placebo Plus BR Among Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and Fatigue

Abstract Introduction: Patients with chronic lymphocytic leukemia (CLL) may have reduced health-related quality of life (HRQL) such as severe fatigue during the course of their disease and its treatment. While current treatments aim to increase progression-free survival, it is also important to maintain good HRQL for as long as possible. Methods: Ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in patients with previously treated CLL and in patients with CLL with del17p, and has recently been shown to reduce the risk of disease progression or death by 80% when added to standard chemoimmunotherapy with BR. In this randomized, double-blind, placebo-controlled, phase 3 study, where patients with active CLL following ≥ 1 prior therapy were randomized 1:1 to receive BR (≤ 6 cycles) with either ibrutinib (420 mg daily) (n = 289) or placebo (n = 289), HRQL and fatigue data were examined. Measures included the FACIT-Fatigue, EORTC QLQ-C30-CLL16, and EQ-5D-5L, which capture general physical and emotional impacts of disease and treatments as well as CLL-specific symptoms. Because examination of mean values may obscure meaningful changes in outcomes, fatigue scores were also examined by baseline quartile with respect to clinical, sociodemographic, and HRQL factors as well as for change over time. Individual CLL symptom items were also examined. The association between changes in hemoglobin levels and fatigue was also examined. Results: Of the 578 patients enrolled, 540 (93%) provided FACIT-Fatigue responses at baseline. No notable mean changes from baseline over time were observed in any HRQL scores within or between the treatment groups. Those in the lowest fatigue score quartile (ie, worst baseline fatigue) were more likely to have an Eastern Cooperative Oncology Group performance score of 1, be in a later stage of disease, have more cytopenias, a greater number of prior therapies, and worse HRQL. Among those with the worst baseline fatigue, unadjusted results indicate apparent improvements in fatigue score over time for both treatments during the first 6 cycles of BR therapy, and subsequently greater continued improvements in fatigue were observed with ibrutinib + BR versus placebo + BR (p < 0.05 at cycle 10) (Figure 1). Similarly, for those with the worst baseline fatigue, mean hemoglobin values appear to increase over time after cycle 2, with comparable changes in each arm (Figure 2). In addition, of the patients who reported feeling ill or unwell at baseline (item 38 on CLL16), a greater proportion reported a return to wellness with ibrutinib + BR (40.0%) versus placebo + BR (27.3%) at cycle 10. This pattern was consistently observed from cycle 2 through cycle 19. Conclusions: These data suggest that addition of ibrutinib to BR is not associated with a negative impact on HRQL and that, among patients with the worst fatigue at baseline, ibrutinib appears to be associated with greater reductions in fatigue versus placebo. Improvements in fatigue appear to be consistent with improvements in hemoglobin and improvements in CLL disease status. Disclosures Traina: Janssen: Employment. Fraser:Hoffman LaRoche: Consultancy, Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Cramer:Astellas: Other: Travel grant; Mundipharma: Other: Travel grant; Glaxo Smith Klein/Novartis: Research Funding; Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Gilead: Other: Travel grant, Research Funding. Santucci Silva:Novartis: Other: Travel reimbursement; Merck: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Other: Travel reimbursement, Research Funding; Hoffman LaRoche: Other: Travel reimbursement, Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Mahler:Janssen: Employment, Other: Travel reimbursement. Salman:Janssen/J&J: Employment, Equity Ownership. Howes:Janssen/J&J: Employment, Equity Ownership.

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Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽

10.1182/blood.v128.22.233.233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 233-233 ◽

Cited By ~ 53

Author(s):

Susan M. O'Brien ◽

Richard R. Furman ◽

Steven E. Coutre ◽

Ian W. Flinn ◽

Jan Burger ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3 ◽

Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

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Inhibition Of PI3K-δ and -γ Isoforms By IPI-145 In Chronic Lymphocytic Leukemia Overcomes Signals From PI3K/AKT/S6 Pathway and Promotes Apoptosis

Blood ◽

10.1182/blood.v122.21.4167.4167 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4167-4167 ◽

Cited By ~ 3

Author(s):

