Blinatumomab after R-CHOP Debulking Therapy for Patients with Richter Transformation: Preliminary Results of the Multicenter Phase 2 Blinart Trial from the Filo Group
Authors: Guieze Romain , Ysebaert Loic , Molina Lysiane , Roos-Weil Damien , Michallet Anne-Sophie , Hivert Benedicte , Gay Julie , Saad Alain , Fornecker Luc Mathieu , Broséus Julien , Rouille Valérie , Auvray Laëtitia , Delmer Alain Jacques , Feugier Pierre 
Published: November 2020

Background
Richter syndrome (RS) refers as to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients (pts) with chronic lymphocytic leukemia (CLL). The outcome of RS pts is usually very poor with both low response rates to chemoimmunotherapy and short survival, except for the minority of them whose tumor cells are clonally unrelated to the underlying CLL. While BCR and BCL2 inhibitors have transformed the management of CLL pts, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017).
Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of pts with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. More recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in pts with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016).
We hypothesized that blinatumomab would improve response in RS pts failing to achieve CR after initial debulking with R-CHOP.
Methods
We report here the first results of a currently ongoing phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for pts with untreated RS of DLBCL histology (NCT03931642). The pts achieving complete remission (CR) after 2 cycles of R-CHOP21 discontinued study while those with persisting (PR, SD) or progressive disease (PD) were eligible to receive an 8-week course of blinatumomab induction. An additional 4-week consolidation cycle was optional and might be proposed according to the treating-physician decision, especially in pts who were ineligible for stem-cell transplantation. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. Interim analysis (Simon two-stage design) was planned after completion of blinatumomab induction in 10 pts.
Results
A total of 15 pts out of 35 has already been enrolled in the trial to date. Median age was 67 years (range, 38-80) andsex ratioM/F was 12/3. CLL features at baseline were as follows: 9/15 (60%) pts hadTP53alterations and 10/13 (77%) unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-4): 10 (67%) pts previously received chemo-immunotherapy, 10 (67%) pts were exposed to BCR inhibitors and 3 (20%) to venetoclax.
As of the data cut-off of July 1st, 2020, the blinatumomab induction course has been completed for 5 pts while it is still on-going in 3 others. Three pts are still on R-CHOP debulking. Four pts discontinued study before receiving blinatumomab for the following reasons: 2 pts achieved CR after R-CHOP, 1 patient died because of febrile neutropenia after R-CHOP and 1 patient discontinued study before starting R-CHOP (no RS criteria after pathology review). Regarding toxicity during blinatumomab, data are available for the 5 pts having completed the blinatumomab induction to date. Four pts had at least one grade 1 adverse event (AE), 2 had grade ≥3 AE. The most common AE, regardless of relationship to blinatumomab, were grade 1 fever (2 pts) and grade 2 leukopenia (2 pts). Other grade &gt;1 AE were observed in 1 pt only (grade 3 anxiety, grade 2 anemia, grade 2 neutropenia, grade 3 lymphopenia). In terms of neurologic event, 1 pt had grade 1 AE (paresthesia, myoclonus and muscle contraction) and another one presented grade 4 confusion while on first 9 μg/d dose leading to permanent discontinuation of blinatumomab. In terms of efficacy, after R-CHOP debulking therapy (n=10 evaluable pts), 2 pts achieved CR (and did not pursuit on study), 5 pts were in PR and 3 pts were progressive. At evaluation after the blinatumomab induction (n=5 evaluable pts), 2 pts achieved CR, 1 patient PR and 2 pts were progressive.
Conclusions
Our preliminary data suggest that blinatumomab shows encouraging anti-tumor activity and acceptable toxicity in pts with RS. Further analyses are warranted to validate these conclusions. Updated efficacy/safety in the remaining pts enrolled in the trial will be presented at the meeting.

Disclosures
Guieze: astrazanecka:Honoraria, Other: advisory board;gilead:Honoraria, Other: travel funds;janssen cilag:Honoraria, Other: advisory board, travel funds;roche:Other: travle funds;abbvie:Honoraria, Other: advisory board, travel funds.Ysebaert:AbbVie:Consultancy;Janssen:Consultancy;Roche:Consultancy.Fornecker:Roche:Consultancy;Takeda:Consultancy.Broséus:Gilead:Honoraria;AstraZeneca:Consultancy, Honoraria;Janssen:Honoraria, Research Funding;Novartis:Honoraria, Research Funding.Feugier:astrazeneca:Consultancy, Honoraria, Research Funding;abbvie:Consultancy, Honoraria, Research Funding;roche:Consultancy, Honoraria, Research Funding;gilead:Consultancy, Honoraria, Research Funding;janssen:Consultancy, Honoraria, Research Funding.

OffLabel Disclosure:
Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells. It has been approved as a second line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia.