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A PHASE II STUDY OF MINI-HYPER-CVD PLUS VENETOCLAX IN PATIENTS WITH PHILADELPHIA CHROMOSOME-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Author(s): ,
Jayastu Senapati
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Hagop Kantarjian
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Nicholas Short
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Marina Konopleva
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Farhad Ravandi
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Nitin Jain
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Philip A. Thompson
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Naveen Pemmaraju
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
William G. Wierda
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Gautam Borthakur
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Tapan M. Kadia
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Guillermo Garcia-Manero
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Musa Yilmaz
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Jennifer Thankachan
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Min Zhao
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Christopher Loiselle
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Makiel T. Talley
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Monica I. Kwari
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Rebecca S. Garris
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
Elias J. Jabbour
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,États-unis;Leukemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Leukemia,MD Anderson Cancer Center,Houston,Stati Uniti;Leukemia,MD Anderson Cancer Center,Houston,United States;Leukemia,MD Anderson Cancer Center,Houston,Estados Unidos;Leukemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Leukemia,MD Anderson Cancer Center,Houston,Estados Uni
(Abstract release date: 05/12/22) EHA Library. Senapati J. 06/10/22; 357232; P369
Jayastu Senapati
Jayastu Senapati
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P369

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

Venetoclax (VEN), an orally active Bcl-2 antagonist, has shown activity in acute lymphoblastic leukemia (ALL) in preclinical models and in combination with navitoclax (BCL-XL inhibitor) in early clinical studies. Combining VEN with other active agents in ALL might synergize this antileukemic effect.

Aims

We aimed to evaluate the efficacy and tolerability of VEN added to mini-hyper CVD (mHCVD) chemotherapy in patients (pts) with relapsed/refractory (R/R) ALL.

Methods

Pts ≥18 years of age with R/R Philadelphia chromosome negative (Ph-) B- or T-cell ALL/lymphoblastic lymphoma (LBL) were eligible. Pts were required to have a PS of ≤3, bilirubin ≤1.5 mg/dl, AST/ALT ≤3 x ULN and creatinine ≤2 mg/dl. Treatment consisted of mHCVD for up to 8 cycles. VEN was given at a dose of 400 mg daily on D1-14 of C1 and on D1-7 of C2-8. Rituximab (if CD20+) and prophylactic IT chemotherapy x 8 doses were given in C1-C4. Pts with T-cell ALL received an additional 2 cycles of nelarabine (650 mg/m2 daily on D1-5) and peg-asparaginase (1,500 IU/m2 [capped at 3750 IU] on D5), without VEN, during consolidation and another 2 cycles during maintenance. Responding pts received vincristine and prednisone maintenance with VEN daily on D1-14 of each 28-day cycle for up to 2 yrs.

Results

From 6/2019 to 2/2021, 20 pts with R/R ALL were treated, 15 (75%) with B-ALL, 4 (20%) with T-ALL (including 1 ETP-ALL) and 1 (5%) with T-LBL. The median age was 45 yrs (range, 20-70). The median lines of prior therapy was 2 (range 1-5). Of the 15 B-ALL pts, 6 had previously received both blinatumomab (blina) and inotuzumab (INO), 7 had received blina without INO, and 2 had received neither. Overall, 11 pts (55%) had undergone prior stem cell transplantation (SCT).

Pt disposition is shown in Fig. 1A. One pt was in measurable residual disease (MRD)-positive CR at trial enrollment; all others had active disease and were evaluable for response assessment. Pts received a median of 2 cycles of mHCVD-VEN (range, 1-6). Overall, 12 of 19 evaluable pts (63%) responded (9 CR, 3 CRi), 9 (75%) of whom after 1 cycle. Response in B-ALL was 9/15 (60%) and in T-ALL was 3/4 (75%). Six of the 12 responders (50%) attained MRD negativity (MRD-ve). Of the 12 responders, 4 (33%) underwent SCT, 3 of whom subsequently relapsed and 1 of whom is in continued MRD-ve CR. All of the 8 responders (67%) who did not undergo SCT, subsequently relapsed and died, with a median duration of response of 2.1 mos. Six of the 7 non-responders have died. With a median follow up of 15 months (mos), 5 pts are alive with a median RFS and OS of 6.2 and 7.1 mos respectively (Fig. 1B. The median OS in responders was 8.8 mos (Fig. 1C).