Kumudha Balakrishnan ◽

Marisa Peluso ◽

Min Fu ◽

Nathalie Y. Rosin ◽

Jan A. Burger ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

Therapeutic Potential ◽

Lymphocytic Leukemia ◽

B Cell Malignancies ◽

Employment Equity ◽

Enhanced Production ◽

Significant Difference ◽

Equity Ownership

Abstract The functional relevance of the B cell Receptor (BCR) pathway and identification of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B cell malignancies. Inhibition of protein and lipid kinases (Bruton Tyrosine Kinase [BTK] and phosphoinositide 3-kinase [PI3K]) with ibrutinib and GS-1101 has been shown to be active in treatment of chronic lymphocytic leukemia (CLL). Importantly, differential expression and function of PI3K isoforms support isoform-selective inhibition of this kinase in CLL. Whilst PI3K-α and PI3K-β are ubiquitously expressed, PI3K-δ and PI3K-γ are primarily restricted to leukocytes. Since CLL cells generally express high levels of active PI3K-δ, great interest has been focused on inhibition of PI3K-δ. However, given the distinct and non-overlapping roles of PI3K-δ and PI3K-γ in immune cells, exploration of the therapeutic potential of combined inhibition of both PI3K-δ and PI3K-γ in CLL patients is warranted. IPI-145 is a potent, orally bioavailable, inhibitor of PI3K-δ and PI3K-γ isoforms with KD values of 0.023 nM and 0.24 nM, respectively. Treatment of primary CLL cells (n=51) with IPI-145 (1 µM) resulted in significant apoptosis (median 33%; range 12 – 40%). Patients with mutated (n=13) or unmutated IGHV gene status (n=13), previously untreated (n=21) or treated (n=8), displayed no significant difference in apoptosis from IPI-145. Samples with different prognostic markers such as 13q (del) or FISH negative samples were equally sensitive to IPI-145. Side by side studies of IPI-145 with ibrutinib and GS-1101, revealed that IPI-145 is comparatively potent (IC50 7.6 µM, compared to >10 µM) in promoting apoptosis. Crosslinking with anti-IgM enhanced the survival of primary CLL cells in association with activation of PI3K-δ,γ/AKTSer473/pBadSer136/S6Ser235/236 pathway, which was in turn mitigated upon treatment with IPI-145 (n=9). Consistent with cell death, cleavage of PARP and decrease in anti-apoptotic protein Mcl-1 (but not Bcl-2 or Bcl-xL) was observed. Measurement of the C-C chemokine, CCL3, a biomarker for BCR signaling inhibition in CLL, demonstrated 15 to 48 – fold increase upon anti-IgM stimulation, which was reversed when cells were treated with 1 µM IPI-145 (10 to 80-fold decrease; n=6). Alternatively, co-culturing CLL primary cells with bone marrow stromal cells to mimic the leukemic microenvironment induced the protein levels of all four Class I PI3K isoforms and downstream PI3K/AKT/S6 signaling axis, which was significantly attenuated by IPI-145. To mimic the proliferative state in lymph node pseudofollicles, CLL cells were stimulated to proliferate with CD40L/IL-2/IL-10 and the effect of IPI-145 was measured. Both pAKT and Ki-67 expression were markedly inhibited in primary CLL cells at concentrations of IPI-145 in the low nanomolar range (EC50<10nM; n=2), suggesting a potent anti-proliferative effect of IPI-145 on CLL cells in the nodal environment. Given the significant role of the chemo-attractant, SDF-1, in the directed migration of B-cells, chemotaxis assay demonstrated reduction in migration of CLL cells towards SDF-1 in presence of IPI-145 (% control reduction - median 23%; range 2-42%; n=8). Furthermore, IPI-145 treatment enhanced production of reactive oxygen species (n=6). Taken together, these results demonstrate the potential of combined inhibition of the PI3K-δ and -γ isoforms in CLL, and support clinical investigation of IPI-145 in B-cell malignancies, including CLL. Disclosures: Balakrishnan: Infinity Pharmaceuticals Inc: Research Funding. Peluso:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Faia:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Kutok:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. McGovern:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Gandhi:Infinity Pharmaceuticals., Inc: Research Funding.

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Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽

10.1182/blood.v130.suppl_1.683.683 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 683-683

Author(s):

Jeffrey P. Sharman ◽

Habte Yimer ◽

Michael Boxer ◽

Nicholas Di Bella ◽

Sunil Babu ◽

...

Keyword(s):

Quality Of Life ◽

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Induction Treatment ◽

Future Health ◽

Employment Equity ◽

Equity Ownership ◽

Eortc Qlq

Abstract Introduction: Maintenance and/or improvements in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an ongoing, open-label, single-arm Phase II study of the combination of obinutuzumab (GA101; G) and bendamustine (B) (BG) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with BG (Sharman et al. ASCO 2017). Here, we present the HRQoL data from GIBB. Methods: In the GIBB trial, patients received BG by intravenous infusion over six 28-day cycles: obinutuzumab 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle 1, then 1000mg on D1 of Cycles 2-6; B 90mg/m2 on D2-3 of Cycle 1, and on D1-2 of Cycles 2-6. The European Organisation for Research and Treatment of Cancer Quality of Life - Core (EORTC QLQ-C30) questionnaire includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries; EORTC website, accessed July 25, 2017). Both questionnaires were completed by patients on D1 of Cycles 1 (baseline), 3, and 6, at the end of induction treatment (defined as +28 days from D1 of Cycle 6 or early treatment termination visit), at the response visit (defined as 2-3 months after the end of induction treatment, for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits. HRQoL scores were linear transformed to a 0-100 point scale. Mean baseline scores and mean score changes at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. Results: Of 102 patients enrolled in the trial, 98 completed a questionnaire at baseline and at least one other questionnaire during a follow-up visit. Questionnaire completion rates were 86.7%, 77.6%, 80.6%, and 86.7% at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Median age was 61 years and 68.4% of patients were male. According to the EORTC QLQ-C30 (Figure 1), clinically meaningful improvements were observed for global health status at the response visit, and for role functioning at the end of induction treatment and at the response visit. A trend was observed for improvement in emotional functioning. The greatest improvement in HRQoL score was observed for fatigue (mean baseline score: 37.64), with mean changes from baseline of −4.01, −5.48, −11.67, and −16.34 at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Improvements were also observed for insomnia (mean baseline score: 33.33), with mean changes from baseline of −6.59, −9.09, −9.7, and −10.98, respectively. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the end of induction treatment and/or at the response visit. The greatest change at the response visit was observed for fatigue (−21.23) and future health worries (−20.24). A positive trend was also observed for improvements in the social activities scale. Conclusions: We previously reported that BG is an effective regimen for first-line treatment of CLL with no unexpected safety signals. In addition, the HRQoL data from the GIBB trial suggest that BG treatment improves patient HRQoL. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries at the time of the response visit. Disclosures Sharman: Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Other: GIBB is sponsored by Genentech Inc. Third-party editorial support, under the direction of Anthony Masaquel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Yimer: Juno pharma: Equity Ownership; Bellucum Pharma: Equity Ownership. Babu: Alexion: Speakers Bureau; Abbvie: Consultancy. Li: Genentech: Employment, Equity Ownership. Mun: Genentech: Employment, Equity Ownership. Trask: Genentech: Employment, Other: stock. Masaquel: Genentech Inc.: Employment, Other: I Receive Roche stock options. Reyes: Genentech Inc.: Employment, Equity Ownership.

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A Phase 2 Study of Idelalisib Monotherapy in Previously Untreated Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽

10.1182/blood.v124.21.1986.1986 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1986-1986 ◽

Cited By ~ 19

Author(s):

Andrew D. Zelenetz ◽

Nicole Lamanna ◽

Thomas J. Kipps ◽

Steven E. Coutre ◽

Susan O'Brien ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Lymphoid Tissues ◽

Small Lymphocytic Lymphoma ◽

Employment Equity ◽

Treatment Naïve ◽

Equity Ownership ◽

Systemic Therapies

Abstract BACKGROUND: PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (Zydelig, IDELA,), a potent and selective orally administered inhibitor of PI3Kδ, in combination with rituximab weekly x 8 has yielded an ORR of 97% in patients (pts) ≥65 years with previously untreated CLL or SLL (O’Brien, ASCO 2013). This report describes the preliminary experience in treating a similar cohort of pts with IDELA monotherapy. METHODS: Enrollment began in November, 2013. Treatment-naive pts ≥65 yrs with CLL or SLL, requiring treatment per IWCLL 2008 criteria, and with measurable lymphadenopathy, were treated with IDELA 150 mg bid continuously. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, using modified IWCLL guidelines (Hallek 2008, Cheson 2012). RESULTS: As of 21 July 2014, 37 pts were enrolled: 78% male; CLL/SLL in 92%/8%; median age 70 years; 73% Rai III or IV; WHO 0-1/2 in 97%/3%. 46% had ≥1 B-symptom. Hepatomegaly and splenomegaly were present in 14% and 57% respectively. Adverse prognostic factors: 14% del(17p) and/or TP53 mutated; 22% del(11q); 41% IGHV unmutated; β-2 microglobulin median 4.35 mg/L (range: 2.1-12.4). The median idelalisib exposure was 4.8 months (range 0.9-8.5). There has been one discontinuation at 3 mo for respiratory distress, assessed as related to a prior condition. The median absolute lymphocyte count was 59.7 K/µl (range: 0.8-294) at baseline peaking at 100 K/µl (range: 2-385) at week 4. 27 pts were evaluable for response, having reached the first evaluation time point of 8 weeks. Of these 27, the ORR was 81% with 9 (33%) PR and 13 (48%) PR with lymphocytosis. Splenomegaly has responded in 88% of 17 evaluable pts and hepatomegaly in 75% of 4 evaluable pts. The most frequent treatment emergent adverse events (TEAE) (% all Grade/% Grade ≥3) were rash (27/3), URI (16/0), constipation (14/0), cough (14/0), nausea (11/0), pyrexia (11/0), arthralgia (8/0), back pain (8/0), diarrhea (8/3), and pneumonia (8/5). Pneumonitis was observed in 2 pts (5%), Gr ≥3 in 1(3%). Gr ≥3 treatment emergent lab abnormalities included transaminase elevation (8%), anemia (5%), and neutropenia (20%); there was no Gr ≥3 thrombocytopenia. One pt had a TEAE leading to dose reduction. CONCLUSIONS: IDELA has substantial single agent activity in treatment-naïve pts with CLL or SLL. Early lymphocytosis is observed with monotherapy in this population, as opposed to an attenuation of lymphocytosis seen in the earlier cohort treated with IDELA plus weekly rituximab. IDELA was well tolerated and had a manageable safety profile in this preliminary analysis. Disclosures Zelenetz: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. O'Brien:Gilead Sciences: Research Funding. Aiello:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Flinn:Gilead Sciences: Research Funding.

