Five-Year Follow-up of Safety and Efficacy of a Phase III Randomized Trial of Ofatumumab Therapy Versus Physicians' Choice in Patients with Bulky Fludarabine Refractory Chronic Lymphocytic Leukemia

Abstract Background : In 2014, a planned interim analysis of an open-label, two-arm, randomized, phase III study of ofatumumab (OFA) vs physicians' choice (PC) treatment (most patients received rituximab-, alemtuzumab-, alkylator-, or fludarabine-based therapies) in patients with bulky fludarabine-refractory chronic lymphocytic leukemia (BFR CLL) was performed to assess the effectiveness of OFA in the time-period prior to administering small molecule kinase inhibitors. The study did not meet its primary endpoint of progression-free survival (PFS) as assessed by the independent review committee (median PFS 5.4 months vs 3.6 months; hazard ratio [HR]=0.79, 95% confidence interval [CI]: 0.50, 1.24; p=0.268). Here, we report the 5-year follow-up of the study. Methodology : Patients with BFR CLL who required therapy and had received at least 2 prior therapies were randomized (2:1) to receive either OFA or PC therapy. Eligible participants were stratified based on del (17p) status, the Eastern Cooperative Oncology Group (ECOG) Performance Status (0, 1, or 2), and fludarabine-refractory status (no response vs <6 months response).Patients in the OFA arm received an initial dose of 300 mg, followed 1 week (w) later with 2000 mg once weekly for 7 w, followed 4 w later by one infusion of 2000 mg every 4 w for 4 infusions, with total 12 infusions over 24 w. Patients in PC therapy received non-OFA regimen permitted therapies for CLL and standard of care regimens for up to 6 months. After 24 w in the OFA arm, if patients achieved at least stable disease or better, they were further randomized to either OFA extended arm (additional dose regimen of 2000 mg once every 4 w up to 24 w) or OFA observation arm (no further therapy). Patients in PC arm who received OFA after experiencing progressive disease (PD) had an option to receive single-agent OFA therapy in the salvage arm. The primary objective of the study was to evaluate improvement in PFS. The key secondary objectives were overall response rate (ORR), overall survival (OS), and evaluation of safety and tolerability of OFA. Results: After 24 w of OFA treatment, 122 patients who were randomized to PC (n=43) or OFA (n=79) underwent a second randomization (24 continued OFA in the extended arm and 13 stopped OFA in the observation arm). Of the 43 patients who were randomized to PC arm, 22 received OFA salvage therapy at PD. Patient disposition is described in Figure 1. Patients received a median of 6 and 3 treatment cycles in the OFA and PC arms, respectively. The interim analysis of PFS was presented earlier (Osterborg et al., 2016). The investigator-assessed ORR for the OFA and PC arms remained unchanged from the interim analysis (49% vs 37%, respectively). However, in the OFA salvage arm (55%), there was a 5% increase in the investigator-assessed ORR compared to that of the previous analysis. The median OS for the OFA arm vs PC arm was 19.2 months vs 14.5 months (HR=0.75, 95% CI: 0.48, 1.17; p=0.173, log-rank test). The most common adverse events (AEs) in the OFA and PC arms (>15% in either) were neutropenia (21% vs 19%), pneumonia (18% vs 19%), and anemia (9% vs 19%), respectively. Grade 3, 4, and 5 AEs (>10%) in the OFA and PC arms were neutropenia (17% vs 16%), pneumonia (14% vs 9%), febrile neutropenia (9% vs 12%), and anemia (6% vs 14%), respectively. Serious AEs (≥5%) in the OFA and PC arms were pneumonia (13% vs 16%), febrile neutropenia (9% each), pyrexia (5% vs 7%), anemia (3% vs 9%), sepsis (0% vs 9%), autoimmune hemolytic anemia (0% vs 5%), and neutropenic sepsis (1% vs 5%), respectively. There were 8 (10%) on-treatment deaths in the OFA arm and 5 (12%) on-treatment deaths in the PC arm. Post-treatment anti-cancer therapies are described in Table 1. Conclusions: At the 5-year follow-up of this phase III trial, there was a numerical but statistically not significant longer median OS (+4.7 months) in the OFA arm. As only few patients had the chance to receive a kinase inhibitor later, the study displays the survival of BFR CLL patients in the period prior to receiving small molecule inhibitors. This and other studies have demonstrated a longer PFS with the use of low-dose maintenance CD20 monoclonal antibody therapy vs not, a finding that may be re-explored in the new targeted therapeutic landscape in CLL. OFA is a safe option in multi-resistant advanced CLL cases. Disclosures Miklos: AOP Orphan: Honoraria; Novo nordisk: Honoraria. Strugov:Janssen: Honoraria, Other: Travel expense, Research Funding; Abbvie: Other: Travel expense. Lewerin:Abbvie: Consultancy. Grosicki:Affimed: Research Funding. Steurer:Novartis: Consultancy, Honoraria, Research Funding. Montillo:Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Middeke:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stefanelli:Novartis: Employment, Equity Ownership. Vincent:Novartis: Employment. G:Novartis: Employment. Österborg:Beigene: Research Funding; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, 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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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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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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Detailed Safety Analysis of Venetoclax Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v128.22.2033.2033 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2033-2033 ◽

