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1502 Venetoclax and Blinatumomab for Adult Patients with Relapsed/Refractory or MRD Positive Ph-Negative B-Precursor ALL: First Results of the GMALL-Bliven Trial

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Bispecific Antibody Therapy, Clinical Research, Combination therapy, Therapies, Adverse Events, Minimal Residual Disease
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Lars Fransecky1*, Walter Fiedler, MD2, Christoph Röllig, MD, MSc3*, Tim Sauer, MD4*, Simon Raffel, MD4*, Winfried Alsdorf5*, Lisa Heberling6*, Kumaran Nagarajan7*, Britta Steer7*, Philipp Nakov, MD8*, Björn Steffen, MD9*, Dorothee Deckbar10*, Sonja Bendig11*, Lorenz Bastian12*, Martin Neumann13*, Monika Brueggemann, PhD14*, Nicola Goekbuget, MD15 and Claudia D Baldus, MD1*

1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
2University Hospital Hamburg-Eppendorf, Hamburg, DEU
3Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
4Heidelberg University Hospital, Heidelberg, Germany
5Universitaetsklinikum Hamburg Eppendorf, Hamburg, Germany
6University Hospital Dresden, TU Dresden, Germany, Dresden, Germany
7UKSH Campus Kiel, Kiel, Germany
8University Hospital Schleswig Holstein Campus Kiel, Kiel, Germany
9Department of Internal Medicine II, Hematology and Oncology, Goethe University Hospital Frankfurt, Frankfurt, Germany
10Goethe University Frankfurt, Frankfurt, Germany
11University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, DEU
12CATCH-ALL, UKSH Campus Kiel, Kiel, Germany
13Medical Department II, University Cancer Center Schleswig-Holstein, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
14University Hospital Schleswig-Holstein, Kiel, DEU
15Goethe University Hospital, Frankfurt, Germany


Prognosis of adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (BCP-ALL) remains poor. Monotherapy with Blinatumomab in ALL induced a complete remission (CR) in 44% of patients and measurable residual disease (MRD) negative molecular remission (MOL-CR) in 33%. Median overall survival of 7.7 months remains unsatisfactory. In the MRD setting, median survival was 36 months in the context of subsequent allogeneic stem cell transplantation (SCT). The combination of Blinatumomab with Venetoclax may be an effective option in ALL.


In this multicenter phase 1 clinical trial the GMALL study group evaluates the safety of Blinatumomab in combination with Venetoclax in R/R or MRD positive BCP-ALL (NCT05182385). Using RNA sequencing, functional intracellular BH3 profiling, T cell immunomonitoring and effector cell cytotoxicity assays we aim to further elucidate synergy of this combination.


The BLIVEN trial includes patients with CD19-positive Ph-negative BCP-ALL aged 18 years and older, with no upper age limit. Eligible patients had either R/R ALL (bone marrow blasts >5%) or molecular failure/relapse (MRD >1xE-04). To assess safety, we determined maximum tolerated dose (MTD) as primary endpoint of the phase I part of the trial as designated recommended phase 2 dose (RP2D). Key secondary endpoint was the MOL-CR rate. Treatment consisted of oral Venetoclax in continuous dosing on day -7 to day 42 of target doses ranging between 200-800 mg once daily, and Blinatumomab as continuous intravenous infusion of 28 µg/d 4 weeks on and 2 weeks off, starting on day 1. For patients with R/R ALL, a cautionary dose step of 9 µg/d Blinatumomab was implemented for one week. MRD was analyzed in the reference laboratory using real-time quantitative PCR (RQ-PCR) of immunoglobulin and T-cell receptor (IG/TR) rearrangements.


