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IMMUNE RESTORATION AND SYNERGISTIC ACTIVITY WITH FIRST-LINE (1L) IBRUTINIB (IBR) PLUS VENETOCLAX (VEN): TRANSLATIONAL ANALYSES OF CAPTIVATE PATIENTS WITH CLL
Author(s): ,
Isabelle Solman
Affiliations:
Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,États-unis;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Vereinigte Staaten;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Stati Uniti;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,United States;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Estados Unidos;Pharmacyclics LLC, an Ab
,
Raghuveer Singh Mali
Affiliations:
AbbVie,North Chicago, IL,États-unis;AbbVie,North Chicago, IL,Vereinigte Staaten;AbbVie,North Chicago, IL,Stati Uniti;AbbVie,North Chicago, IL,United States;AbbVie,North Chicago, IL,Estados Unidos;AbbVie,North Chicago, IL,Verenigde Staten;AbbVie,North Chicago, IL,Estados Unidos;AbbVie,North Chicago, IL,United States;AbbVie,North Chicago, IL,USA
,
Lydia Scarfo
Affiliations:
Ospedale San Raffaele,Milan,Italie;Ospedale San Raffaele,Milan,Italien;Ospedale San Raffaele,Milan,Italia;Ospedale San Raffaele,Milan,Italy;Ospedale San Raffaele,Milan,Italia;Ospedale San Raffaele,Milan,Italië;Ospedale San Raffaele,Milan,Itália;Ospedale San Raffaele,Milan,Италия;Ospedale San Raffaele,Milan,Italien
,
Michael Choi
Affiliations:
University of California San Diego,San Diego, CA,États-unis;University of California San Diego,San Diego, CA,Vereinigte Staaten;University of California San Diego,San Diego, CA,Stati Uniti;University of California San Diego,San Diego, CA,United States;University of California San Diego,San Diego, CA,Estados Unidos;University of California San Diego,San Diego, CA,Verenigde Staten;University of Cali
,
Carol Moreno
Affiliations:
Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona,Barcelona,Espagne;Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona,Barcelona,Spanien;Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona,Barcelona,Spagna;Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona,Barcelona,Spain;Hospital de la Santa Creu I Sant Pau, A
,
Andrew Grigg
Affiliations:
Austin Hospital,Heidelberg, VIC,Australie;Austin Hospital,Heidelberg, VIC,Australien;Austin Hospital,Heidelberg, VIC,Australia;Austin Hospital,Heidelberg, VIC,Australia;Austin Hospital,Heidelberg, VIC,Australia;Austin Hospital,Heidelberg, VIC,Australië;Austin Hospital,Heidelberg, VIC,Austrália;Austin Hospital,Heidelberg, VIC,Австралия;Austin Hospital,Heidelberg, VIC,Australien
,
James P. Dean
Affiliations:
Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,États-unis;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Vereinigte Staaten;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Stati Uniti;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,United States;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Estados Unidos;Pharmacyclics LLC, an Ab
Edith Szafer-Glusman
Affiliations:
Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,États-unis;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Vereinigte Staaten;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Stati Uniti;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,United States;Pharmacyclics LLC, an AbbVie Company,South San Francisco, CA,Estados Unidos;Pharmacyclics LLC, an Ab
(Abstract release date: 05/12/22) EHA Library. Solman I. 06/11/22; 357008; S144
Isabelle Solman
Isabelle Solman
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: S144

Type: Oral Presentation

Session title: CLL: Translational research

Background
Ibr and Ven work synergistically through their distinct and complementary modes of action: BTK inhibition by Ibr decreases levels of anti-apoptotic MCL-1 and BCL-XL proteins, but not BCL-2, and therefore increases sensitization to BCL-2 inhibition by Ven in vivo. Single agent Ibr has been shown to normalize CLL-associated immune cell alterations in number and function but the impact of the Ibr plus Ven combination (I+V) on immune cells has not been evaluated.

Aims
To 1) confirm BCL-2 sensitization by single-agent Ibr and 2) monitor changes in the cellular immune profile of patients (pts) treated with I+V in CAPTIVATE (NCT02910583), a multicenter phase 2 study evaluating 1L I+V treatment (tx) in CLL and SLL.

Methods
Ibr (420mg po daily) effects on anti-apoptotic proteins were evaluated by flow cytometry with samples from 4 previously untreated pts with CLL treated for 1 cycle (28 days). Immune restoration was evaluated in 79 previously untreated pts with CLL enrolled in the CAPTIVATE Minimal Residual Disease (MRD) cohort. Pts received 3 cycles of Ibr, followed by 12 cycles of I+V (Ibr 420 mg/d orally; Ven ramp-up to 400 mg/d orally). Pts who met criteria for confirmed undetectable MRD (Confirmed uMRD) were then randomized 1:1 to placebo fixed-duration (FD) tx or Ibr at cycle 16; pts who did not meet Confirmed uMRD criteria (uMRD Not Confirmed) were randomized 1:1 to Ibr or I+V. Cryopreserved peripheral blood mononuclear cells at baseline (pre-dose cycle 1) and day 1 of cycles 4, 7, 16, 20, 23, and 29 in each of the 4 arms were analyzed by high-dimensional flow cytometry (34-color panel). Immune cell subset counts of B cells, T cells, monocytes, dendritic cells (DCs), myeloid-derived suppressor cells, natural killer cells, and innate lymphoid cells were calculated and compared to those of 20 age-matched healthy donors. Median changes from baseline are reported.