Cited By ~ 3

Author(s):

Danielle M. Brander ◽

Michael Y. Choi ◽

Andrew W. Roberts ◽

Shuo Ma ◽

L. Leanne Lash ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Grade 3 ◽

Over Time

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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Ofatumumab + Chlorambucil Versus Chlorambucil Alone In Patients With Untreated Chronic Lymphocytic Leukemia (CLL): Results Of The Phase III Study Complement 1 (OMB110911)

Blood ◽

10.1182/blood.v122.21.528.528 ◽

2013 ◽

Vol 122 (21) ◽

pp. 528-528 ◽

Cited By ~ 34

Author(s):

Peter Hillmen ◽

Tadeusz Robak ◽

Ann Janssens ◽

K Govindbabu ◽

Sebastian Grosicki ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Clinical Activity ◽

Advisory Committees ◽

Overall Response ◽

Grade 3

Abstract Introduction Chemoimmunotherapy with purine analogues and the anti-CD20 antibody rituximab is the standard of care as initial therapy in younger and physically fit patients with chronic lymphocytic leukemia (CLL). However, most CLL patients are elderly and/or have comorbidities, meaning that fludarabine-containing regimens are often inappropriate, carry greater toxicity, and treatment of these patients remains challenging. Most randomized studies in previously untreated CLL have been conducted in younger or fit patients and results cannot necessarily be extrapolated to older, less fit patients. While chlorambucil (CHL) remains a standard of care for this patient population, more effective but tolerable treatment choices are still needed. Ofatumumab (O) demonstrated superior preclinical activity, compared to rituximab, against cells with low CD20 density like CLL and showed clinical activity as monotherapy, with high overall response rates (ORR) in patients with refractory CLL. Therefore, the addition of O to CHL could provide superior clinical outcomes than CHL alone, while being tolerable, for patients who are elderly and/or have comorbidities and currently have limited treatment options. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) and were considered inappropriate for fludarabine-based therapy due to advanced age and/or co-morbidities were randomized (1:1) to receive either O+CHL or CHL. CHL was given orally (10mg/m2 at days 1-7 of each 28 day cycle) and O was administered as intravenous infusions (Cycle 1: 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1). O premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was a minimum of 3 cycles, until best response up to a maximum of 12 cycles. The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC) and secondary endpoints included overall response rate (ORR), overall survival (OS) and safety. Patients 447 patients from 16 countries were randomized. Baseline demographics and disease characteristics were well balanced between the 2 arms. Median age was 69 years with 82% ≥65 years and/or having ≥2 comorbidities. All modified Rai stages were represented (Low 8%, intermediate 51%, high 40%). 56% of patients had unmutated IgVH, 6% showed 17p deletions and 75% had β-2-microglobulin levels ≥3500μg/L. Results PFS as assessed by an IRC was significantly prolonged in the O+CHL arm (22.4 months) compared to CHL alone (13.1 months, p<0.001). ORR was higher for O+CHL vs CHL (82% vs 69%, p=0.001), with a superior CR rate (12% vs 1%). 37% of O+CHL subjects with an IRC-assessed CR were MRD negative. With a median follow-up of 29 months, median OS was not reached for O+CHL or CHL. Median duration of treatment for both arms was 6 cycles and 82% of patients received 6 or more cycles of O+CHL. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 50% of patients receiving O-CHL and 43% of patients on CHL with the most common being neutropenia (O+CHL: 26%, CHL: 14%). Grade ≥3 infusion-related AEs were reported in 10% of patients. No fatal infusion reactions were reported. Grade ≥3 infections were reported in 15% (O+CHL) and 14% (CHL) of patients, with the most common infection being pneumonia (O+CHL: 4%, CHL: 3%). Deaths during treatment occurred in 2% of subjects in both arms. Conclusion Ofatumumab added to chlorambucil (O+CHL) demonstrated clinically important improvements with a manageable side effect profile in patients with CLL who have not received prior therapy and who are considered inappropriate for fludarabine based therapy. Disclosures: Hillmen: Roche Pharmaceuticals: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: The use of ofatumumab in combination with chlorambucil in previously untreated CLL. The reported trial will support the extension of the ofatumumab licence. Robak:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GlaxoSmithKline: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau; Amgen: Speakers Bureau. Mayer:Glaxo: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Panagiotidis:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Kimby:Pharmacyclics: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Teva: 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; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Emergent: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schuh:GSK: Honoraria, Research Funding. 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. McKeown:GSK: Employment. Carey:GlaxoSmithKline: Employment. Gupta:GSK: Employment. Chang:GSK: Employment. Lisby:Genmab: Employment, hold stock options Other. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees.

