Preliminary Results of a Phase 1b Study (GO28440) Combining GDC-0199 (ABT-199) with Bendamustine/Rituximab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Abstract Introduction New therapies are needed for patients (pts) with chronic lymphocytic leukemia (CLL). BCL2 is an anti-apoptotic protein that is overexpressed in CLL and may be associated with resistance to available therapies; GDC-0199 is an orally available, selective BCL2 inhibitor. The combination of bendamustine (B) and rituximab (R) has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated pts with CLL and is often used in these pts. Preclinical data suggest that GDC-0199 combined with BR may show synergistic activity in CLL. Moreover, clinical data from single-agent studies of GDC-0199, and in combination with rituximab in pts with CLL, support combining GDC-0199 with BR in this population. Data presented here are from an ongoing phase 1b study that is evaluating the maximum tolerated dose of GDC-0199 when given in combination with BR, as well as the safety, tolerability, and order of administration of this combination in R/R or previously untreated pts with CLL. Methods Pts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts ranging from 100 to 600 mg/day of GDC-0199 using a 3+3 dose escalation design. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or BR (Schedule B) introduced first, both incorporating a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS). Prophylaxis measures to mitigate TLS include IV hydration, treatment to prevent hyperuricemia and hospitalization. After completing combination therapy, R/R pts will continue single-agent GDC-0199 until disease progression. Previously untreated pts will continue single-agent GDC-0199 for up to 18 months. Dose-limiting toxicity (DLT) data are identified after all pts in a cohort have completed ³21 days of combination treatment at the target dose of GDC-0199 and focus on treatment emergent TLS and cytopenias. Figure 1 Figure 1. Results As of May 2014, 6 pts with R/R CLL have been enrolled in the dose finding stage of the study with a median time on study of 67 (range 43-113) days. All 6 pts were enrolled on Schedule A; 3 pts were enrolled in the 100 mg GDC-0199 cohort and 3 pts were enrolled in the 200 mg cohort. Baseline characteristics of the 6 pts are as follows: median age 67 (range 52-71) years, 3 male pts, median of 2 prior CLL therapies (range 1-3, including 4 pts with previous exposure to fludarabine, cyclophosphamide and rituximab [FCR] and 1 with previous exposure to FCR and B), beta-2 microglobulin ≥3.5 mg/L in 2 pts, and unmutated IGHV in 5 pts. Prior to starting therapy, the median lymphocyte count was 40.85 x 109 cells/L (range 2.11-169 x 109 cells/L), hemoglobin level was 101.5 g/L (range 99-134 g/L), neutrophil count was 2.54 cells/μL (range 1.81-3.8 cells/μL), and platelet count was 83.5 x 109/L (range 49-250 x 109/L). Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 1 pt, medium risk 4 pts, and high risk 1 pt. Cytogenetic data are available for 3 pts: 1 pt had del17p, 2 pts had del 11q, and 3 pts had del 13q. No DLTs were observed. All 6 pts have experienced adverse events (AEs, Figure 2). The most common AE was anemia with most Grade ³3 AEs being hematological toxicities (Figure 2). One serious AE of bronchitis was observed in a pt enrolled in the 100 mg GDC-0199 cohort and resolved after treatment. Two pts in the 100 mg GDC-0199 cohort discontinued BR after the 21-day DLT window secondary to treatment emergent cytopenia: 1 with neutropenia after completing 1 cycle of BR (previous treatment FCR without baseline cytopenia) and the second with thrombocytopenia after completing 3 cycles of BR (previous treatment FCR and chlorambucil with thrombocytopenia at screening). Both pts remain on single-agent GDC-0199. No TLS events (laboratory or clinical) were observed and no deaths reported. Figure 2 Figure 2. Conclusion This is the first study to evaluate the combination of GDC-0199 and BR in pts with CLL. Despite 5 pts being identified as medium or high risk for TLS, no pts developed TLS as a result of the ramp-up dosing of GDC-199 and prophylactic measures. The most frequent AEs were hematological toxicities and generally manageable; however, 2 pts had to discontinue BR (after 1 and 3 cycles) but were able to remain on GDC-0199. Dose escalation in R/R pts is continuing in order to evaluate the optimal dose/schedule with a plan to enroll previously untreated pts in the near future. Disclosures Boyd: Genentech: Research Funding; US Oncology/McKesson: Research Funding; Celgene: Consultancy. Morschhauser:Genentech: Travel grant Other; Gilead, Mundipharma, Bayer, Spectrum, Celgene: Honoraria. Wendtner:AbbVie, Genentech, Hoffman-La Roche, Mundipharma: Consultancy, Research Funding. Lymp:Genentech: Employment. Hilger:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Stilgenbauer:Genentech, Hoffman La Roche: Honoraria, Research Funding.

