Detailed Safety Analysis of Venetoclax Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Abstract Background: Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor FDA-approved for patients with del(17p) chronic lymphocytic leukemia (CLL) and who have received ≥1 prior therapy. Based on preclinical evidence of synergy, VEN plus rituximab is being assessed in an ongoing Phase 1b study. Methods: Patients with relapsed/refractory (R/R) CLL received daily VEN with stepwise ramp-up over 3-4 weeks to reach daily doses of 200-600mg. After 1 week at the target dose, monthly rituximab was added for 6 doses. Responses and progression were assessed by iwCLL criteria with CT scan and bone marrow biopsy. Bone marrow assessments were done at screening, completion of combination therapy (month 7), and 2 months after clinical/radiologic criteria of iwCLL response were met. Minimal residual disease (MRD) was assessed in peripheral blood and marrow aspirates using ≥4 color flow cytometry (min sensitivity: 0.01%). Data cutoff was 04March2016, with analysis focusing on updated safety of cytopenias experienced on the course of treatment. Results: Forty-ninepatients enrolled (48 CLL/1 SLL). Patients had received a median of 2 prior therapies (range: 1-5) and disease in 25 (51%) was considered refractory to the most recent therapy. Median time on study was 28 (<1-42) months, with 31 patients active on study. Eighteen patients discontinued: 11 due to disease progression, 3 due to toxicity (peripheral neuropathy [1], MDS [1], and death due to TLS [1]), 3 withdrew consent, and 1 was lost to follow up. Across all doses, the most common AEs of any grade were diarrhea (57%), neutropenia (55%), upper respiratory tract infection (55%), and nausea (51%). Peripheral blood cytopenias were the most common Grade 3/4 AEs (neutropenia [53%], thrombocytopenia [16%], anemia [14%], febrile neutropenia [12%], and leukopenia [12%]). Twenty-seven (55%) patients had a history of neutropenia, of whom 6 were receiving G-CSF support prior to starting VEN. Overall, in the first month of therapy, 15 (31%) experienced an AE of neutropenia (any grade). Thereafter, the rate of new AEs of neutropenia decreased over time. While there was individual patient variability, mean ANC was stable over time. Overall, 26 (53%) patients had Grade 3/4 neutropenia. Neutropenia was generally well tolerated and managed by G-CSF support in 24 patients, in addition to ≥1 dose modification in 11 of the 24 patients. Of 8 (16%) patients who experienced grade 3 infections, 2 were while neutropenic. There were no grade 4 infections. Among the 11 (22%) patients who developed any-grade thrombocytopenia, none occurred within 2 weeks of a reported bleeding-related AE. One patient had thrombocytopenia overlapping with disease progression on therapy. Objective response rate for all patients was 86% (n=42), with 51% (n=25) who had complete response (CR/CRi; 12 achieved CR/CRi by month 7). At the completion of combination therapy (month 7), 39 patients had evaluable bone marrow assessments. Thirty (77%) had no histologic evidence of CLL in the bone marrow and 22 patients (56%) had attained bone marrow MRD-negativity. In longer follow up at any point during treatment for all 49 patients, 37 (75%) patients achieved complete marrow clearance and 28 (57%) achieved marrow MRD-negativity. Conclusions: Transient manageable neutropenia was the most common AE, with first onset usually seen within the first month of treatment and the onset of new neutropenia AEs decreased over time. No patients discontinued the study due to cytopenias. Patients were able to continue on study and high rates of response to treatment were observed. VEN given with rituximab achieved rapid and profound reductions in disease burden in peripheral blood and bone marrow. 77% of evaluable patients achieved morphologic clearance by month 7, and 57% were MRD-negative at any point on study. Figure 1 Figure 1. Disclosures Brander: TG Therapeutics: Research Funding; Gilead: Honoraria. Roberts:AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; AbbVie: Research Funding. Lash:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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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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Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽

10.1182/blood.v124.21.327.327 ◽

2014 ◽

Vol 124 (21) ◽

pp. 327-327 ◽

Cited By ~ 27

Author(s):

Susan O'Brien ◽

Jeffrey A. Jones ◽

Steven Coutre ◽

Anthony R. Mato ◽

Peter Hillmen ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Efficacy And Safety ◽

Advisory Committees ◽

Previously Treated ◽

Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

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Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green Study

Blood ◽

10.1182/blood.v126.23.493.493 ◽

2015 ◽

Vol 126 (23) ◽

pp. 493-493 ◽

Cited By ~ 9

Author(s):

Stephan Stilgenbauer ◽

Osman Ilhan ◽

Darius Woszczyk ◽

Christoph Renner ◽

Eva Mikuskova ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Safety And Efficacy ◽

Grade 3

Abstract Background The glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101; GAZYVA/GAZYVARO; G) combined with chlorambucil (Clb) has superior efficacy to Clb monotherapy and to rituximab plus Clb with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL), as shown in the CLL11 study (Goede V, et al. NEJM 2014). GREEN is an ongoing, non-randomized, multi-cohort phase IIIb study (NCT01905943) investigating the safety (primary objective) and efficacy of G alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL and assessing various strategies (cohorts 1-3) for reducing the rate of infusion-related reactions (IRRs) during the first infusion of G (Bosch F, et al. Blood 2014). We report safety and efficacy data from a subgroup of previously untreated patients in cohort 1 who received G-bendamustine (G-B). Methods Subjects were aged ≥18 years withdocumented CLL (except one case of SLL), an ECOG performance status of 0-2, and adequate hematologic function. Non-fit patients were those with a CrCl of <70 mL/min, and/or a CIRS score of >6. Fit patients comprised all others. Treatment was six 28-day cycles of G-B, where G was administered IV on D1/D2 of C1 (split dose: 25mg D1/975mg D2), and 1000mg on D8 and D15 of C1 and D1 C2-6. B was administered ≥30 minutes after G on D1 and D2 of each cycle at 90mg/m2 IV, or at 70mg/m2 in non-fit patients at the investigator's discretion. Safety endpoints included incidence, type and severity of AEs. Efficacy endpoints included ORR (investigator-assessed) and minimal residual disease (MRD) measured 3 months post-treatment. ORR was strictly assessed per International Workshop Group criteria (iwCLL 2008). Patients with missing response assessment components had their responses downgraded mandatorily. MRD negativity was defined as <1x10-4 malignant B cells in peripheral blood or bone marrow aspirate, measured in a central laboratory by 4-color flow cytometry. The population comprised all patients from cohort 1 of GREEN who received at least a partial dose of both G and B, and was based on a data cut-off of 26 March 2015. Results With a planned overall sample size of 950 patients in GREEN, the G-B subgroup in cohort 1 comprised 158 patients (157 CLL, 1 SLL; 74 fit, 84 non-fit). Median age was 67.6 years, 15.8% of patients had a CIRS score of >6, and 44.9% had a CrCl of <70 mL/min; 31.6% of patients had Binet stage A disease, 38% Binet B, and 30.4% Binet C. 7.0% of patients' disease displayed 17p deletion, 16.5% 11q deletion, and 58.2% unmutated IGHV. 91.1% of patients receiving B and 93.0% of those receiving G took ≥90% of the recommended total dose. The safety profile of G-B was as expected. 50% of patients developed grade 3-5 neutropenia and 12.7% developed a grade 3-5 infection. Other common grade 3-5 AEs included thrombocytopenia (12.7%) and tumor lysis syndrome (TLS; 10.1%). The most common serious AEs were neutropenia (10.8%), pyrexia (7.6%), febrile neutropenia (7.0%), and TLS (5.1%). There were nine deaths - one due to progression, and eight due to AEs (considered related to study drug by the investigator: 1 infection, 1 sudden death, 1 acute hepatic failure, and 1 febrile neutropenia combined with TLS; considered unrelated: 2 infections and 2 secondary neoplasms). IRRs occurred in 55.7% of patients (15.2% grade 3-5, none fatal). Overall, 26 patients (16.5%) prematurely discontinued treatment due to ≥1 adverse event. The ORR was 78.5% (124/158). The rate of CR (including incomplete CR [CRi]) was 32.3% (51/158), PR 46.2% (73/158), SD 10.8% (17/158), and PD 0.6% (1/158); 10.1% (16/158) of patients had missing data. Response rates were similar in non-fit (34.5% CR/CRi, 41.7% PR, 10.7% SD, and 1.2% PD) and fit (29.7% CR/CRi, 51.4% PR, 10.8% SD, and 0% PD) patients. In an intent-to-treat analysis including all missing (not taken or evaluable) MRD results, MRD negativity was 58.9% (93/158, including 56 missing) in blood and 27.8% (44/158, including 95 missing) in bone marrow. With a median observation time of 11.2 months, PFS data were immature and the median was not reached. Conclusions Treatment with G-B in previously-untreated CLL patients is generally well tolerated and the observed toxicities are manageable and not unexpected. G-B achieves a promising rate of CRs and a high rate of MRD-negative remissions, and may offer a new treatment option for fit and non-fit patients with CLL. Disclosures Stilgenbauer: Gilead: Honoraria, Research Funding. Off Label Use: 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 (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL. Renner:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Böttcher:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Research Funding; Beckton Dickinson: Honoraria. Tausch:Gilead: Other: Travel support. Moore:Roche: Employment. Tyson:Roche: Employment, Equity Ownership. Adamis:Roche: Employment. Leblonde:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Speakers Bureau. Bosch:Roche: Consultancy, Research Funding, Speakers Bureau. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-143473 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Paula A. Lengerke Diaz ◽

Michael Y. Choi ◽

Eider F. Moreno Cortes ◽

Jose V. Forero ◽

Juliana Velez-Lujan ◽

...

Keyword(s):

Bone Marrow ◽

Side Effects ◽

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Combination Regimen ◽

Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (>5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as <10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

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Preliminary Safety Results from the Phase IIIb GREEN Study of Obinutuzumab (GA101) Alone or in Combination with Chemotherapy for Previously Untreated or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v124.21.3345.3345 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3345-3345 ◽

Cited By ~ 7

Author(s):

Francesc Bosch ◽

Thomas Illmer ◽

Mehmet Turgut ◽

Agostino Cortelezzi ◽

Susan F. Lasserre ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Safety Data ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Phase Iiib ◽

Unfit Patients ◽

Grade 3

Abstract Background: The novel, glycoengineered type II anti-CD20 monoclonal antibody, obinutuzumab (GA101) has demonstrated superior efficacy to chlorambucil (Clb) monotherapy and to Clb in combination with rituximab (R-Clb) with an acceptable safety profile in CLL. However, an increased rate of infusion-related reactions (IRRs) has been observed with the obinutuzumab(G)-Clb combination compared with R-Clb during the first cycle of treatment. The GREEN study (NCT01905943) is an ongoing phase IIIb, multicenter, open-label trial investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL. We report safety data from cohort 1, which aimed to reduce IRRs on the first day of obinutuzumab administration in previously untreated patients using a lower dose and slower infusion rate than in previous studies. Methods: Subjects aged ≥18 years withdocumented CLL, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate hematologic function are enrolled. Treatment includes obinutuzumab (1000mg) administered intravenously on days (D) 1 (25mg) and 2 (975mg), D8, and D15 of cycle (C) 1, and on D1 of C2–6, alone (any patient: n=18) or in combination with 28-day cycles of chemotherapy: fludarabine plus cyclophosphamide (FC; n=46) for fit patients (cumulative illness rating scale [CIRS] ≤6 and creatinine clearance [CrCl] ≥70mL/min), Clb (n=8) for unfit patients (CIRS >6 and/or CrCl <70mL/min) or bendamustine (B; n=86) for fit/unfit patients. The primary outcome is safety, including the frequency, type and severity of adverse events (AEs). The present analysis focuses on IRRs, defined as treatment-related AEs occurring during or within 24 hours of infusion. Results were assessed to determine if a low obinutuzumab dose (25mg) and slow infusion rate (12.5mg/hour) on D1 (the current recommended C1D1 regimen is 100mg at 25mg/hour) could reduce IRRs. Analysis was based on a data cut-off of 28 April 2014, planned for when the first 150 previously untreated patients had completed cohort 1. Results: Of 158 subjects eligible for the IRR analysis (Table), median age was 65.0 (34.0–83.0) years and the majority were males (65.2%) with Binet stage B (52.5%) or C (31.0%) CLL. Median observation time was 2.09 (0.2–6.0) months and median exposure time was 1.0 (0.0–4.8) month. IRRs occurring in ≥10% of patients were chills (14.6%) and pyrexia (15.2%). Serious IRRs in ≥1% of patients were tumor lysis syndrome (TLS; 3.8%) and pyrexia (1.3%). Grade ≥3 IRRs experienced by ≥1% of patients were TLS (5.7%), hypertension (1.3%) and hypotension (1.3%). IRRs were most frequent in C1D1 (Fig). In the overall safety population (n=172; previously untreated patients) the most frequently reported serious AEs of special interest included IRR (8.1%) and neutropenia (11.0%). AEs of particular interest, thrombocytopenia, cardiac, and hemorrhagic events, were experienced by 16.3%, 3.5% and 3.5% of patients, respectively. Table. Table. Conclusions: Preliminary safety data from the GREEN study, assessing the use of obinutuzumab alone or in combination with chemotherapy (B, FC or Clb) in subjects with untreated CLL, are in line with the known safety profile of obinutuzumab in similar