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Serial Minimal Residual Disease Evaluation in Patients with Chronic Lymphocytic Leukemia Under Long-Term Venetoclax Treatment

Blood ◽

10.1182/blood-2018-99-114048 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1876-1876

Author(s):

Thomas Lew ◽

Mary Ann Anderson ◽

Constantine S. Tam ◽

Sasanka Handunnetti ◽

Dennis Carney ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Minimal Residual

Abstract Background The selective BCL2 inhibitor venetoclax (Ven) achieves an overall response rate of approximately 75-80% as a single agent in relapsed and refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL)1. At one year ~75% of patients (pts) are progression-free at the approved monotherapy dose of 400 mg/day1,2 and Ven is the only novel agent with a significant rate of minimal residual disease (MRD) negativity (MRD-neg)3. The temporal pattern of MRD levels and systematic long term follow up of pts stratified by their MRD status on Ven have not been reported. We report the long term outcomes according to MRD status for 59 pts with RR-CLL/SLL who attained objective disease response to Ven, and the temporal patterns of change in MRD. Methods We reviewed the clinical outcomes to July 2018 of 67 pts with RR-CLL/SLL enrolled since June 2011 on early phase clinical studies of Ven at our two hospitals. Analysis was restricted to the 59 pts who achieved a partial response or complete response by iwCLL criteria. Pts initially received 150-1200mg Ven/day (45 ≥400mg/day) on one of three ongoing trials: Phase 1 Ven monotherapy (NCT01328626) (n=36), Phase 1b Ven plus rituximab (NCT01682616) (n=14), or Phase 2 Ven monotherapy in del(17p) CLL/SLL (NCT01889186) (n=9). For this analysis MRD-negativity was defined as <1 cell in 10-4 leukocytes by ERIC criteria, or no cells with a CLL phenotype when <400,000 cells were analyzed in an assay with a minimum sensitivity of 0.1%. Of those pts reported as MRD-neg this was confirmed at a level of 10-4 in 71%4. Unless otherwise specified, MRD-neg refers to status in the bone marrow (BM) and pts who were not tested were considered to be MRD-pos (n=2 pts). Landmark analyses of time to progression (TTP) by MRD status used the median time to achievement of MRD-neg. Fisher exact test was used to assess the association of clinical, biological and treatment variables with achievement of MRD-neg. TTP and time to MRD-neg were estimated using the method of Kaplan-Meier, and comparisons among groups used the log-rank (Mantel-Cox) test. Results Of the 59 pts who achieved an objective response to Ven, 21 (36%) achieved MRD-neg in the BM and 26 (44%) in the PB. Of the 38 pts who did not achieve BM MRD-neg, 36 (95%) had at least one BM assessment on treatment; the two remaining pts did not clear MRD in the PB. The strongest positive predictor for the achievement of