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Subcutaneous Epcoritamab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Preliminary Results from the Epcore CLL-1 Trial

Blood ◽

10.1182/blood-2021-146563 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2627-2627

Author(s):

Arnon P. Kater ◽

Jacob Haaber Christensen ◽

Hans Herluf Bentzen ◽

Carsten Utoft Niemann ◽

Martin Hutchings ◽

...

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Research Funding ◽

Injection Site Reaction ◽

Steering Committee ◽

Lymphocytic Leukemia ◽

Site Reaction ◽

Phase 1B ◽

Dose Levels

Abstract Background: Small molecules such as Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors have transformed the management of chronic lymphocytic leukemia (CLL). However, such treatments are not curative, and patients (pts) with relapsed or refractory (R/R) CLL following multiple targeted treatments present an emergent challenge with very limited therapeutic options. In addition, success rates of autologous T-cell-based therapies in CLL have been disappointing. In vitro data in CLL cells suggest potentially high efficacy of bispecific T-cell engagers (Martens et al, J Immunother Cancer 2020), but clinical data are extremely limited. Epcoritamab (GEN3013; DuoBody ®-CD3×CD20) is a bispecific antibody that can induce potent activation and cytotoxic activity of CD4+ and CD8+ T cells to specifically eliminate CD20-expressing cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human trial in R/R B-cell non-Hodgkin lymphoma (B-NHL; EPCORE NHL-1; NCT03625037), epcoritamab showed manageable safety and meaningful antitumor activity across a range of aggressive and indolent B-NHLs. The most common treatment-emergent adverse events (AEs) were pyrexia (69%), cytokine release syndrome (CRS; 59%), and injection-site reaction (47%); CRS events were all grade 1-2 and most occurred in cycle 1 (Clausen et al, J Clin Oncol 2021). However, as CLL is characterized by presence of (high numbers of) circulating tumor cells, acquired T-cell dysfunction, and variable expression of CD20, data obtained in B-NHL are difficult to extrapolate to CLL. Herein we present the first results from the dose-escalation part of a phase 1b/2 trial evaluating epcoritamab in pts with R/R CLL. Methods: In this open-label, multicenter, phase 1b/2 trial, toxicity and efficacy of epcoritamab are investigated in adults with R/R CLL (EPCORE CLL-1; NCT04623541). Eligible pts previously received ≥2 lines of systemic antineoplastic therapy, including treatment with (or intolerance to) a BTK inhibitor. Epcoritamab is subcutaneously administered via 1-mL injections in 4-week cycles as follows: once weekly in cycles 1-3, every 2 weeks in cycles 4-9, and monthly in cycles ≥10 until progression or unacceptable toxicity. Step-up dosing during cycle 1 (ie, priming dose followed by an intermediate dose, then full doses) is used in combination with steroid prophylaxis to reduce the risk of CRS. In the dose-escalation part, pts with R/R CLL received epcoritamab at 2 full-dose levels (24 and 48 mg) according to a modified 3+3 design. Primary end points of the dose-escalation part included dose-limiting toxicities (DLTs) during the first 28-day treatment cycle and the incidence and severity of AEs, CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor lysis syndrome (TLS). Results: The first pt was enrolled on November 30, 2020. As of July 12, 2021, 7 pts with R/R CLL received epcoritamab subcutaneously administered at 2 full-dose levels: 24 mg (n=3) and 48 mg (n=4). Six pts completed the DLT evaluation period, and 5 pts had a full response assessment. Pts had received a median of 4 lines of prior therapy (range, 2-5). Six of 7 pts had poor-risk features of del(17p), TP53 mutations, or both. Three of 7 pts had bulky disease. No DLTs occurred at 24 or 48 mg. The most common treatment-emergent AEs (>30%) were CRS (100%), fatigue (71%), injection-site reaction (43%), and nausea (43%). All pts experienced CRS in the first cycle, but no CRS events were higher than grade 2. No cases of ICANS were observed. TLS was not observed. Antileukemic activity has been observed at both dose levels, with partial responses in 3 of 5 pts. Updated clinical and pharmacokinetic data, including data for additional pts treated with epcoritamab, will be presented. Conclusions: These data suggest that epcoritamab is well tolerated in pts with R/R CLL at dose levels up to 48 mg and has clinical activity in pts with high-risk features. The expansion part of this study in pts with R/R CLL and Richter syndrome will open later this year. Disclosures Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; Abbvie: Honoraria, Other: Ad Board, Research Funding. Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. Hutchings: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding. Chen: Genmab: Current Employment. Rios: Genmab: Current Employment. Palenski: AbbVie: Current Employment. Li: Genmab: Current Employment. Mato: AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; MSKCC: Current Employment; Genmab: Research Funding; Johnson and Johnson: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; DTRM BioPharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; AstraZeneca: Consultancy; Sunesis: Consultancy, Research Funding.