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Whole-Exome Sequencing Revealed No Recurrent Mutations within the PI3K Pathway in Relapsed Chronic Lymphocytic Leukemia Patients Progressing Under Idelalisib Treatment

Blood ◽

10.1182/blood.v128.22.2770.2770 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2770-2770 ◽

Cited By ~ 7

Author(s):

Paolo Ghia ◽

Viktor Ljungström ◽

Eugen Tausch ◽

Andreas Agathangelidis ◽

Annika Scheffold ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Research Funding ◽

Somatic Mutations ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Phase 3 ◽

Whole Exome ◽

Equity Ownership

Abstract Introduction: Idelalisib (IDELA) is an ATP-competitive, reversible, and selective small molecule inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) approved for the treatment, in combination with rituximab, of patients with relapsed chronic lymphocytic leukemia (CLL). In the relapsed CLL randomized, controlled trials, IDELA + rituximab showed high response rates with improved progression-free and overall survival as compared with placebo + rituximab. While IDELA therapy has significant efficacy, disease progression after response occurs, indicating that escape mechanisms may develop. However, the molecular basis for relapse or progressive disease (PD) in CLL patients treated with IDELA has not yet been characterized. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 13 CLL patients enrolled in the phase 3 studies; NCT01539512 (study 116; IDELA + rituximab vs placebo + rituximab), 116 extension study NCT01539291 (study 117) and NCT01659021 (study 119; IDELA + ofatumumab). Sample selection criteria included treatment period of at least 180 days (range: 243-703 days), achieving at least partial nodal response followed by PD, PD did not occur within a drug interruption window, PD was not associated with Richter's transformation, and PBMC samples were available from both baseline and time of PD. Whole-exome sequencing (WES) was conducted on the matched samples from 13 subjects fitting the above criteria. In 6/13 cases, DNA was available from CD19+/CD5+ enriched tumor cells, and neutrophils or T-lymphocytes served as a source of germline DNA. These 6 patients were considered as a discovery set for mutational analysis. Established bioinformatics tools were used for detection of somatic mutations and for the comparison of baseline and PD samples. Results: Baseline clinical patient profiles indicated that 12 of 13 patients with PD had unmutated IGHV genes and 8 patients carried TP53 aberrations (ie, 17p deletion and/or TP53 mutation). WES resulted in a mean read depth of 106X within the targeted coding region across samples. In the discovery set, on average 25 somatic mutations (range: 4-44) at baseline and 32 mutations (range: 15-81) at progression were identified. By comparing baseline and PD samples, we identified 88 PD-associated mutations. These specific mutations were tested for in a complete set of 13 patient samples; however, no recurrent progression-associated mutations were identified in more than 1 patient. In particular, no progression-associated mutations were identified in the PI3K signaling pathway or in any other related pathway. Conclusion: Across 3 phase 3 studies in relapsed CLL, WES on 13 samples from patients with PD while on IDELA treatment were evaluated. This analysis detected no relapse-associated mutations in common across this patient set; in particular, no mutations were identified in the drug-binding site (ie, "gateway mutation") or in any other related signaling pathway. Based on these results, we conclude there is no common mutational mechanism of IDELA resistance in this patient group. Disclosures Ghia: Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Adaptive: Consultancy; Abbvie: Consultancy, Honoraria. Tausch:Gilead: Other: Travel support, Speakers Bureau; Celgene: Other: Travel support; Amgen: Other: Travel support. Owen:Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Lundbeck: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria, Research Funding. Barrientos:Gilead: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Munugalavadla:Gilead Sciences: Employment, Equity Ownership. Degenhardt:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Dreiling:Gilead Sciences: Employment, Equity Ownership. Rosenquist:Gilead Sciences: Speakers Bureau. Stilgenbauer:Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding.