populations. Although there is limited exposure time available for subjects in GREEN, IRRs seemed to be more manageable and a lower proportion of subjects with IRRs grade ≥3 was observed compared with previous studies. No new safety signals were reported. However, since the number of discontinuations during C1 was comparable with previous obinutuzumab studies, the decision was taken to further improve IRR rates by assessing additional dexamethasone premedication in cohort 2. Final safety data from the study will be presented at a later timepoint. Figure 1 Figure 1. Disclosures Bosch: Roche: Consultancy, Research Funding, Speakers Bureau. Off Label Use: 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 (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL.. Lasserre:F. Hoffmann–La Roche: Employment. Truppel-Hartmann:F. Hoffmann–La Roche: Employment. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Roche-Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding.

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Bone Marrow Hematopoietic Dysfunction in Untreated Chronic Lymphocytic Leukemia Is Partially Mediated By Exposure to Constituents of the Leukemic Microenvironment

Blood ◽

10.1182/blood-2018-99-118916 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3132-3132

Author(s):

Bryce Manso ◽

Kimberly Gwin ◽

Charla R Secreto ◽

Henan Zhang ◽

Wei Ding ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Healthy Controls ◽

Advisory Committees ◽

The Impact

Abstract Peripheral immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) is well-studied and likely relates to the incidence of serious recurrent infections and second malignancies that plague CLL patients. However, the current paradigms of known immune abnormalities are not able to consistently explain these complications and it is not easy to correct CLL patient immune status. Here, we expand on our preliminary reports that demonstrate bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. We found reduced short-term functional capacity of hematopoietic progenitors in BM using colony forming unit assays (Figure 1A-C) and flow cytometry revealed significant reductions in frequencies of hematopoietic stem and progenitor cell (HSPC) populations (exemplified by Lin-CD34+ HSPCs, Figure 1D). We further report that protein levels of the transcriptional regulators HIF-1α, GATA-1, PU.1, and GATA-2 are overexpressed in distinct HSPC subsets from CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Interestingly, sustained myelopoiesis, evaluated by limiting dilution analysis in long-term culture-initiating cell (LTC-IC) assays maintained for five weeks, revealed no difference between healthy controls and CLL patients. These new data indicate that when HSPCs are removed from the leukemic microenvironment for ample in vitro culture time, they recover the ability to sustain myelopoiesis. To further assess the impact of the CLL microenvironment on HSPC biology, isolated HSPCs (CD34+ BM cells) from healthy controls were exposed in vitro to known leukemic microenvironment constituents. Exposure to TNFα, a cytokine constitutively produced by CLL B cells, resulted in rapid increases in PU.1 and GATA-2 proteins (Figure 2A-D). Similarly, addition of TNFα to the LTC-IC assay resulted in a striking ablation of myelopoiesis, even at the highest input cell concentration. Further, overexpression of PU.1 and GATA-2 were observed in HSPCs following co-culture with CLL B cells, a result that was not recapitulated when cells were exposed to IL-10, another cytokine constitutively produced by CLL B cells. These findings indicate specific components of the leukemic microenvironment are involved in HSPC modulation. Together, these findings expand on our previous observations of BM hematopoietic dysfunction in untreated CLL patients and offer new molecular insights into the contribution of the leukemic microenvironment on immunodeficiency in CLL. Disclosures Ding: Merck: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Near-Tetraploidy Is Strongly Associated with Development of Richter's Transformation in Chronic Lymphocytic Leukemia Patients Receiving Ibrutinib