Between February 2022 and May 2023 a total of 7 patients were enrolled in the phase I part at four German centers (Figure 1). Venetoclax target doses were 400 mg (n=3), 600 mg (n=3), and 800 mg (n=1). Median age was 48.5 years (range 22 – 72 years). MRD assessment was available in 7/7 patients. Molecular BCP-ALL subtypes were identified by RNA sequencing in 5/5 analyzed patients, including ZNF384-rearranged ALL (n=2), BCR::ABL1-like (n=2; IGH::CRLF2 rearranged), and KMT2A-rearranged ALL (n=1). Three of seven patients were treated for hematological relapse, while 4/7 patients had molecular failure/relapse at time of enrolment. Among patients with R/R ALL, 2/3 were refractory to front-line therapy with intensive GMALL induction/consolidation therapy, while 1/3 suffered relapse shortly after failure of second allogeneic SCT.

CTCAE grade IV neutropenia was identified as adverse reaction related to Venetoclax in one patient. Neutropenia resolved before dose limiting toxicity (DLT) evaluation time (i.e. 42 days after Venetoclax initiation). Overall, no DLT was identified throughout the trial and MTD was not reached. No treatment interruption was noted during cycle 1. Two of seven patients received one treatment cycle of BLIVEN only due to treatment failure, 5/7 patients received two treatment cycles.

Response assessment was available for 7/7 patients. Treatment with Blinatumomab/Venetoclax of R/R ALL resulted in CR in 1/3 patients, with the responding patient showing a MOL-CR. The MOL-CR rate in molecular failure/relapse patients was 3/4.


Salvage therapy with Blinatumomab and Venetoclax exhibited good tolerability without treatment-related mortality. No treatment withdrawals were attributed to safety concerns. Two patients did not respond to BLIVEN combination therapy. Interestingly, both patients exhibited IGH::CRLF2 fusion transcripts.The remaining 5 patients obtained MRD responses, including complete MRD responses, of which 2/2 occurred in ZNF384 rearranged BCP-ALL. Further follow-up and larger patient numbers are needed to establish the potential benefit of this regimen in molecular driver subtypes of BCP-ALL. Enrollment to complete phase I of the BLIVEN trial is currently ongoing. Updated results including RP2D will be presented at the meeting.


This is an independent academic early phase I clinical trial conducted under the sponsor role of the Goethe University, Frankfurt, Germany. It received financial support and supply of Venetoclax by AbbVie Inc..

Disclosures: Fransecky: Pfizer: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy. Fiedler: Clinigen: Consultancy; Stemline: Consultancy; Morphosis: Consultancy; Servier: Consultancy, Other: Support for meeting attendance; AbbVie: Consultancy, Honoraria, Other: Support in medical writing; Pfizer: Consultancy; Amgen: Consultancy, Other: Support for meeting attendance, Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Other: Support for meeting attendance; Apis: Research Funding. Röllig: Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria. Sauer: Astellas: Consultancy; Takeda: Consultancy; AbbVie: Consultancy, Other: Travel, Accommodation, Expenses; Amgen: Consultancy; Jazz: Honoraria, Other: Travel, Accommodation, Expenses; BMS: Consultancy; Ridgeline Discovery: Consultancy; Novartis: Consultancy; Stemline: Consultancy; Gilead: Honoraria; Pfizer: Honoraria. Alsdorf: Affimed: Research Funding; Jannsen: Honoraria, Other: Travel expenses; Biontech: Other: Travel expenses, Research Funding; GSK: Honoraria. Bendig: Amgen: Research Funding. Bastian: BeiGene: Other: Travel Honoraria. Brueggemann: Affimed: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Regeneron: Research Funding; Incyte: Consultancy; BD: Speakers Bureau; Jannsen: Speakers Bureau; Pfizer: Speakers Bureau. Goekbuget: Servier: Honoraria, Research Funding; Clinigen: Honoraria, Research Funding; Autolus: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Gilead: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Baldus: Astellas: Consultancy; BMS: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals: Consultancy; Gilead: Consultancy; Jannsen: Consultancy.

OffLabel Disclosure: Venetoclax for treatment of BCP-ALL

*signifies non-member of ASH