The therapy was generally well-tolerated. There were no grade 4-5 adverse events. Four pts had a grade 3 related event (hyperbilirubinemia and mucositis in 1 pt and transaminitis, fatigue and tumor lysis syndrome in 1 pt each). One pt required VEN dose reduction due to cytopenias. The median times to neutrophil and platelet recovery in C1 in responding pts were 18 and 27 days, respectively.

Fig.1: (A) Patient disposition and survival, (B) OS and RFS for the entire cohort, (C) OS of responders and non-responders

Conclusion

Low dose combination chemotherapy with VEN in a population of heavily pretreated R/R ALL was well-tolerated and resulted in a response rate of 63%. This study has now been amended to add navitoclax in an attempt to further improve outcomes.

Keyword(s): ALL, BCL2

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P369

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

Venetoclax (VEN), an orally active Bcl-2 antagonist, has shown activity in acute lymphoblastic leukemia (ALL) in preclinical models and in combination with navitoclax (BCL-XL inhibitor) in early clinical studies. Combining VEN with other active agents in ALL might synergize this antileukemic effect.

Aims

We aimed to evaluate the efficacy and tolerability of VEN added to mini-hyper CVD (mHCVD) chemotherapy in patients (pts) with relapsed/refractory (R/R) ALL.

Methods

Pts ≥18 years of age with R/R Philadelphia chromosome negative (Ph-) B- or T-cell ALL/lymphoblastic lymphoma (LBL) were eligible. Pts were required to have a PS of ≤3, bilirubin ≤1.5 mg/dl, AST/ALT ≤3 x ULN and creatinine ≤2 mg/dl. Treatment consisted of mHCVD for up to 8 cycles. VEN was given at a dose of 400 mg daily on D1-14 of C1 and on D1-7 of C2-8. Rituximab (if CD20+) and prophylactic IT chemotherapy x 8 doses were given in C1-C4. Pts with T-cell ALL received an additional 2 cycles of nelarabine (650 mg/m2 daily on D1-5) and peg-asparaginase (1,500 IU/m2 [capped at 3750 IU] on D5), without VEN, during consolidation and another 2 cycles during maintenance. Responding pts received vincristine and prednisone maintenance with VEN daily on D1-14 of each 28-day cycle for up to 2 yrs.

Results

From 6/2019 to 2/2021, 20 pts with R/R ALL were treated, 15 (75%) with B-ALL, 4 (20%) with T-ALL (including 1 ETP-ALL) and 1 (5%) with T-LBL. The median age was 45 yrs (range, 20-70). The median lines of prior therapy was 2 (range 1-5). Of the 15 B-ALL pts, 6 had previously received both blinatumomab (blina) and inotuzumab (INO), 7 had received blina without INO, and 2 had received neither. Overall, 11 pts (55%) had undergone prior stem cell transplantation (SCT).

Pt disposition is shown in Fig. 1A. One pt was in measurable residual disease (MRD)-positive CR at trial enrollment; all others had active disease and were evaluable for response assessment. Pts received a median of 2 cycles of mHCVD-VEN (range, 1-6). Overall, 12 of 19 evaluable pts (63%) responded (9 CR, 3 CRi), 9 (75%) of whom after 1 cycle. Response in B-ALL was 9/15 (60%) and in T-ALL was 3/4 (75%). Six of the 12 responders (50%) attained MRD negativity (MRD-ve). Of the 12 responders, 4 (33%) underwent SCT, 3 of whom subsequently relapsed and 1 of whom is in continued MRD-ve CR. All of the 8 responders (67%) who did not undergo SCT, subsequently relapsed and died, with a median duration of response of 2.1 mos. Six of the 7 non-responders have died. With a median follow up of 15 months (mos), 5 pts are alive with a median RFS and OS of 6.2 and 7.1 mos respectively (Fig. 1B. The median OS in responders was 8.8 mos (Fig. 1C).

The therapy was generally well-tolerated. There were no grade 4-5 adverse events. Four pts had a grade 3 related event (hyperbilirubinemia and mucositis in 1 pt and transaminitis, fatigue and tumor lysis syndrome in 1 pt each). One pt required VEN dose reduction due to cytopenias. The median times to neutrophil and platelet recovery in C1 in responding pts were 18 and 27 days, respectively.

Fig.1: (A) Patient disposition and survival, (B) OS and RFS for the entire cohort, (C) OS of responders and non-responders

Conclusion

Low dose combination chemotherapy with VEN in a population of heavily pretreated R/R ALL was well-tolerated and resulted in a response rate of 63%. This study has now been amended to add navitoclax in an attempt to further improve outcomes.

Keyword(s): ALL, BCL2

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