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Combination Trial of Duvelisib (IPI-145) with Bendamustine, Rituximab, or Bendamustine/Rituximab in Patients with Lymphoma or Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v126.23.3928.3928 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3928-3928 ◽

Cited By ~ 12

Author(s):

Ian W. Flinn ◽

Mohamad Cherry ◽

Michael Maris ◽

Jeffrey V. Matous ◽

Jesus G. Berdeja ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Expansion Phase ◽

Time Plot

Abstract Background: Duvelisib, a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) is being developed as a potential therapeutic in hematologic malignancies including chronic lymphocytic leukemia (CLL), as well as B and T cell lymphoma. Single agent bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with bendamustine or rituximab alone or with both drugs may improve response rates and the durability of remission. The primary objective of this trial is to characterize the safety, maximum tolerated dose (MTD), and a preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL. Methods: Pts with relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function were enrolled. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID until disease progression or intolerance. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV for NHL pts or 70 mg/m2 IV for CLL pts on Days 1 and 2 of the first six cycles plus duvelisib PO BID until disease progression or intolerance. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib, 25, 50, and 75 mg PO BID were initially explored. Pts were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and April 2015, 48 pts, median age 67 yrs (40-83) were enrolled; 12 NHL pts in the dose escalation portion and 36 pts (18 CLL, 18 NHL) in dose expansion. Pts had a median of 2 prior therapies (1-7). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB), with a higher dose of bendamustine, 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). The MTD was not reached in this study but given recent data of single agent duvelisib showing no advantage in doses >25 mg BID, pts on the expansion phase were treated with 25mg BID. The AE profile of the drug combination is consistent with toxicities of the single agents (Table 1). There have been 2 potentially treatment-related deaths (cardiac arrest in a pt with history of hypertension and diabetes, and pneumonia), both on Arm 1. 38 pts were evaluable for response with an ORR of 74% (8% CR, 66% PR, 16% SD and 10% PD). The ORR of NHL and CLL pts were 64% and 92% respectively. With a median follow up of 16.25 mos, median progression free survival is 13.7 mos overall. Median overall survival (OS) has not been reached, but 15 mo OS probability is 82%. Pharmacokinetics analysis is consistent with the monotherapy Phase I trial of duvelisib (Figure 2) and is not effected by bendamustine. Conclusions: Analysis of duvelisib administered in combination with bendamustine and rituximab shows these combinations to be generally well-tolerated with encouraging response. Further follow-up is required to better characterize both response rates and durability of remissions. Table 1. Treatment-related AEs (≥15% all pts) ARM 1 (N=28) ARM 2 (N=18) ARM 3 (N=2) Preferred Term G 1/2 G 3/4 G 1/2 G 3/4 G 1/2 G 3/4 Treated (N=48) RASH 8 (29%) 3 (11%) 3 (17%) 3 (17%) 0 17 (35%) DIARRHEA 8 (29%) 3 (11%) 2 (11%) 1 (6%) 1 (50%) 0 15 (31%) FATIGUE 9 32%) 0 4 (22%) 1 (6%) 1 (50%) 0 15 (31%) NAUSEA 5 (18%) 0 4 (22%) 0 1 (50%) 0 10 (21%) ALANINE AMINOTRANSFERASE INCREASED 5 (18%) 1 (4%) 3 (17%) 0 0 0 9 (19%) NEUTROPENIA 1 (4%) 5 (18%) 0 3 (17%) 0 0 9 (19%) ASPARTATE AMINOTRANSFERASE INCREASED 4 (14%) 1 (4%) 3 (17%) 0 0 0 8 (17%) ANAEMIA 3 (11%) 1 (4%) 2 (11%) 0 1 (50%) 0 7 (15%) PRURITUS 3 (11%) 0 3 (17%) 0 0 0 6 (13%) UPPER RESPIRATORY TRACT INFECTION 5 (18%) 0 1 (6%) 0 0 0 6 (13%) CONSTIPATION 4 (14%) 0 1 (6%) 0 0 0 5 (10%) MUCOSAL INFLAMMATION 3 (11%) 1 (4%) 1 (6%) 0 0 0 5 (10%) Figure 1. Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear) Figure 1. Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear) Disclosures Flinn: Celgene Corporation: Research Funding. Berdeja:Curis: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Array: Research Funding; Acetylon: Research Funding; Takeda: Research Funding; Celgene: Research Funding; BMS: Research Funding; Onyx: Research Funding; MEI: Research Funding; Novartis: Research Funding.

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A Dose Escalation Study of Ibrutinib with Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Blood ◽

10.1182/blood.v124.21.1987.1987 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1987-1987 ◽

Cited By ~ 10

Author(s):

Daniel A. Pollyea ◽

Steven Coutre ◽

Lia Gore ◽

Nichole Adler ◽

Pamela Harris ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Median Number ◽