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Correlation Between Serum Ofatumumab Concentrations, Baseline Patient Characteristics and Clinical Outcomes in Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ofatumumab.

Blood ◽

10.1182/blood.v114.22.3433.3433 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3433-3433 ◽

Cited By ~ 4

Author(s):

Anders Österborg ◽

Birgitte Biilmann Ronn ◽

Roxanne C Jewell ◽

Thomas J Kipps ◽

Jiri Mayer ◽

...

Keyword(s):

Monoclonal Antibody ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Pivotal Trial ◽

Employment Equity ◽

Baseline Factors ◽

Equity Ownership ◽

Univariate Analyses

Abstract Abstract 3433 Poster Board III-321 Introduction Monoclonal antibody (mAb) therapies represent an important clinical advance for patients (pts) with CLL, yet little is known about the pharmacokinetics (PK) and pharmacodynamics of mAb therapy in these pts. Ofatumumab is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity in vitro. Ofatumumab is being evaluated in a pivotal trial for pts with fludarabine-refractory CLL also refractory to alemtuzumab (FA-ref; n=59) or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy (BF-ref; n=79). Overall response rate (ORR; primary endpoint) was 58% in FA-ref and 47% in BF-ref pts at an interim analysis; median progression-free survival (PFS) was 5.7 and 5.9 months, respectively. We evaluated relationships between baseline factors and ofatumumab PK and between PK parameters and treatment outcomes from the pivotal trial. Patients and Methods Pts received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2-12, 2000 mg). Response (1996 NCI-WG criteria) was assessed by an Independent Review Committee over 24 weeks of therapy. Blood samples for PK analysis were collected at Dose 1, Dose 8 (last weekly dose), and Dose 12 (last monthly dose). A population PK model was employed that included data from a previous study (Coiffier et al, Blood 2008;111:1094). For Dose 1, Cmax was determined; for Doses 8 and 12, Cmax, Cmin, AUC, clearance (CL), volume of distribution (Vss) and t½ were determined. The relationships between baseline pt characteristics and disease factors and PK parameters were evaluated by multivariate regression analysis. Associations between PK and ORR or PFS were explored using univariate and multivariate logistic regression or Cox regression analyses. Results 90% of the 154 pts received 8 weekly infusions of ofatumumab and 55% received all 12 infusions. PK parameters were similar between FA-ref and BF-ref pts. In multivariate analysis, higher Cmax at Dose 1 was significantly associated with lower % of bone marrow infiltration (p<0.001), lower Rai stage (p=0.002), lower lymphocyte count (p=0.006), smaller BSA (p<0.001) and lower total bilirubin (p=0.013). The majority of responders and non-responders were still receiving treatment at Dose 8; thus, this dose represents an informative time point for analysis. Baseline factors that influenced PK parameters at Dose 8 are shown in the table. Based on univariate analyses, higher Cmax and Cmin at Dose 8 were associated with increased likelihood of response (Table); in addition, significantly higher Cmax, Cmin and AUC were observed in responders versus non-responders (p<0.05 for each; data not shown). Higher Cmax, AUC and Cmin and lower CL at both Doses 8 and 12 were significantly correlated with longer PFS (p<0.05 for each). Based on exploratory multivariate analyses, PK parameters were not independent predictors of ORR or PFS. Conclusions These data demonstrate that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. The pivotal study is ongoing, and further analyses of associations between disease-related factors, PK and treatment response will be performed at study completion. Such analyses will help us to better understand the response kinetics of biological therapy and to optimize the dose. Disclosures Österborg: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Biilmann Ronn:Genmab: Employment. Jewell:GlaxoSmithKline: Employment, Equity Ownership. Kipps:Physicians' Educational Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Mayer:GlaxoSmithKline: Consultancy. Stilgenbauer:GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Hellmann:Novartis, BMS: Consultancy, Honoraria. Robak:GlaxoSmithKline, Roche: Advisory Board, Research Funding. Furman:GlaxoSmithKline: Consultancy, Speakers Bureau. Hillmen:GlaxoSmithKline: Consultancy, Honoraria for Advisory Boards. Trneny:GlaxoSmithKline: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Kozak:GlaxoSmithKline, Amgen: Consultancy. Chan:GlaxoSmithKline: Employment. Arning:GlaxoSmithKline: Employment, Equity Ownership. Losic:Genmab: Employment, Stock Ownership. Davis:GlaxoSmithKline: Employment, Stock ownership. Wilms:Genmab: Employment, Equity Ownership. Russell:Genmab: Employment, Equity Ownership. Wierda:Genmab, GlaxoSmithKline: Honoraria, Research Funding.

