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LONG TERM OUTCOMES OF IFCG REGIMEN FOR FIRSTLINE TREATMENT OF PATIENTS WITH CLL WITH MUTATED IGHV AND WITHOUT DEL(17P)/TP53 MUTATION
Author(s): ,
Nitin Jain
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Philip Thompson
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Jan Burger
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Alessandra Ferrajoli
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Koichi Takahashi
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Zeev Estrov
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Gautam Borthakur
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Prithviraj Bose
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Tapan Kadia
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Naveen Pemmaraju
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Koji Sasaki
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Marina Konopleva
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Elias Jabbour
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Naveen Garg
Affiliations:
Radiology,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Radiology,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Radiology,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Radiology,The University of Texas MD Anderson Cancer Center,Houston,United States;Radiology,The University of Texas MD Anderson Cancer Center,Houston,Esta
,
Xuemei Wang
Affiliations:
Biostatistics,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Biostatistics,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Biostatistics,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Biostatistics,The University of Texas MD Anderson Cancer Center,Houston,United States;Biostatistics,The University of Texas MD Anderson Cancer
,
Rashmi Kanagal-Shamanna
Affiliations:
Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,United States;Hematopathology,The University of Texas MD Ander
,
Keyur Patel
Affiliations:
Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,United States;Hematopathology,The University of Texas MD Ander
,
Wei Wang
Affiliations:
Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,United States;Hematopathology,The University of Texas MD Ander
,
Sa Wang
Affiliations:
Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,United States;Hematopathology,The University of Texas MD Ander
,
Jeffrey Jorgensen
Affiliations:
Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Hematopathology,The University of Texas MD Anderson Cancer Center,Houston,United States;Hematopathology,The University of Texas MD Ander
,
Wanda Lopez
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Ana Ayala
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
William Plunkett
Affiliations:
Experimental Therapeutics ,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Experimental Therapeutics ,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Experimental Therapeutics ,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Experimental Therapeutics ,The University of Texas MD Anderson Cancer Center,Houston,United States;Expe
,
Varsha Gandhi
Affiliations:
Experimental Therapeutics,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Experimental Therapeutics,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Experimental Therapeutics,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Experimental Therapeutics,The University of Texas MD Anderson Cancer Center,Houston,United States;Experime
,
Hagop Kantarjian
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
,
Susan O'Brien
Affiliations:
Chao Family Comprehensive Cancer Center,University of California Irvine Medical Center,Orange,États-unis;Chao Family Comprehensive Cancer Center,University of California Irvine Medical Center,Orange,Vereinigte Staaten;Chao Family Comprehensive Cancer Center,University of California Irvine Medical Center,Orange,Stati Uniti;Chao Family Comprehensive Cancer Center,University of California Irvine Medi
,
Michael Keating
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
William Wierda
Affiliations:
Leukemia,The University of Texas MD Anderson Cancer Center,Houston,États-unis;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas MD Anderson Cancer Center,Houston,Estados U
(Abstract release date: 05/12/22) EHA Library. Jain N. 06/12/22; 357013; S149
Nitin Jain
Nitin Jain
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S149

Type: Oral Presentation

Session title: CLL: Clinical

Background

Chemoimmunotherapy with FCR has been an effective treatment for patients (pts) with CLL. Pts with mutated IGHV (IGHV-M) have favorable long-term outcomes after receiving FCR. We designed an investigator-initiated, phase 2 trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). We report here long-term outcomes with a median follow-up of 56.8 months.

Aims
Investigate the role of combined chemoimmunotherapy and targeted therapy in CLL.

Methods
Eligibility included age ≥18, IGHV-M, no del(17p)/TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (4-color flow-cytometry, sensitivity 10-4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with marrow U-MRD at end of Cycle 12 stop all therapy. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by exam, blood counts and peripheral blood MRD every 6 months. NGS MRD (sensitivity 10-6) was performed in bone marrow in pts with available samples.

Results

45 pts initiated treatment. Median age was 60 [range, 25-71]. 69% had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study.

The 5-year PFS and OS are 97.7% (95% CI 94–100%) and 97.8% (95% CI 94–100%), respectively. No pt had CLL progression or Richter transformation. One pt developed therapy-related MDS; this pt is being monitored for 38+ months without any therapy for MDS with normal blood counts. The sole event noted on both the PFS and OS curve is a pt death from heart failure.