Blood ◽

10.1182/blood.v128.22.3198.3198 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3198-3198

Author(s):

Cecelia R. Miller ◽

Amy S. Ruppert ◽

Nyla A. Heerema ◽

Kami J. Maddocks ◽

Jadwiga Labanowska ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Complex Karyotype ◽

Advisory Committees ◽

Data Set ◽

Richter’S Transformation ◽

Richter's Transformation

Abstract Ibrutinib is a promising targeted therapy for chronic lymphocytic leukemia (CLL). However, a small subset of patients progress on ibrutinib either through progressive CLL or Richter's transformation. Patients responding to ibrutinib and then progressing with Richter's transformation do so most commonly within the first 2 years of treatment and have an extremely poor prognosis. Identifying biomarkers associated with this transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas; however, its incidence in CLL has not been described. We investigated the prevalence of near-tetraploidy in CLL patients prior to starting ibrutinib and identified it as a pre-treatment biomarker for Richter's transformation. We examined near-tetraploidy in a large series of CLL patients enrolled across four ibrutinib clinical trials at the Ohio State University, for which extensive correlative studies and follow up data are available (previously described by Maddocks et al., JAMA Oncol, 2015). We identified this abnormality in 9 of 300 patients (3.0%, 95% CI: 1.4-5.6) in blood or bone marrow samples taken prior to starting therapy. Near-tetraploidy was detected by the presence of four signals with four or more fluorescence in situ hybridization (FISH) probes and confirmed in the metaphase karyotype of each patient in at least one cell. Near-tetraploidy was associated with aggressive disease characteristics including: Rai stage 3/4 (p=0.03), deletion 17p (p=0.03), and complex karyotype (p=0.01), as well as trisomy 12 (p=0.05). With a median follow-up time of 40.5 months, in patients positive with near-tetraploidy, one patient (11%) progressed with CLL on ibrutinib, six patients (67%) progressed with Richter's transformation, and two patients (22%) were still on treatment. Cumulative incidence of Richter's transformation was significantly higher in patients with near-tetraploidy (Figure; p<0.0001). Notably, near-tetraploidy was not associated with progression with CLL alone (p=0.53). In a multivariable model, both near-tetraploidy (HR 8.66, 95% CI 3.83-19.59, p<0.0001) and complex karyotype (HR 4.78, 95% CI 1.42-15.94, p=0.01) were independent risk factors for discontinuing ibrutinib due to Richter's transformation. Our results suggest that near-tetraploidy is a distinct biomarker to assess in patients initiating ibrutinib which would predict a high risk for Richter's transformation. As a biomarker it will be important to confirm this association in a second independent data set as well as interrogate the distinct pathophysiology of this genomic subset of CLL. Figure Figure. Disclosures Lozanski: Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Awan:Novartis Oncology: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Research Funding. Blum:Pharmacyclics: Research Funding. Woyach:Acerta: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding.