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A Phase I Study Combining CDK2/9 Inhibitor CYC065 with Venetoclax, a BCL2 Inhibitor, to Treat Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood-2019-128956 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1761-1761

Author(s):

William G. Wierda ◽

Seung Tae Lee ◽

Rong Chen ◽

Daniella Zheleva ◽

David Blake ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Annual Meeting ◽

Research Funding ◽

Human Study ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Downstream Targets ◽

Protein Levels ◽

Equity Ownership ◽

Rnap Ii

Cyclin dependent kinases (CDKs) are critical for cell cycle regulation and transcriptional elongation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased survival. CYC065 is a potent and orally‐available inhibitor of CDK2 and CDK9. CDK9 regulates transcription of genes through phosphorylation of RNA polymerase II (RNAP II) C-terminal domain (CTD). Through inhibition of CDK9, CYC065 suppresses CDK9-dependent gene expression and reduces the level of MCL1, a key anti-apoptotic protein. In the first-in-human study, CYC065 was administered by 4-hour infusion every 3 weeks in patients with advanced solid cancers. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of RNAP II CTD Ser2, a direct substrate of CDK9, and protein levels of downstream targets, such as MCL1, were determined in patient peripheral blood mononuclear cells (PBMCs). Durable MCL1 suppression was observed after a single dose in 11 out of 13 patients treated at the recommended phase 2 dose (RP2D) of 192 mg/m2. Five of these 13 patients achieved stable disease lasting ≥6 cycles (Do, KT et al, AACR Annual Meeting 2018 Abs CT037). Chronic lymphocytic leukemia (CLL) is a disease that depends upon the overexpression of anti-apoptotic proteins (MCL1, BCL2) for survival. Venetoclax, a BCL2 inhibitor, is one of the most active agents against CLL. However upregulation of MCL1 is associated with resistance to venetoclax (Oppermann S et al., Blood, 2016). Preclinical studies have demonstrated that CYC065 and venetoclax are synergistic in primary CLL cells, inducing apoptosis (Chen R et al, AACR Annual Meeting 2018 Abs 3905). This synergy may arise from targeting parallel anti-apoptotic mechanisms in the intrinsic apoptotic pathway that promote survival in CLL cells. The above findings support the conduct of an ongoing clinical study (NCT03739554) investigating a combination of CYC065 with venetoclax in CLL. CYC065 will be administered intravenously via 4-hour infusion on Day 1 and Day 15 in combination with daily venetoclax. One cycle is 28 days. Initial dose escalation is 33% and then 25% upon occurrence of the first dose limiting toxicity (DLT). RP2D is the highest dose level at which less than one-third of at least 6 patients experience a DLT during the first treatment cycle. Eligible patients are ≥18 years with CLL relapsed or refractory to standard treatment(s) including those with Richter transformation; adequate bone marrow, renal and liver functions are required. All patients will be asked to participate in the pharmacokinetic and pharmacodynamic studies. Plasma levels of CYC065 and its metabolites as well as venetoclax will be determined. PBMCs will be collected to assess MCL1 levels and phosphorylation and protein levels of other downstream targets of CDK9 inhibition. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and CT scans will be performed regularly to assess response according to standard criteria. Disclosures Wierda: Pharmacyclics LLC: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Gilead Sciences: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc: Research Funding. Chen:Cyclacel Ltd: Research Funding. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Plunkett:Cyclacel Ltd: Research Funding.

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Final Results from the Multicenter, Open-Label, Phase II GIBB Study of Obinutuzumab+Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-122482 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4317-4317

Author(s):

Jeff P. Sharman ◽

John M Burke ◽

Habte A Yimer ◽

Michael A. Boxer ◽

Sunil Babu ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Peripheral Blood ◽

Research Funding ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Induction Treatment ◽