Lymphocytic Leukemia ◽

Small Lymphocytic Lymphoma ◽

Bcr Signaling ◽

Expansion Cohort

Abstract Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is dependent upon dysregulated signaling through the B-cell receptor (BCR) pathway. Bruton’s tyrosine kinase (BTK) mediates BCR signaling, and inhibition of BTK with ibrutinib, a selective, irreversible BTK inhibitor, is effective and well tolerated for patients (pts) with relapsed/refractory CLL/SLL. However, complete remissions (CRs) are infrequent, mechanisms of resistance to single-agent ibrutinib have been identified, and the duration of response beyond 3 years is unknown. Lenalidomide, a multi-functional immunomodulatory agent, is active in CLL/SLL, but limited by tumor flare reactions, which occur secondary to B-cell activation. Ibrutinib and lenalidomide modulate several key overlapping factors involving the CLL tumor microenvironment, and therefore a phase 1 combination study with lenalidomide dose escalation was undertaken. Methods: The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with ibrutinib. Secondary objectives included assessments of efficacy, PK/PD, and other mechanistic correlative studies. A 1-month (cycle 0) period of 420 mg of daily oral ibrutinib was administered as a single agent to decrease BCR signaling and mitigate lenalidomide-associated tumor flare. Beginning with the second month (cycle 1), ibrutinib was given concomitantly with lenalidomide. Four dose escalation cohorts of lenalidomide were planned using a 3+3 design; 2.5, 5, 7.5 and 10 mg. After the 2.5 mg cohort, intra-patient dose escalation was employed: in cohort 2, pts received 2.5 mg in week 1 followed by 5 mg subsequently; pts in cohort 3 received 2.5 mg in week 1, 5 mg in week 2 and 7.5 mg subsequently; pts in cohort 4 will receive 2.5 mg in week 1, 5 mg in week 2, 7.5 mg in week 3 and 10 mg subsequently. Ibrutinib was not dose escalated (420 mg). Pts receive 12 cycles of the combination, after which lenalidomide is discontinued and ibrutinib continues until unacceptable toxicity or disease progression. Eligible pts had relapsed/refractory CLL/SLL with adequate organ and bone marrow function. Pts who relapsed after stem cell transplantation were excluded. Results: To date, 11 pts were enrolled; 9 are evaluable (1 voluntarily withdrew consent prior to completing 3 cycles, the protocol-defined minimum to be evaluable, and 1 was a screen fail). The median age was 65 (49-81). Eight were male and 8 had CLL. Median Rai stage was 1 (1-4). The median number of prior therapies was 2 (range 1-8); 3 were purine analog resistant. Six had bulky (>5 cm) disease. Two had del(17p13.1) and 4 had del(11q22.3). The median number of cycles completed was 8 (range 1-13). Adverse events (AEs) were reported according to the NCI CTCAE v4.0. Possibly related grade 1/2 AEs that occurred in >1 patient included: rash (n=4), muscle cramps (n=3) and abdominal discomfort (n=2). Possibly related grade 3 AEs included neutropenia (n=4), lymphocytosis (n=2), neutropenic fever (n=1), anemia (n=1) and thrombocytopenia (n=1). There was 1 possibly related grade 4 AE, neutropenia, which was pre-defined as DLT, in the 7.5 mg lenalidomide cohort. One patient experienced grade 2 tumor pain, thought to be due to a lenalidomide-associated tumor flare reaction. Four pts required a lenalidomide dose reduction, for neutropenia (n=2) and fatigue (n=2). Six required a treatment hold, of either lenalidomide or both agents, for a median 7 days (2-28), for neutropenia (n=2), anemia (n=1), fatigue/diarrhea (n=1), atrial fibrillation (n=1) and to obtain a lymph node biopsy (n=1). Lymphocytosis was noted in 5 pts, peaking at a median of 22.5 days. The ORR is 100% (9/9), with all responders experiencing PRs. One progressed with Richter’s transformation during cycle 7, 4 months after achieving a PR. All 9 remain alive with a median follow up of 263 days (range 97-391). The 7.5 mg dose cohort is currently being expanded to 6 pts; after the MTD is determined, a 10 patient dose expansion cohort will commence. Conclusions: Ibrutinib with lenalidomide appears to be well tolerated, although lenalidomide dose reductions were common. Tumor flare reactions were rare. Response assessments at higher dose cohorts of lenalidomide are ongoing. Completed phase 1 data, preliminary data from the expansion cohort and correlative findings will be presented. Disclosures Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for CLL/SLL. Byrd:Genentech: Research Funding; Pharmacyclics: Research Funding.

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Phase II Study of Flavopiridol in Relapsed Chronic Lymphocytic Leukemia Demonstrating High Response Rates in Genetically High-Risk Disease

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.6944 ◽

2009 ◽

Vol 27 (35) ◽

pp. 6012-6018 ◽

Cited By ~ 160

Author(s):

Thomas S. Lin ◽

Amy S. Ruppert ◽

Amy J. Johnson ◽

Beth Fischer ◽

Nyla A. Heerema ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Single Agent ◽

Tumor Lysis Syndrome ◽

Response To Therapy ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Treatment Schedule ◽

Genomic Features

PurposePatients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.Patients and MethodsPatients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy.ResultsSixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P ≤ .01), resulted in improved tolerability and treatment delivery.ConclusionFlavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.