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Phase II Trial of Single Agent Panobinostat (LBH589) In Relapsed or Relapsed/Refractory Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood.v116.21.3952.3952 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3952-3952 ◽

Cited By ~ 7

Author(s):

Irene Ghobrial ◽

Tiffany Poon ◽

Meghan Rourke ◽

Stacey Chuma ◽

Janet Kunsman ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Stable Disease ◽

Research Funding ◽

Bone Marrow Involvement ◽

Ct Scans ◽

Advisory Committees ◽

Bone Marrow Biopsies ◽

Grade 3

Abstract Abstract 3952 Introduction: This study aimed to determine the safety and activity of panobinostat (LBH589) in patients with relapsed or relapsed/refractory Waldenstrom Macroglobulinemia (WM). This was based on our preclinical studies showing that panobinostat induces significant activity in cell lines and patient samples. Methods: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any prior lines of therapy, 2) measurable disease and symptomatic disease, 3) off prior chemotherapy> 3 weeks, or biological/novel therapy for WM > 2 weeks. Patients received panobinostat at 30 mg three times a week (Mondays, Wed and Fridays). Patients were assessed after every cycle for the first 6 cycles and then every 3 months thereafter. Subjects who had response or stable disease were allowed to continue on therapy until disease progression or unacceptable toxicity. A planned restaging was performed at the end of cycle 6 including CT scans and bone marrow biopsies. Results: Twenty-seven patients have been enrolled to date. The median age is 62 years (47-80), the median lines of prior therapy is 3 (range, 1–7). All of the patients received prior rituximab. The median hemoglobin at screening is 10.3 g/dL (range 8.2–14.3), the median IgM M-spike by protein electropheresis at study entry is 1.9 g/dL (range, 0.63–5.1), and median serum IgM at baseline is 3610 mg/dL (range, 804- 10, 300). The median bone marrow involvement at enrollment was high for patients with WM, 50%, range (5-95%), with more than 10 patients having 70% or higher bone marrow involvement at baseline. The median number of cycles on therapy is 4 (range 1 – 12). 4 of the patients came off due to toxicity. Minimal response (MR) or better has been achieved in 15 (60%) of patients, with 6 (24%) PR, 9 (36%) MR. In addition, 9 (36%) patients achieved stable disease and 1 (4%) showed progression. The median decrease in IgM is 1020 mg/dL (0- 3970 decrease in IgM) with a median % decrease of 37.13%. Responses were prompt. The median time to first response was 2 cycles (range, 2–4). Bone marrow biopsies at the end of study (or at 6 months follow up) are available on 7 patients, of which 3 showed a significant decrease in bone marrow involvement and 4 showed stable involvement. The 4 patients who had stable bone marrow disease showed 1 PR and 3 MR responses by paraprotein level. Grade 3 and 4 toxicities include 4 (15%) cases of anemia including 1 case of hemolytic anemia, 1 (3%) case of grade 4 leucopenia (but the patient had grade 3 leucopenia at baseline), 7 (26%) of neutropenia, 14 (52%) of thrombocytopenia, 1 (4%) grade 3 GI bleed due to thrombocytopenia, 1 (3%) Grade 4 hyperglycemia and 1 (3%) grade 3 syncope and 3 (27%) grade 3 fatigue. The most common grade 2 toxicities were thrombocytopenia, anemia, and fatigue. There were 5 (20%) cases of asymptomatic pulmonary infiltrates of ground glass opacity observed on routine CT scans in follow up. Of these, 3 came off study for other reasons not related to the pulmonary infiltrates, 1 received a course of corticosteroids and had improvement of infiltrates, and 1 had dose reduction of therapy. All patients except for 2 have been dose reduced due to thrombocytopenia, fatigue, diarrhea, or anemia. Dose reductions include 25 mg three times a week, 20 mg three times a week and 20 mg three times every other week. The protocol was amended to allow a starting dose of 25 mg three times a week, which is better tolerated than 30 mg in this patient population. Conclusions: Panobinostat is an active therapeutic agent in patients with relapsed or refractory WM, with an overall response rate of 60% in patients with relapsed or refractory WM. The dose schedule of 25 mg three times a week is better tolerated in this patient population. Further studies to include this agent in combination with rituximab or bortezomib are being evaluated. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Keryx Biopharmaceuticals: Honoraria. Treon:Millennium Pharmaceuticals, Genentech BiOncology, Biogen IDEC, Celgene, Novartis, Cephalon: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; Novartis Corporation: Research Funding; Genentech: Consultancy, Research Funding.