Results
In pts treated with single-agent Ibr for 1 cycle, MCL-1, BCL-XL and BCL-2 expression decreased by 74%, 95% and 10%, respectively, in lymph node emigrant (CD5+ CXCR4dim) CLL cells, confirming increased BCL-2-dependence and corresponding inhibitor sensitization. In CAPTIVATE pts treated with I+V, a rapid and significant decrease in circulating CLL cells was observed within the first 3 cycles of Ven tx initiation (Fig 1A, cycle 7). From cycle 16 and onwards, Confirmed uMRD pts had CLL cell counts similar to healthy donors (≤0.8 CLL cell/mL), while in uMRD Not Confirmed pts counts were 1.5 to 22.9 CLL cell/mL. Subsequently, normal B-cell count restoration occurred in Confirmed uMRD pts randomized to placebo (FD tx) with a recovery to levels similar to healthy donors (+332% at cycle 29; Fig 1B). Across all arms, abnormal counts of T cell subsets, classical monocytes and conventional DCs characteristic of CLL were normalized to healthy donor levels (‒49%, +101% and +91% respectively) within the first 6 months of tx and were maintained thereafter regardless of randomized tx. Plasmacytoid DCs counts recovered by cycle 20 (+598%) in all 4 arms.

Conclusion
Sensitization to BCL-2 inhibitor effects by Ibr supports the synergistic activity of I+V. The FD regimen (Confirmed uMRD, placebo arm) of I+V effectively eradicated CLL cells to healthy donor levels and enabled sustained regeneration of normal B cell counts in contrast to ongoing therapy in the remaining tx arms. Combination I+V also allowed for normalization of other critical immune cells, including T cell subsets, classical monocytes, and conventional and plasmacytoid DCs. These data demonstrate promising evidence of immune restoration with FD I+V tx.

Keyword(s): Chronic lymphocytic leukemia, Flow cytometry, Ibrutinib, Immune reconstitution

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: S144

Type: Oral Presentation

Session title: CLL: Translational research

Background
Ibr and Ven work synergistically through their distinct and complementary modes of action: BTK inhibition by Ibr decreases levels of anti-apoptotic MCL-1 and BCL-XL proteins, but not BCL-2, and therefore increases sensitization to BCL-2 inhibition by Ven in vivo. Single agent Ibr has been shown to normalize CLL-associated immune cell alterations in number and function but the impact of the Ibr plus Ven combination (I+V) on immune cells has not been evaluated.

Aims
To 1) confirm BCL-2 sensitization by single-agent Ibr and 2) monitor changes in the cellular immune profile of patients (pts) treated with I+V in CAPTIVATE (NCT02910583), a multicenter phase 2 study evaluating 1L I+V treatment (tx) in CLL and SLL.

Methods
Ibr (420mg po daily) effects on anti-apoptotic proteins were evaluated by flow cytometry with samples from 4 previously untreated pts with CLL treated for 1 cycle (28 days). Immune restoration was evaluated in 79 previously untreated pts with CLL enrolled in the CAPTIVATE Minimal Residual Disease (MRD) cohort. Pts received 3 cycles of Ibr, followed by 12 cycles of I+V (Ibr 420 mg/d orally; Ven ramp-up to 400 mg/d orally). Pts who met criteria for confirmed undetectable MRD (Confirmed uMRD) were then randomized 1:1 to placebo fixed-duration (FD) tx or Ibr at cycle 16; pts who did not meet Confirmed uMRD criteria (uMRD Not Confirmed) were randomized 1:1 to Ibr or I+V. Cryopreserved peripheral blood mononuclear cells at baseline (pre-dose cycle 1) and day 1 of cycles 4, 7, 16, 20, 23, and 29 in each of the 4 arms were analyzed by high-dimensional flow cytometry (34-color panel). Immune cell subset counts of B cells, T cells, monocytes, dendritic cells (DCs), myeloid-derived suppressor cells, natural killer cells, and innate lymphoid cells were calculated and compared to those of 20 age-matched healthy donors. Median changes from baseline are reported.

Results
In pts treated with single-agent Ibr for 1 cycle, MCL-1, BCL-XL and BCL-2 expression decreased by 74%, 95% and 10%, respectively, in lymph node emigrant (CD5+ CXCR4dim) CLL cells, confirming increased BCL-2-dependence and corresponding inhibitor sensitization. In CAPTIVATE pts treated with I+V, a rapid and significant decrease in circulating CLL cells was observed within the first 3 cycles of Ven tx initiation (Fig 1A, cycle 7). From cycle 16 and onwards, Confirmed uMRD pts had CLL cell counts similar to healthy donors (≤0.8 CLL cell/mL), while in uMRD Not Confirmed pts counts were 1.5 to 22.9 CLL cell/mL. Subsequently, normal B-cell count restoration occurred in Confirmed uMRD pts randomized to placebo (FD tx) with a recovery to levels similar to healthy donors (+332% at cycle 29; Fig 1B). Across all arms, abnormal counts of T cell subsets, classical monocytes and conventional DCs characteristic of CLL were normalized to healthy donor levels (‒49%, +101% and +91% respectively) within the first 6 months of tx and were maintained thereafter regardless of randomized tx. Plasmacytoid DCs counts recovered by cycle 20 (+598%) in all 4 arms.

Conclusion
Sensitization to BCL-2 inhibitor effects by Ibr supports the synergistic activity of I+V. The FD regimen (Confirmed uMRD, placebo arm) of I+V effectively eradicated CLL cells to healthy donor levels and enabled sustained regeneration of normal B cell counts in contrast to ongoing therapy in the remaining tx arms. Combination I+V also allowed for normalization of other critical immune cells, including T cell subsets, classical monocytes, and conventional and plasmacytoid DCs. These data demonstrate promising evidence of immune restoration with FD I+V tx.

Keyword(s): Chronic lymphocytic leukemia, Flow cytometry, Ibrutinib, Immune reconstitution

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