Open Label ◽

Equity Ownership ◽

Anti Cd20 ◽

Over Time

Background: Bendamustine+rituximab (BR) is an effective chemoimmunotherapy for newly diagnosed chronic lymphocytic leukemia (CLL) and is the most commonly used chemoimmunotherapy in CLL patients requiring therapy (Seymour et al. Cancer. 2019). In a phase III study, the anti-CD20 antibody obinutuzumab (G) showed improved survival in combination with chlorambucil (clb) compared with rituximab (R)+clb, suggesting that G may be a better anti-CD20 monoclonal antibody to combine with bendamustine (B). Here, we report the final study results for the phase II, single-arm, open-label GIBB study (NCT02320487), in which the combination of bendamustine+obinutuzumab (BG) was evaluated in previously untreated patients with CLL. This is also one of the first studies to characterize the evolution of minimal residual disease (MRD) status over time in previously untreated CLL patients receiving chemoimmunotherapy. Methods: Newly diagnosed patients requiring treatment for CLL had ECOG PS 0-2, and adequate cell counts and organ function. BG treatment was given IV over six 28-day (d) cycles and included obinutuzumab (cycle 1: 100 mg d1, 900 mg d2, and 1000 mg on d8 and d15, and cycles 2-6: 1000 mg d1 of each cycle) plus bendamustine (90 mg/m2 cycle 1: d2 and d3; and cycles 2-6: d1 and d2). The primary end point was complete response (CR), including CR and incomplete CR (CRi), per 2008 iwCLL guidelines after induction treatment. Secondary end points included progression-free survival (PFS) and overall survival (OS). MRD negativity (MRD−) was defined as < 1 cell per 10,000 leukocytes (ie, 10−4) and was measured at baseline, end of treatment (28 d after cycle 6), clinical response assessment, and every 6 months thereafter for ≤ 2 years. Results: Overall, 102 patients were enrolled on this study. Patients had a median age of 61 years (range, 35-90), and 97% had ECOG PS of 0-1. Of 74 patients evaluated for IgVH status, 49 patients (66%) had unmutated IgVH. Overall, 79% of patients completed 6 cycles of BG. 50% of patients achieved a CR/CRi (95% CI, 40%-60%), which contributed to an 89% overall response rate (95% CI, 82%-95%). At a median follow-up of 34.3 mo, median PFS was 35.5 mo (95% CI, 35.0 mo to not reached) and median OS was not reached (Figure 1). Seven patients died during the study (3 from cardiac events not attributed to treatment by investigators and 4 from other non-progressive disease causes). The most common grade 3/4 treatment-emergent adverse events (> 5%) were neutropenia (25%), infusion-related reactions (9%), anemia (8%), thrombocytopenia (8%), pneumonia (6%), and tumor lysis syndrome (6%). The rate of grade 3/4 febrile neutropenia was 5%. Achievement of MRD− in evaluable peripheral blood and bone marrow at the clinical response assessment was shown in 33/74 (45%; 95% CI, 33%-57%) and 30/51 (59%; 95% CI, 44%-72%) patients, respectively. In the 79 patients (77%) who achieved MRD− in peripheral blood throughout the study, the median duration of MRD− response was 28.9 mo (95% CI, 23.0 to not reached). Of these 79 MRD− patients, 28 became MRD+, and the median time from identification of MRD+ status to progressive disease/death was 10.5 mo (95% CI, 6.3-17.9). An exploratory Cox proportional multivariate analysis identified 2 factors that were significantly associated with longer durations of MRD− responses: mutated (vs unmutated) IgVH with a HR = 0.13 (95% CI, 0.03-0.61), and CD38 ≥ 30% (vs < 30%) with a HR = 0.35 (95% CI, 0.14-0.92). When stratified by IgVH status, the PFS distributions for IgVH mutated and unmutated groups were similar (Figure 1). Median OS was not reached in all patients and irrespective of IgVH status. Conclusions: Final results for the GIBB study showed that the BG combination was an effective regimen for previously untreated patients with CLL, with no unexpected safety signals. Complete response and MRD− in peripheral blood were achieved in approximately half of all patients after induction treatment and persisted over time. IgVH mutated status was associated with a longer duration of MRD− and median PFS. In summary, BG is a clinically active CLL regimen with durable MRD− rates over time; overall outcomes are consistent with other firstline studies of anti-CD20 antibody and bendamustine combinations. Disclosures Sharman: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Yimer:Amgen: Consultancy; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Boxer:Rigel: Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Arizona Oncology: Employment; Incyte: Speakers Bureau; Gerson Lerman: Consultancy; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau. Babu:Fort Wayne Medical Oncology & Hematology: Employment; Bristol Myers Squibb: Consultancy, Research Funding; Fort Wayne Medical Oncology & Hematology: Equity Ownership; Abbvie: Research Funding; Eli Lilly: Honoraria, Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Incyte: Research Funding; AstraZeneca: Honoraria; Lutheran Hospital, Fort Wayne, Indiana: Membership on an entity's Board of Directors or advisory committees. Li:Roche: Equity Ownership; Genentech: Employment. Mun:Genentech: Employment, Equity Ownership. Danilov:Curis: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Abbvie: Consultancy; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Seattle Genetics: Consultancy; Janssen: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination therapy of obinutuzumab and bendamustine in previously untreated patients with chronic lymphocytic leukemia.