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Anti-CXCL12/SDF-1 Spiegelmer® Nox-A12 Alone and In Combination With Bendamustine and Rituximab In Patients With Relapsed Chronic Lymphocytic Leukemia (CLL): Results From A Phase IIa Study

Blood ◽

10.1182/blood.v122.21.1635.1635 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1635-1635 ◽

Cited By ~ 5

Author(s):

Marco Gobbi ◽

Michael Steurer ◽

Federico Caligaris-Cappio ◽

Marco Montillo ◽

Ann Janssens ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Additional Patient ◽

Dose Titration ◽

Advisory Committees ◽

Therapeutic Concept ◽

Design For All

Abstract Background NOX-A12 is a novel, potent, L-stereoisomer RNA aptamer (Spiegelmer(®)) that binds and neutralizes CXCL12/SDF-1, a chemokine which attracts and activates immune- and non-immune cells via interaction with its receptors, CXCR4 and CXCR7. The signaling of CXCL12 has been shown to play an important role in the pathophysiology of chronic lymphocytic leukemia (CLL), especially in the interaction of leukemic cells with tissue microenvironment. The therapeutic concept of NOX-A12 is to mobilize these bone marrow- and tissue-resident CLL cells into the blood, thereby removing CLL cells from the nurturing milieu and sensitizing them to cytotoxic drugs such as bendamustine and rituximab (BR). Methods To date, 19/33 planned patients have been enrolled into a multicenter Phase IIa study of NOX-A12 alone and in combination with BR in relapsed CLL patients. Here we report interim data on PK, PD and preliminary efficacy of a pilot group consisting of 3 cohorts of 3 patients each. In the pilot phase, cohorts received single doses of 1, 2 or 4 mg/kg NOX-A12 alone, respectively, two weeks prior to 6 cycles of combined treatment of NOX-A12 with BR repeated every 28 days. During combination therapy, NOX-A12 was administered 1-2 hours prior to rituximab following a dose titration design for all patients: NOX-A12 doses were increased from 1 mg/kg to 2 mg/kg and 4mg/kg at cycles 1, 2 and 3, respectively. During cycles 4-6, doses of NOX-A12 were kept at the highest individually titrated dose. Bendamustine (70 - 100 mg/m², according to SPC) was given on day 2 and 3 (cycle 1) or 1 and 2 (cycle 2-6), combined with 375 mg/m2 rituximab on day 1 for the first cycle and 500 mg/m2 for subsequent cycles. Tumor response was assessed according to NCI-WG 1996 criteria (updated by iwCLL 2008). Results In total, 10 patients were enrolled in the pilot group (one additional patient was enrolled due to one patients' under dosing). The median age was 69 years (range 57-77) with 8 women and 2 men being included. Median prior therapies were 2 (range 1-2), whereby all patients were bendamustine naïve and 6 patients had received rituximab treatment prior to enrolment. 2, 4 and 4 patients presented at screening with Binet stage A, B, and C, respectively. 8 patients showed at least 1 cytogenetic aberration at the beginning of treatment. Tumor assessments before enrolment and at end of cycles 3 and 6 were evaluated. Plasma profiles of NOX-A12 in the patient population of the pilot group (Figure 1) were similar to those of healthy volunteers in which a plasma half-life of approximately 38 h was observed. After single doses of NOX-A12, the exposure was dose-linear with peak plasma concentrations of 1.7, 3.5, and 6.7 µM in the corresponding cohorts. CLL cells in the peripheral blood were found to be increased throughout the observational period of 3 days (Figure 2). In all patients presenting with lymphadenopathy, the lymph node size decreased markedly. NOX-A12 as single agent was safe and very well tolerated. All patients responded to the combination treatment of NOX-A12 and BR (ORR 100%); one patient had to be withdrawn from treatment due to multiple infections during cycle 4 having achieved a partial response (PR). At the end of cycle 6, seven patients (78%) showed a PR and two patients (22%) achieved a complete remission (CR). In combination with BR, NOX-A12 was equally safe and well tolerated. Conclusions Proof of principle was achieved as single doses of NOX-A12 reached the expected plasma exposure which translated into an effective and prolonged mobilization of CLL cells into the peripheral blood. In addition, the 100% ORR and 22% CR as well as the virtual absence of additional toxicity on top of BR observed in this pilot group compares very favorably with historical controls. Provided that this promising clinical picture will be maintained in the total sample of 33 patients, further development of this novel anti-CXCL12/SDF-1 Spiegelmer(®) seems warranted. Disclosures: Montillo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dümmler:NOXXON Pharma AG: Employment. Zöllner:NOXXON Pharma AG: Employment. Zeitler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Kruschinski:NOXXON Pharma AG: Employment.