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Preliminary Results of a Phase 1b Study (GP28331) Combining GDC-0199 (ABT-199) and Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.4687.4687 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4687-4687 ◽

Cited By ~ 8

Author(s):

Ian Flinn ◽

Mark Brunvand ◽

Martin JS Dyer ◽

Peter Hillman ◽

Jeffrey Jones ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Combination Therapy ◽

Research Funding ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

Phase 1B ◽

Cd20 Antibody ◽

Anti Cd20 ◽

Gradual Dose

Abstract Introduction Despite progress in chronic lymphocytic leukemia (CLL) treatment, new therapies are needed especially for relapsed/refractory (R/R) patients (pts). BCL2 is an anti-apoptotic protein expressed at high levels in all cases of CLL. GDC-0199 is an oral, highly selective BCL2 inhibitor. Clinical data for GDC-0199 have shown promising anti-CLL activity. Obinutuzumab (Gazyva®, Gazyvaro™) is a Type II, glycoengineered anti-CD20 antibody that has increased direct cell death, and enhanced antibody-dependent cell-mediated cytotoxicity. Obinutuzumab and chlorambucil have demonstrated improved progression-free survival compared to rituximab and chlorambucil in previously untreated pts with CLL. Also, preclinical data suggest that GDC-0199 combined with obinutuzumab may show synergistic activity in CLL. Collectively, these data support combining GDC-0199 and obinutuzumab for pts with CLL. We present data from an ongoing phase 1b study that is evaluating the safety and tolerability of GDC-0199 in combination with obinutuzumab in R/R or previously untreated pts with CLL. Methods Pts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are enrolled in a 3+3 study design with cohorts ranging from 100 to 600 mg/day of GDC-0199. Study eligibility is not restricted by cytogenetics or CLL risk profile. Study drug administration incorporates a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS), and staggering of the two agents. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or obinutuzumab (Schedule B) introduced first. After completing combination therapy, R/R pts continue single-agent GDC-0199 until disease progression. Adverse events (AEs) are graded according to NCI-CTCAE v.4 criteria. Dose-limiting toxicities (DLTs) are identified during the first 21 days of combination treatment and focus on potential AEs of TLS, infusion related reactions (IRRs), and cytopenias. Results As of May 2014, 9 R/R pts are on the dose finding stage of the study; 4 additional R/R pts were enrolled and discontinued following clinical TLS events in other GDC-0199 studies. No clinical TLS was observed in these 4 pts. The data presented here describe the 9 pts who continue on study treatment. Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 0 pts, medium risk 4 pts, and high risk 5 pts. Median time on study was 98 (range 7-252) days. No DLTs were observed in the 3 pts enrolled in the 100 mg GDC-0199 dosing cohort. Six pts were enrolled in the 200 mg GDC-0199 dosing cohort due to expansion following a DLT of laboratory TLS (characterized by asymptomatic laboratory abnormalities in potassium and phosphate) observed in 1 of the first 3 pts. Baseline characteristics include: median age 69 (range 59-80) years, 6 male pts, median of 4 prior CLL therapies (range 1-6), beta-2 microglobulin of ≥3.5 mg/L in 7 of 8 pts with available data, and IGVH mutation in 1 of 7 pts with available data. Cytogenetic data are available for 4 pts: none had del17p, 1 pt had del 11q, 1 pt had trisomy 12 and 2 pts had del 13q. The most common AEs included neutropenia (Figure 2). Dose interruptions of GDC-0199 or obinutuzumab in response to AEs were observed in 5 pts (2 pts had dose interruptions for obinutuzumab only [IRRs], and 3 pts had dose interruptions for GDC-0199 [mainly electrolyte abnormalities and cytopenias] and obinutuzumab [IRRs]); 1 pt in the 100 mg GDC-0199 dosing cohort had a dose reduction to 50 mg per day after 2 cycles of combination therapy due to ongoing neutropenia, and subsequently completed 6 cycles of combination treatment. IRRs were limited to the first infusion of obinutuzumab and were of Grade ≤2. One event of Grade 3 pneumonia required hospitalization. No treatment emergent bleeding events or deaths occurred on study. <![if !vml]><![endif]> Conclusion This is the first study combining GDC-0199 and the novel anti-CD20 antibody obinutuzumab in CLL and suggests that the combination is safely administered at the doses given. Prophylactic measures and a gradual dose ramp-up of GDC-0199 appear to reduce the incidence of TLS. Despite 9 pts being identified as medium or high risk for TLS, only 1 developed laboratory TLS, which was transient and managed. No clinical TLS was observed in these 9 pts. Dose escalation continues in R/R pts at 400 mg/day of GDC-0199. Schedule B and previously untreated pts will be enrolled in the near future. Disclosures Flinn: Genentech: Research Funding. Brunvand:Genentech: Speakers Bureau. Hillman:Roche Pharmaceuticals: Honoraria, Research Funding. Jones:Genentech: Advisory Board Other. Lymp:Genentech: Employment. Elhamy:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Kipps:Cegene, Pharacyclics, AbbVie, Genentech: Advisory Board Other, Research Funding.