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Mechanisms of Adaptation to Ibrutinib in High Risk Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-116739 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 585-585 ◽

Cited By ~ 4

Author(s):

Valeria Spina ◽

Gabriela Forestieri ◽

Antonella Zucchetto ◽

Alessio Bruscaggin ◽

Tamara Bittolo ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Nuclear Localization ◽

Peripheral Blood ◽

Research Funding ◽

Clonal Evolution ◽

Lymphocytic Leukemia ◽

Adaptation Process ◽

Over Time ◽

Stimulation Of

Abstract Introduction. Ibrutinib inhibits the BTK molecule downstream the B-cell receptor (BCR). Though highly active in high risk chronic lymphocytic leukemia (CLL), the most typical response achievable in patients is a minimal residual disease (MRD) positive partial remission (PR) which is maintained until the development of genetically driven resistance caused by the acquisition of mutations in the BTK or PLCG2 genes. The study aims at characterizing the adaptation process allowing residual CLL cells to persist despite BTK inhibition. Methods. The IOSI-EMA-001 study (NCT02827617) is an observational study consisting in the prospective and longitudinal collection of peripheral blood samples and clinical data from high risk CLL patients treated with ibrutinib. Peripheral blood CLL cells longitudinally drawn from patients before treatment start and at fixed timepoints under ibrutinib were monitored by: i) next generation flow cytometry approaches for changes in proliferation rate, surfaceome, and pathway activation; and ii) CAPP-seq targeted deep next generation (sensitivity ~10-3) for clonal evolution. Results. The study cohort comprised 31 high risk CLL patients, including 15 treatment naïve, 16 relapsed, 80% IGHV unmutated, 42% 17p deleted and 55% TP53 mutated. Median duration of ibrutinib treatment was 45 weeks (24-72 weeks). All patients obtained a MRD positive PR that was maintained in all but one who progressed with a PLCG2 mutation (VAF 3%). Compared to baseline, under ibrutinib therapy CLL cells slowed down their proliferation, as suggested by the decreased expression of Ki-67, the reduction of the proliferating fraction (CXCR4dimCD5bright), and the increase of the resting fraction (CXCR4brightCD5dim). Compared to baseline, under ibrutinib therapy CLL cells also upregulated BCR and adhesion/homing proteins, and decreased the expression of BCR inhibitor proteins. Upon stimulation of the BCR with anti-IgM, the downstream path through pBTK and pPLCG2 was inhibited by ibrutinib, while conversely the downstream path through pAKT and pERK was still inducible throughout all the assessed timepoints. The proportion of CLL cells harboring nuclear localization of NF-kB progressively increased over time under ibrutinib. NF-kB nuclear localization was inducible throughout all the assessed timepoints by CD40L stimulation of the non-canonical NF-kB pathway, but not by anti-IgM stimulation of the BCR/canonical NF-kB pathway. Overall, 880 individual mutations were longitudinally discovered and monitored across a total of 121 sequential timepoints collected during ibrutinib treatment. Clonal evolution was observed in (67.7%) cases, a proportion rate previously documented in CLL treated with chemoimmunotherapy. Clonal evolution appeared to be heterogeneous involving different genes without a stereotypic targeting. Consistently, none of the main driver gene mutations was homogeneously selected or suppressed by ibrutinib suggesting that the biological adaptation of CLL cells under ibrutinib is not genetically driven. Clonal evolution propensity was not associated with any of the biomarkers of the disease, and it did not decrease over time under ibrutinib. Conclusions. Taken together these results suggest that residual CLL cells persisting under ibrutinib therapy adapt their phenotype by upregulating adhesion molecules, chemokine receptors and BCR molecules, and by maintaining a competence of BCR signaling through the PI3K/AKT/ERK pathway. The progressive selection of CLL cells having NF-kB in the nucleus, likely due to the BTK independent non-canonical NF-kB pathway, might explain their survival despite ibrutinib therapy. Finally, clonal evolution is not suppressed by ibrutinib chemotherapy, and despite does not seem to be directly involved in such adaptation process, may ultimately favor the acquisition of BTK and PLCG2 ibrutinib resistance mutations. Disclosures Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Montillo:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Tedeschi:Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria.

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Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Final Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽

10.1182/blood-2019-123630 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3491-3491 ◽

Cited By ~ 1

Author(s):

Alexey Danilov ◽

Habte A Yimer ◽

Michael Boxer ◽

John M Burke ◽

Sunil Babu ◽

...

Keyword(s):

Quality Of Life ◽

Health Status ◽

Chronic Lymphocytic Leukemia ◽

Global Health ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Future Health ◽

Equity Ownership

Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

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