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A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽

10.1182/blood-2018-99-118990 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1863-1863

Author(s):

Juliana Velez Lujan ◽

Michael Y. Choi ◽

Chaja Jacobs ◽

Colin McCarthy ◽

Alaina Heinen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Grade 3

Abstract Standard treatment for patients with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the combined use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (Ibr), a first-in-class BTK inhibitor, is effective in previously untreated patients including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The complete response rate in patients receiving single agent Ibr is relatively low (overall response rate of 86% and complete response of 4% based on 2008 iwCLL criteria), though most patients have durable remissions. The combination of Ibr with mAbs like Obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, can ameliorate the Ibr-induced lymphocytosis and increase the overall and complete response rates. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibr in combination with G for first-line therapy of previous untreated pts with CLL. The study completed enrollment of 32 previously untreated patients with CLL. Patients received G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibr 420mg po (1-3 hours before starting G infusion), and daily for up to 3 years. All patients received prophylactic medications. Patients were assessed for response by 2008 iwCLL criteria two months after completion of G, as the primary efficacy endpoint. The median age of the patients was 65 (range: 46-78) years. 84% of the patients had a CIRS >6, 45% had a Rai stage III-IV and 19% had an ECOG performance ≤2. The median baseline absolute lymphocyte count (ALC) was 79x103/mm3(range: 1.4-412.4). Patients showed the following FISH/cytogenetic abnormalities: del(13q) in 55%, trisomy 12 in 23% and del(11q) in 19%. Only 2 (6%) of these patients showed del(17p). From the patients with IGVH mutational status available (n=17), 11 (65%) were unmutated (>98% homology). Most adverse events (AEs) were grade 1-2 (74%). Six patients (19%) had grade 1-2 G-infusion-related reaction (IRR) and only one patient (3%) showed grade 3 IRR (without the need for G discontinuation). We observed neutropenia (all grades: 52%, grade 3-4: 23%), thrombocytopenia (all grades: 71%, grade 3-4: 19%) and anemia (all grades: 26%). There were no cases of febrile neutropenia. Two patients (6%) had grade 1 bleeding (one patient with asymptomatic lower gastrointestinal bleeding and the second patient with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. Two patients (6%) developed pneumonia, one was community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Three patients (9%) discontinued Ibr due to atrial fibrillation grade 1 (n=1), rash and headaches grade 2 (n=1), and persistent grade 4 thrombocytopenia (n=1). Twenty-three patients were evaluable for response assessment by 2008 iwCLL criteria (median follow-up of 11 months). 84% of the patients showed a rapid decrease in ALC from baseline during the first cycle of treatment and only four patients (13%) required more than 3 cycles of treatment to achieve an ALC response. The overall response rate was 100%. The majority of pts had a partial response and six of 23 evaluable patients (26%) achieved a complete remission with detectable Minimal Residual Disease in the bone marrow by multiparametric flow cytometry. In summary, Ibr-G combination has been generally well tolerated. AEs have been consistent with the known safety profiles of Ibr and G individually. The patients that discontinued Ibr remain in follow-up without disease progression. 100% of evaluable patients achieved response after 6 months of combination therapy, and 26% of patients met CR criteria. One important finding thus far has been a very low rate of IRR, (19% grade 1-2 and 3% grade 3-4), suggesting that Ibr can strongly mitigate the incidence and severity of G associated IRR. Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Gilead: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Speakers Bureau. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.

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