BM MRD-neg was treatment with Ven plus rituximab (9 of 14 [64%]) achieved vs 13 of 45 [27%] on Ven monotherapy (p=0.02)). Complex karyotype was a negative predictor in pts receiving ≥400mg/day. TP53 aberrant state (mutation and/or del(17p)), bulky adenopathy >5cm and fludarabine-refractoriness were not significantly associated with achievement of MRD-neg, irrespective of dose (table 1). The median time to MRD-neg was 8.2 (range 2 - 46) mths for BM (fig 1A) and 5 (range <1 - 50) mths for PB, with 22/26 (85%) pts who achieved PB MRD-neg doing so within 12 mths of starting Ven. 25/26 had a contemporaneous or subsequent BM aspirate and 20 (80%) achieved BM MRD-neg after a median of 3 (<1 - 17) further mths. After a median follow up of 25 (range 2 - 55) mths since attainment of BM MRD-neg, 8/21 (38%) pts have developed confirmed re-emergence of BM MRD, and a further 2 pts have re-developed PB MRD-pos. Median time to reemergence of BM MRD has not been reached (59% BM MRD relapse free at 2 years post attainment). In a landmark analysis from median time to BM MRD-neg (8.2 mths), TTP by iwCLL criteria was significantly longer among BM MRD-neg pts (n = 21; median TTP 65 mths [95% CI 47 - undefined]) than BM MRD-pos pts (n = 31; median 22 mths [95% CI 14 - 39]; Hazard Ratio (HR) 0.11; p<0.0001) (figure 1B). Similar patterns held for the equivalent landmark analysis according to PB MRD (HR 0.21; p = 0.0002). Conclusions Venetoclax frequently induces BM MRD-neg, and pts achieving BM MRD-neg have very durable responses. Combined Ven plus rituximab increases the rate of BM MRD-neg. With Ven therapy, PB MRD status appears to be a reasonable surrogate for BM MRD status, but further validation is required. Achievement of BM MRD-neg should be the aim of therapy with Ven and Ven-based combination approaches may be the most effective way to achieve this.Roberts; N Engl J Med; 2016;374:311-22.Stilgenbauer; Lancet Oncol; 2016;17:768-78.Seymour; Lancet Oncol; 2017;18:230-40.Rawstron; Leukemia; 2016;30:929-36. Disclosures Lew: Walter and Eliza Hall: Employment, Patents & Royalties. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria, Travel funding; Gilead: Honoraria; Pharmacyclics: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria. Roberts:AbbVie: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; Genentech: Research Funding; Janssen: Research Funding. Seymour:Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding.

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Long Term Outcomes of Venetoclax Therapy for Complex Karyotype Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-113905 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4431-4431 ◽

Cited By ~ 1

Author(s):

Thomas Lew ◽

Mary Ann Anderson ◽

Constantine S. Tam ◽

Sasanka Handunnetti ◽

Dennis Carney ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Complex Karyotype ◽

