IBRUTINIB, FLUDARABINE, CYCLOPHOSPHAMIDE, AND OBINUTUZUMAB (GA101) (IFCG) FOR PREVIOUSLY UNTREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH MUTATED IGHV AND NON-DEL(17P)
(Abstract release date: 05/18/17)
EHA Library. Jain N. 06/24/17; 181750; S463
Nitin Jain
Contributions
Contributions
Abstract
Abstract: S463
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:30 - 16:45
Location: Hall B
Background
Patients with mutated IGHV (IGHV-M) have favorable long-term outcomes (10-year PFS of >60%) after receiving first-line FCR.
Aims
To develop an FC-based chemoimmunotherapy regimen of finite duration that included ibrutinib and obinutuzumab. The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and a more potent antibody (obinutuzumab).
Methods
We designed an investigator-initiated phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through addition of ibrutinib and obinutuzumab. Key eligibility included age ≥18, IGHV-M, no del17p. Pts received 3 courses of iFCG. G-CSF was not mandated. Primary endpoint: CR/CRi with bone marrow (BM) MRD-neg (4-color flow-cytometry) after 3 courses of iFCG. Pts meeting primary endpoint received ibrutinib with obinutuzumab (iG) for C3-6, then ibrutinib C7-12. Pts not achieving primary endpoint received iG (C4-12). All pts who are MRD neg at 1 year will stop all therapy, including ibrutinib. Pts MRD+ at 1 year may continue ibrutinib. Historic C3 BM MRD-neg with FCR in IGHV-M 26% (Strati, Blood 2014). Target BM MRD-neg after iFCG x3 is 45%. Sample size 45.
Results
Since activation (April 2016), 26 patients were consented; 23 initiated treatment. We report data on these 23 patients. This is the first report of this trial. Median age is 59 years (range, 25-71); there were 18 men. Prognostic markers included [FISH: del13q (n=17), negative (n=3); trisomy 12 (n=3); CD38+ (n=7); ZAP70+ (n=6/21 evaluated)]. By trial design, all patients had IGHV-M. Median B2M was 2.6 (range, 1.4-8.1). Median pretreatment WBC count was 81.1 K/µL (range, 3.1-224), platelet count 120 K/µL (range, 62-292), hemoglobin 12.4 g/dL (range, 9.1-15.6).
Eighteen patients have completed 3 courses of iFCG and had initial response assessment (the remaining 5 patients have not yet completed 3 courses of treatment). All 18 patients achieved a clinical response; 14/18 (78%) achieved MRD-negative remission in the marrow at 3 month (Table 1) and 16/18 (89%) achieved MRD-negative remission as their overall best response. Overall, 7/18 achieved CR/CRi with MRD-negative status in bone marrow at 3 months. All patients with PR had bulky adenopathy at baseline, and had residual lymphadenopathy ranging from 1.8 to 3.5 cm after 3 courses of iFCG. No patient has progressed, and all but one continue to receive treatment on protocol.
Of the 23 pts, 11 pts had G3-4 neutropenia and 5 pts had G3-4 thrombocytopenia. 4 pt had neutropenic fever. 1 pt who achieved MRD-neg CR developed pulmonary MAC infection, and declined further therapy. 1 pt had atrial fibrillation. G3 ALT developed in 3 pts. FC was dose reduced in 10 pts; ibrutinib dose-reduced in 2 pts.
Response at 3 Month | Best Response | |||
N=18 | Marrow MRD | N=18 | Marrow MRD | |
ORR | 18/18 (100) | 14/18 (78) neg | 18/18 (100) | 16/18 (89) neg |
CR/CRi PR | 7 (39) 11 (61) | 7/7 (100) neg 7/11 (64) neg | 9 (50) 9 (50) | 9/9 (100) neg 7/9 (78) neg |
Conclusion
iFCG achieves high rate of MRD-neg remission after 3 courses. Pt enrollment continues, and updated results will be presented at the EHA meeting.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Targeted therapy, Minimal residual disease (MRD), Chronic Lymphocytic Leukemia
Abstract: S463
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:30 - 16:45
Location: Hall B
Background
Patients with mutated IGHV (IGHV-M) have favorable long-term outcomes (10-year PFS of >60%) after receiving first-line FCR.
Aims
To develop an FC-based chemoimmunotherapy regimen of finite duration that included ibrutinib and obinutuzumab. The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and a more potent antibody (obinutuzumab).
Methods
We designed an investigator-initiated phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through addition of ibrutinib and obinutuzumab. Key eligibility included age ≥18, IGHV-M, no del17p. Pts received 3 courses of iFCG. G-CSF was not mandated. Primary endpoint: CR/CRi with bone marrow (BM) MRD-neg (4-color flow-cytometry) after 3 courses of iFCG. Pts meeting primary endpoint received ibrutinib with obinutuzumab (iG) for C3-6, then ibrutinib C7-12. Pts not achieving primary endpoint received iG (C4-12). All pts who are MRD neg at 1 year will stop all therapy, including ibrutinib. Pts MRD+ at 1 year may continue ibrutinib. Historic C3 BM MRD-neg with FCR in IGHV-M 26% (Strati, Blood 2014). Target BM MRD-neg after iFCG x3 is 45%. Sample size 45.
Results
Since activation (April 2016), 26 patients were consented; 23 initiated treatment. We report data on these 23 patients. This is the first report of this trial. Median age is 59 years (range, 25-71); there were 18 men. Prognostic markers included [FISH: del13q (n=17), negative (n=3); trisomy 12 (n=3); CD38+ (n=7); ZAP70+ (n=6/21 evaluated)]. By trial design, all patients had IGHV-M. Median B2M was 2.6 (range, 1.4-8.1). Median pretreatment WBC count was 81.1 K/µL (range, 3.1-224), platelet count 120 K/µL (range, 62-292), hemoglobin 12.4 g/dL (range, 9.1-15.6).
Eighteen patients have completed 3 courses of iFCG and had initial response assessment (the remaining 5 patients have not yet completed 3 courses of treatment). All 18 patients achieved a clinical response; 14/18 (78%) achieved MRD-negative remission in the marrow at 3 month (Table 1) and 16/18 (89%) achieved MRD-negative remission as their overall best response. Overall, 7/18 achieved CR/CRi with MRD-negative status in bone marrow at 3 months. All patients with PR had bulky adenopathy at baseline, and had residual lymphadenopathy ranging from 1.8 to 3.5 cm after 3 courses of iFCG. No patient has progressed, and all but one continue to receive treatment on protocol.
Of the 23 pts, 11 pts had G3-4 neutropenia and 5 pts had G3-4 thrombocytopenia. 4 pt had neutropenic fever. 1 pt who achieved MRD-neg CR developed pulmonary MAC infection, and declined further therapy. 1 pt had atrial fibrillation. G3 ALT developed in 3 pts. FC was dose reduced in 10 pts; ibrutinib dose-reduced in 2 pts.
Response at 3 Month | Best Response | |||
N=18 | Marrow MRD | N=18 | Marrow MRD | |
ORR | 18/18 (100) | 14/18 (78) neg | 18/18 (100) | 16/18 (89) neg |
CR/CRi PR | 7 (39) 11 (61) | 7/7 (100) neg 7/11 (64) neg | 9 (50) 9 (50) | 9/9 (100) neg 7/9 (78) neg |
Conclusion
iFCG achieves high rate of MRD-neg remission after 3 courses. Pt enrollment continues, and updated results will be presented at the EHA meeting.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Targeted therapy, Minimal residual disease (MRD), Chronic Lymphocytic Leukemia
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