INITIAL RESULTS OF A MULTICENTER, INVESTIGATOR-INITIATED STUDY OF MRD DRIVEN TIME LIMITED THERAPY WITH ZANUBRUTINIB, OBINUTUZUMAB AND VENETOCLAX
Author(s): ,
Jacob Soumerai
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Anthony Mato
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Jason Carter
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Ahmet Dogan
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Ephraim Hochberg
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Jeffrey Barnes
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Audrey Hamilton
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Jeremy Abramson
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Connie Batlevi
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Erel Joffe
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Matthew Matasar
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Ariela Noy
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Colette Owens
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
M. Lia Palomba
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Tak Takvorian
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Kelsey Flaherty
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Lauren Ramos
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Morgan Choma
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Chaya Friedman
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Puja Chadha
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Elizabeth Simkins
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Daneal Portman
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Neena Mahajan
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Rosalba Martignetti
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Lindsey Roeker
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Omar Abdel-Wahab
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
Andrew Zelenetz
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
EHA Library. Soumerai J. 06/12/20; 294982; S162
Jacob Soumerai
Jacob Soumerai
Contributions
Abstract

Abstract: S162

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: CLL - Targeted therapy II

Background
Venetoclax (Ven; BCL2 inhibitor) and Obinutuzumab (O; CD20 antibody) is approved for patients with previously untreated chronic lymphocytic leukemia (CLL) and achieves frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven and Ibrutinib (BTK inhibitor) appears synergistic with frequent uMRD, but this combination is associated with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor (minimal ITK inhibition) that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. 

Aims
(1) To determine the rate of uMRD response. (2) To determine the time to uMRD response. (3) To determine the proportion of patients who successfully discontinue therapy.

Methods
In this multicenter, investigator-initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment per iwCLL, ECOG PS <2, ANC >1,000/ul, PLT >75,000/ul (ANC >0/ul, PLT >20,000/ul if due to CLL). Informed consent was obtained from all pts.

BOVen was administered in 28 day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (or split D1-2 if absolute lymphocyte count >25,000/ul or lymph node >5cm), 8, and 15 of C1, then D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg PO daily).

Treatment duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10-4) starting C7D1 then every 2 cycles. Once PB-uMRD was determined and confirmed in bone marrow (BM), pts completed 2 additional cycles then discontinued therapy.

The primary endpoint was BM-uMRD, and median time to uMRD was estimated using the Kaplan-Meier method. Response was assessed per 2018 iwCLL criteria. Adverse events (AE) were assessed per CTCAE v5.

Results
The study accrued 39 pts (3-10/19): median age was 59 years (23-73), there was a 3:1 male predominance, 26/39 (67%) had CLL IPI high or very high risk, 28/39 (72%) had unmutated IGHV, and 4/39 (10%) had 17p del and/or TP53 mutated. All pts were evaluable for toxicity with 37 evaluable for efficacy.

At a median follow up of 9 months (mo; 3-12+), 26/37 (70%) pts achieved PB-uMRD and 23/37 (62%) pts achieved BM-uMRD. The median time to PB-uMRD was 6 mo (4-10+). Of 26 with PB-uMRD, 23 had BM-uMRD with 15/23 completing 2 additional cycles and discontinued. Two pts had detectable BM-MRD, and 1 pt with PB-uMRD awaits BM. The frequency of pts achieving objective and complete responses were 97% (36/37) and 27% (10/37).

The most common treatment emergent AEs were neutropenia (49%), infusion related reaction (41%), bruising (41%), diarrhea (39%) and thrombocytopenia (36%). Grade ≥3 AEs occurring in ≥5% pts were neutropenia (15%), thrombocytopenia (5%) and pneumonia (5%).

Of 17 pts at high risk for TLS on C1D1, 2 cycles of BO reduced TLS risk to low/medium at Ven initiation in 15 (88%). No pts had laboratory/clinical TLS (Howard).

Conclusion
BOVen is well tolerated and achieves rapid uMRD: 70% PB-uMRD and 62% BM-uMRD with limited follow-up (to be updated on presentation). Fifteen (41%) had confirmation of the prespecified uMRD endpoint and are in follow-up off therapy per protocol. The value of MRD-directed treatment duration will be evaluated with continued follow up.

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Chronic lymphocytic leukemia, Therapy

Abstract: S162

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: CLL - Targeted therapy II

Background
Venetoclax (Ven; BCL2 inhibitor) and Obinutuzumab (O; CD20 antibody) is approved for patients with previously untreated chronic lymphocytic leukemia (CLL) and achieves frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven and Ibrutinib (BTK inhibitor) appears synergistic with frequent uMRD, but this combination is associated with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor (minimal ITK inhibition) that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. 

Aims
(1) To determine the rate of uMRD response. (2) To determine the time to uMRD response. (3) To determine the proportion of patients who successfully discontinue therapy.

Methods
In this multicenter, investigator-initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment per iwCLL, ECOG PS <2, ANC >1,000/ul, PLT >75,000/ul (ANC >0/ul, PLT >20,000/ul if due to CLL). Informed consent was obtained from all pts.

BOVen was administered in 28 day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (or split D1-2 if absolute lymphocyte count >25,000/ul or lymph node >5cm), 8, and 15 of C1, then D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg PO daily).

Treatment duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10-4) starting C7D1 then every 2 cycles. Once PB-uMRD was determined and confirmed in bone marrow (BM), pts completed 2 additional cycles then discontinued therapy.

The primary endpoint was BM-uMRD, and median time to uMRD was estimated using the Kaplan-Meier method. Response was assessed per 2018 iwCLL criteria. Adverse events (AE) were assessed per CTCAE v5.

Results
The study accrued 39 pts (3-10/19): median age was 59 years (23-73), there was a 3:1 male predominance, 26/39 (67%) had CLL IPI high or very high risk, 28/39 (72%) had unmutated IGHV, and 4/39 (10%) had 17p del and/or TP53 mutated. All pts were evaluable for toxicity with 37 evaluable for efficacy.

At a median follow up of 9 months (mo; 3-12+), 26/37 (70%) pts achieved PB-uMRD and 23/37 (62%) pts achieved BM-uMRD. The median time to PB-uMRD was 6 mo (4-10+). Of 26 with PB-uMRD, 23 had BM-uMRD with 15/23 completing 2 additional cycles and discontinued. Two pts had detectable BM-MRD, and 1 pt with PB-uMRD awaits BM. The frequency of pts achieving objective and complete responses were 97% (36/37) and 27% (10/37).

The most common treatment emergent AEs were neutropenia (49%), infusion related reaction (41%), bruising (41%), diarrhea (39%) and thrombocytopenia (36%). Grade ≥3 AEs occurring in ≥5% pts were neutropenia (15%), thrombocytopenia (5%) and pneumonia (5%).

Of 17 pts at high risk for TLS on C1D1, 2 cycles of BO reduced TLS risk to low/medium at Ven initiation in 15 (88%). No pts had laboratory/clinical TLS (Howard).

Conclusion
BOVen is well tolerated and achieves rapid uMRD: 70% PB-uMRD and 62% BM-uMRD with limited follow-up (to be updated on presentation). Fifteen (41%) had confirmation of the prespecified uMRD endpoint and are in follow-up off therapy per protocol. The value of MRD-directed treatment duration will be evaluated with continued follow up.

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Chronic lymphocytic leukemia, Therapy

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