41/45 pts completed 12 cycles of treatment (4 pts came off study prior to C12). All 41 pts achieved marrow U-MRD4 by flow-cytometry and per protocol, all 41 pts discontinued ibrutinib. After a median follow-up of 44.2 mos post-discontinuing ibrutinib, 6 pts had an MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 27.2 mos (range, 20.7-49.0 mos) after stopping all therapy. All 6 pts are being monitored with no clinical progression or active therapy; notably, all 6 pts were MRD+ at 10-6 by marrow NGS after the completion of 3 cycles of iFCG and 4/5 (1 missed sample) were MRD+ at 10-6 by marrow NGS after the completion of Cycle 12.

Of the 16 pts who were marrow NGS MRD+ at 10-6 after 3 cycles of iFCG, 6/16 had an MRD recurrence in blood in follow-up vs. 0/20 who were NGS MRD negative/indeterminate (p = 0.004). Of the 12 pts who were marrow NGS MRD+ at 10-6 after Cycle 12, 4/12 had an MRD recurrence in blood in follow-up vs. 1/26 who were NGS MRD negative/indeterminate (p = 0.02).

Conclusion

The iFCG regimen, using only 3 cycles of chemotherapy (as opposed to 6 cycles of chemoimmunotherapy) achieves a very high rate of U-MRD in previously-untreated pts with CLL with IGHV-M CLL. No pt had disease progression with a median follow-up of close to 5 years. The 5-year PFS is 97.7%; this is favorable compared to 5-year PFS of ≈65% with FCR (CLL10), ≈70% with ibrutinib (A041202 trial), and 81% with ibrutinib (RESONATE-2) for IGHV-M CLL. Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity by NGS during therapy.

Keyword(s): Chronic lymphocytic leukemia

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S149

Type: Oral Presentation

Session title: CLL: Clinical

Background

Chemoimmunotherapy with FCR has been an effective treatment for patients (pts) with CLL. Pts with mutated IGHV (IGHV-M) have favorable long-term outcomes after receiving FCR. We designed an investigator-initiated, phase 2 trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). We report here long-term outcomes with a median follow-up of 56.8 months.

Aims
Investigate the role of combined chemoimmunotherapy and targeted therapy in CLL.

Methods
Eligibility included age ≥18, IGHV-M, no del(17p)/TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (4-color flow-cytometry, sensitivity 10-4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with marrow U-MRD at end of Cycle 12 stop all therapy. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by exam, blood counts and peripheral blood MRD every 6 months. NGS MRD (sensitivity 10-6) was performed in bone marrow in pts with available samples.

Results

45 pts initiated treatment. Median age was 60 [range, 25-71]. 69% had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study.

The 5-year PFS and OS are 97.7% (95% CI 94–100%) and 97.8% (95% CI 94–100%), respectively. No pt had CLL progression or Richter transformation. One pt developed therapy-related MDS; this pt is being monitored for 38+ months without any therapy for MDS with normal blood counts. The sole event noted on both the PFS and OS curve is a pt death from heart failure.

41/45 pts completed 12 cycles of treatment (4 pts came off study prior to C12). All 41 pts achieved marrow U-MRD4 by flow-cytometry and per protocol, all 41 pts discontinued ibrutinib. After a median follow-up of 44.2 mos post-discontinuing ibrutinib, 6 pts had an MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 27.2 mos (range, 20.7-49.0 mos) after stopping all therapy. All 6 pts are being monitored with no clinical progression or active therapy; notably, all 6 pts were MRD+ at 10-6 by marrow NGS after the completion of 3 cycles of iFCG and 4/5 (1 missed sample) were MRD+ at 10-6 by marrow NGS after the completion of Cycle 12.

Of the 16 pts who were marrow NGS MRD+ at 10-6 after 3 cycles of iFCG, 6/16 had an MRD recurrence in blood in follow-up vs. 0/20 who were NGS MRD negative/indeterminate (p = 0.004). Of the 12 pts who were marrow NGS MRD+ at 10-6 after Cycle 12, 4/12 had an MRD recurrence in blood in follow-up vs. 1/26 who were NGS MRD negative/indeterminate (p = 0.02).

Conclusion

The iFCG regimen, using only 3 cycles of chemotherapy (as opposed to 6 cycles of chemoimmunotherapy) achieves a very high rate of U-MRD in previously-untreated pts with CLL with IGHV-M CLL. No pt had disease progression with a median follow-up of close to 5 years. The 5-year PFS is 97.7%; this is favorable compared to 5-year PFS of ≈65% with FCR (CLL10), ≈70% with ibrutinib (A041202 trial), and 81% with ibrutinib (RESONATE-2) for IGHV-M CLL. Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity by NGS during therapy.

Keyword(s): Chronic lymphocytic leukemia

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