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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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Frontline Combined Chemoimmunotherapy with Fludarabine, Cyclophosphamide, Alemtuzumab and Rituximab (CFAR) in High-Risk Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.208.208 ◽

2009 ◽

Vol 114 (22) ◽

pp. 208-208 ◽

Cited By ~ 2

Author(s):

Sameer A Parikh ◽

Michael Keating ◽

Susan O'Brien ◽

Alessandra Ferrajoli ◽

Stefan Faderl ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Hematologic Toxicity ◽

Frontline Therapy ◽

Grade 3 ◽

Tract Infections ◽

Cmv Reactivation

Abstract Abstract 208 Background: Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial. Methods: All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course. Results: A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months. Conclusion: CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR. Disclosures: Keating: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

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Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v116.21.2455.2455 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2455-2455 ◽

Cited By ~ 4

Author(s):

Thomas J. Kipps ◽

William G. Wierda ◽

Jeffrey A. Jones ◽

Lode J. Swinnen ◽

Jianning Yang ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Cell Transplant ◽

Phase 2 ◽

Anti Tumor Activity

Abstract Abstract 2455 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50 ≤ 1μM) against T and B lymphoid malignancies that over-express Bcl-2. A phase 1 trial demonstrated oral navitoclax monotherapy to be well-tolerated and to have anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). However, thrombocytopenia (TCP) was the dose-limiting toxicity (DLT). Phase 3 studies showed improved outcomes in CLL pts with the fludarabine/cyclophosphamide/rituximab (FCR) combination, and a phase 2 trial showed bendamustine/rituximab (BR) to be effective for pts with relapsed or refractory CLL. Navitoclax enhanced R (monotherapy and in combination with chemotherapy) efficacy in preclinical models of B-cell lymphoma. Methods: This is an ongoing, international, phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of oral navitoclax in combination with FCR (Arm A) or BR (Arm B) in pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥100/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. After obtaining informed consent, pts were assigned to Arm A or Arm B based on physician preference, each consisting of 28-day dose-escalation cycles with once-daily, pre-infusion, navitoclax treatment on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Navitoclax starting dose was 110 mg daily. Dose escalation to the next cohort (200 mg) was according to a continuous reassessment model. Tumor responses were evaluated using NCI-WG 1996 criteria. Pts could continue on navitoclax therapy for 1 yr in the absence of progressive disease or significant toxicity. Results: As of July 2010, 7 pts enrolled in the initially prioritized Arm B (BR+navitoclax); all completed the first cohort of 110 mg (median age 60 yr [range 55–72]). Study sites are currently enrolling pts in Arm A (FCR+navitoclax); 2 pts have enrolled to date. The median number of prior therapies was 2 (range 1–7). One pt had a DLT of elevated AST (Arm B, 110 mg cohort) and 1 pt had a DLT of neutropenic fever (Arm A, 110 mg cohort). In Arm B, neither TCP nor neutropenia have been DLTs. For the 7 pts with navitoclax-related AEs, the most common were diarrhea (3 pts), nausea (5 pts), and fatigue (3 pts). Seven pts remain on study; 2 pts discontinued due to disease progression and 2 withdrew per physician preference. In Arm B, preliminary antitumor best responses were assessable in 4 pts who received 2 cycles; 1 CRi in a pt with del17p- (based on lymph node [LN] response and no morphologic evidence of CLL in the bone marrow), 2 unconfirmed CRs (based on LN response and no bone marrow at this time), and 1 PR in a pt with del17p- (this pt subsequently received an allogeneic stem cell transplant). Preliminary PK results for the Arm B 110 mg cohort indicated that navitoclax PK was similar in Cycle 1 (navitoclax+BR) and Cycle 2 (navitoclax alone), and appeared comparable to PK in the navitoclax monotherapy study. Conclusions: Early results show that the combination of navitoclax with BR is well-tolerated, without DLTs of TCP or neutropenia, and show evidence of anti-tumor activity. Data are limited in the FCR portion of the study. The maximum tolerated dose of navitoclax has not been reached. Accrual is ongoing and following completion of the dose-escalation components of this study, expanded cohorts of pts will be assessed using the recommended phase 2 dose of navitoclax to further assess the tolerability and dose, and to continue to explore for efficacy signals in combinations. Preliminary data in combination with BR are encouraging. Disclosures: Kipps: Abbott Laboratories: Research Funding; Genentech/Roche: Research Funding. Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Swinnen: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yang: Abbott: Employment. Cui: Abbott: Employment. Busman: Abbott: Employment. Krivoshik: Abbott: Employment. Enschede: Abbott: Employment. Humerickhouse: Abbott: Employment.