Advisory Committees ◽

Pre Treatment

Abstract Background The selective BCL2 inhibitor venetoclax (Ven) achieves an overall response rate of approximately 75 - 80% as a single agent in patients (pts) with relapsed and refractory chronic lymphocytic leukemia / small lymphocytic lymphoma (RR-CLL/SLL)1. Ven is associated with 1 year estimates of progression free survival of ~75% for the approved single agent dose of 400 mg daily1,2 with promising efficacy among pts previously treated with ibrutinib3. Early reports of pre-treatment factors impacting durability of clinical benefit have identified bulky adenopathy, >3 lines of prior therapy and del(17p) as putative adverse factors in univariate analyses1. In analyses of data from ibrutinib and idelalisib naïve patients, the dominant predictors were fludarabine refractory disease and complex karyotype (CK), with del(17p) and/or TP53 mutations not reaching significance4. However, a systematic longer term follow up of pts with RR-CLL/SLL harboring CK treated with Ven has not been reported. We report the long term follow up of 31 pts with RR-CLL/SLL with a known karyotype treated with Ven ≥400 mg/d. Methods We retrospectively reviewed 67 pts with RR-CLL/SLL enrolled on early phase clinical studies of Ven at our two hospitals between June 2011 and July 2018 as of July 2018. The pts were treated in one of three ongoing clinical trials: Phase 1 Ven monotherapy (NCT01328626) (n=41), Phase 1b Ven plus rituximab (NCT01682616) (n=16), or Phase 2 Ven monotherapy in del(17p) CLL/SLL (NCT01889186) (n=10). Our analysis was restricted to pts who received ≥400 mg/daily2 and whose pre-treatment karyotype was known (n=31). CK is defined by the presence of ≥3 chromosomal aberrations using conventional cytogenetic analysis5. Time to progression (TTP) was estimated by the method of Kaplan and Meier, and comparisons among groups used the log-rank test (Mantel-Cox) and Fisher's exact test for categorical variables. Results 31 pts (median age 68 [range 45-83]) had known karyotype prior to Ven. They had received a median of 3 (1 - 8) prior therapies, but none had prior BTK inhibitor or idelalisib exposure. 12 pts had RR-CLL/SLL with known CK (median number of aberrations 4, range 3 - 8) and 19 were known non CK. Disease was fludarabine refractory in 15 pts and 16 had evidence of TP53 dysfunction (TP53 mutation and / or del(17p)) (Table 1). The median follow up was 33 (range 1 - 67) months. Twenty-eight (90%) pts responded and 18 (58%) have developed progressive disease; 7 with Richter transformation (RT) and 11 with CLL. RT occurred significantly earlier than CLL progression at a median of 7 (range 1 - 22) months v 33 (22 - 48) months, respectively (p = 0.0004). CK did not impact likelihood of overall response or complete response (CR) (p = 0.46), but was associated with a lower rate of attainment of minimal residual disease negative (MRD-neg) BM status (8% vs 47% in pts with non CK; p = 0.046). Four pts with CK achieved CR; one was fludarabine refractory, three harbored aberrations in TP53 and one lacked both risk factors. RT was largely confined to pts with CK CLL who had a 50% incidence of RT (6 of 7 RT events; p = 0.007). Two pts with CK RR-CLL/SLL received concomitant rituximab with Ven therapy: one developed Hodgkin variant RT at ~1 month, the other achieved a PR without clearance of PB or BM MRD, with progressive CLL at 25 months. Of the 5 pts with non CK RR-CLL/SLL who received Ven and rituximab, 4 (80%) achieved MRD-neg CR with no progressions at a median follow up of 57 (range 33 - 60) months and one achieved PR, with progressive CLL at 58 months. Compared to pts with a known non CK, patients with CK had significantly shorter TTP (median 22 [95% CI 4 - 48] months v 67 [95% CI 33 - undefined] months; p = 0.0011) (Figure 1). Conclusions Patients with CK RR-CLL/SLL treated with Ven have inferior outcomes relative to those with non-CK, predominantly due to early emergence of presumably unrecognized subclinical RT, consistent with patterns previously observed for ibrutinib and chemo-immunotherapy. Careful screening of these patients for nascent RT is important. However, deep remissions are possible in some patients and confer durable disease control. Ven combination therapies merit exploration with the aim of improving depth of response and outcomes in RR-CLL/SLL harboring CK.Roberts; N Engl J Med; 2016;374:311-22.Stilgenbauer; Lancet Oncol; 2016;17:768-78.Jones; Lancet Oncol; 2018;19:65-75.Anderson; Blood; 2017;129:3362-70.Rigolin; Blood; 2012;119:2310-3. Disclosures Lew: Walter and Eliza Hall: Employment, Patents & Royalties. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Tam:Pharmacyclics: Honoraria, Travel funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Roche: Honoraria; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding. Roberts:Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax. Seymour:Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding.

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Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽

10.1182/blood.v130.suppl_1.901.901 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 901-901

Author(s):

Sara Bringhen ◽

Massimo Offidani ◽

Pellegrino Musto ◽

Anna Marina Liberati ◽

Giulia Benevolo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Cell Transplant ◽

Newly Diagnosed ◽

Community Based ◽

Advisory Committees ◽

Risk Of Death ◽

Grade 3 ◽

To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

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