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Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients

Blood ◽

10.1182/blood.v122.21.675.675 ◽

2013 ◽

Vol 122 (21) ◽

pp. 675-675 ◽

Cited By ~ 21

Author(s):

Jan A. Burger ◽

Michael J. Keating ◽

William G. Wierda ◽

Julia Hoellenriegel ◽

Ghayathri Jeyakumar ◽

...

Keyword(s):

High Risk ◽

Subdural Hematoma ◽

Research Funding ◽

Tp53 Mutation ◽

Single Agent ◽

Infectious Complications ◽

Lymphocytic Leukemia ◽

High Rate ◽

Grade 3

Abstract The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a promising new targeted therapy for patients with mature B cell malignancies, especially CLL and mantle cell lymphoma (MCL). Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed CLL, based on the Phase 1/2 experience. To accelerate and improve responses to ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; we update this Phase 2 single-center clinical trial with a median follow-up of 14 months. Methods Patients were treated with ibrutinib 420 mg PO daily continuously throughout the study Rituximab (375 mg/m2) was administered weekly for the first four weeks (cycle 1), then monthly until cycle 6.at which point patients continued on ibrutinib monotherapy. Study inclusion required high-risk disease (del17p or TP53 mutation [treated or untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL with del11q. Results Characteristics of the 40 patients enrolled included median age of 65 (range 35–82) with a median of 2 prior therapies. There were14 female and 26 male patients. 20 patients had del17p or TP53 mutation (4 without prior therapy), and 13 patients had del11q. 32 patients had unmutated IGHV, only one patient mutated IGHV, the remaining patients had inconclusive IGHV results. The median β2 microglobulin was 4.2 mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 patients continue on therapy (16 out of 20 with del17p or TP53 mutation) without disease progression. 39 patients were evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow cytometry, The ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 8 patients that came off study, 3 patient died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one patient had progressive disease, and one proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which coincided with a significant weight gain at 3 and 6 months. Conclusion Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-risk CLL patients, which induces high rates of durable responses. Responses were associated with significant improvements in QOL. Compared to ibrutinib monotherapy, the redistribution lymphocytosis resolves more rapidly and completely (see Figure), and consequently the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into longer progression-free and overall survival will be addressed in an upcoming larger, randomized trial of ibrutinib versus iR in relapsed/refractory CLL. Disclosures: Burger: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ibrutinib (PCI-32765) for treatment of high-risk CLL patients. O'Brien:Pharmacyclics: Research Funding.

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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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