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854 Phase 2 Response-Adapted Study of Ibrutinib with Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, and Rituximab (TEDDI-R) for Secondary CNS Lymphoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Initial treatment strategies in aggressive B Cell lymphomas
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphomas, non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Monday, December 11, 2023: 3:00 PM

Jillian Simard, MD1*, James D Phelan, PhD1*, Christopher Melani, MD1, Rahul Lakhotia, MBBS1, Stefania Pittaluga, MD, PhD2*, Jagan R. Muppidi, MD, PhD1*, Michail Lionakis, MD, ScD3*, Cody J Peer4*, Amynah Pradhan, NP1*, Matthias Holdhoff, MD5*, Lode J. Swinnen6, Kieron Dunleavy, MD7*, Catherine Lai, MD8, Sami Ibrahimi, MD9*, Michael Glantz10*, John A Butman11*, Kim Johnson, RN12*, Seth M. Steinberg, PhD13*, William Figg, PharmD14*, Elaine S. Jaffe, MD15, Louis M. Staudt, MD, PhD1, Wyndham H. Wilson, MD, PhD1* and Mark Roschewski, MD1

1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
2Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
3Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
4Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
5Department of Neuro-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
6Johns Hopkins Cancer Center, Baltimore, MD
7Medstar Georgetown University Hospital, Washington, DC
8Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
9University of Oklahoma Health Sciences Center, Oklahoma City, OK
10Department of Neurosurgery, Penn State College of Medicine, Hershey Medical Center, Hershey, PA
11Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD
12Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
13Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD
14Molecular Pharmacology Section, Genitourinary Malignancies Section, Center for Cancer Research, National Cancer Institute,, National Institutes of Health, Bethesda, MD
15CCR Lab of Pathology, National Cancer Institute, Bethesda, MD

Background: Secondary CNS lymphomas (SCNSL) are aggressive and there are few treatment options. CNSLs often have underlying chronic active B-cell receptor signaling that responds to BTK inhibitors, but the response duration is short. TEDDI-R achieves durable remissions in primary DLBCL of the CNS (PCNSL), but the molecular profile of SCNSL tumors that are BTK-responsive is unknown. We present results from an ongoing response-adapted study of ibrutinib with TEDD-R in SCNSL [NCT03964090].

Methods: Pts with aggressive B-cell lymphomas with CNS +/- systemic involvement are eligible if age ≥18, PS<3, and adequate organ function. Pts are untreated with CNS involved or relapsed in the CNS after therapy. Prior BTKi is allowed. HIV is excluded. Baseline tests: brain MRI, PET/CT of body, bone marrow (BM), CSF flow cytometry, and fundoscopic exam. Pts receive isavuconazole as fungal prophylaxis throughout therapy. Pts first receive ibrutinib 560mg x 14d in a treatment window to determine ibrutinib-responsiveness. Pts with ≥20% reduction after ibrutinib receive TEDDI-R, and if <20% reduction receive TEDD-R (no ibrutinib). Chemotherapy is 4 cycles x21d as an outpatient and includes intrathecal chemotherapy. There is no maintenance therapy or planned consolidation. Response is assessed after cycles 2 and 4. Complete responses (CR) are confirmed with FDG-PET brain/body, CSF analysis, and BM. Surveillance scans are q3m for 1y, q4m x 1y, q6m x 1y, then annually. The primary endpoint is PFS.

Results: 50 pts enrolled between June 2019 and March 2023 with median age 63 (range 26-89), and 15 (30%) aged ≥70. 17 pts (34%) were female. 28 (56%) pts had DLBCL: 21 (42%) non-GCB, 5 (10%) GCB, 1 (2%) PMBL, and 1 (2%) unknown. 16 (32%) pts had HGBL: 10 (20%) with MYC/BCL2-R and 6 (12%) with MYC/BCL6-R. Two (4%) pts each had MCL and EBV-LPD, and 1 pt each had plasmablastic (2%) and Burkitt (2%). Five (10%) pts were treatment naïve and 45 (90%) were relapsed or refractory. 25 (50%) had synchronous CNS and peripheral disease, and 25 (50%) were isolated to the CNS. All relapsed or refractory pts had prior anthracycline, 29 (58%) prior HD-MTX, and 8 (18%) prior CAR-T. Forty-three pts completed the ibrutinib window and were evaluable for responsiveness; 25 (58%) were ibrutinib-responsive and 18 (42%) were ibrutinib-resistant (Figure 1). The overall response rate (ORR) to TEDDI-R (n=28) was 96%, including a CR rate of 71%. The overall response rate to TEDD-R (n=20) was 35%, with a CR rate of 25%. G3 or G4 neutropenia occurred in 43% and 31% of cycles, respectively, and febrile neutropenia occurred in 11%. G3 or G4 thrombocytopenia occurred in 31% and 12% of cycles, respectively, and G3 anemia occurred in 37%. G3 non-hematologic AEs (% pts) included UTI (20%), hypokalemia (22%), sepsis (14%), diarrhea (16%), hypotension (12%), fatigue (10%), anorexia (10%), adrenal insufficiency (10%), and atrial fibrillation (8%). Few G4 AEs were noted. No opportunistic infections (including Aspergillus) were observed. 14 (28%) pts had hand-foot syndrome.

After a median follow-up of 24m, the 1-year PFS and OS of all patients were 37.8% and 59.9%, respectively. Pt deaths were due to disease progression (20 pts, 83%), pneumonia (3 pts, 13%), and a cardiac event (1 pt, 4%). The 1-year PFS and OS for pts with ibrutinib-responsive compared to ibrutinib-resistant tumors were 57.0% vs. 16.7% (p=0.0006) and 73.8% vs. 47.9% (p=0.06) (Figure 2). Most (86%) ibrutinib-responsive DLBCL/HGBL tumors were CD10-negative. CD10-negative DLBCL/HGBL pts had an ORR of 77% and a CR rate of 70%. The 1-year PFS and OS for pts with CD10-negative DLBCL/HGBL were 50.5% and 65.0%, respectively. There was no difference in PFS or OS in pts aged <70 versus ≥70 (p=0.87 and p=0.74, respectively). We performed comprehensive genomic profiling on 27 DLBCL/HGBL tumors according to the LymphGen algorithm. 80% (n=4) MCD, 75% (n=3) BN2, 50% (n=2) EZB, and 50% (n=7) unclassified tumors were responsive to ibrutinib.

Conclusions: Pts with ibrutinib-responsive SCNSL achieve a high rate of CR to TEDDI-R, and preliminary data suggest these remissions are durable. Most ibrutinib-responsive tumors are CD10-negative and enriched for MCD and BN2. TEDDI-R can be delivered as an outpatient to pts of all ages.

Disclosures: Dunleavy: Genentech: Research Funding. Lai: AbbVie: Consultancy; Taiho: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Genentech: Consultancy; BMS: Consultancy; Rigel: Consultancy; Astellas: Consultancy; Daiichi: Consultancy; Jazz: Consultancy, Research Funding. Ibrahimi: Ipsen Bio, BMS, Sobi Inc: Consultancy.

OffLabel Disclosure: Ibrutinib. FDA approved for treatment of hematologic malignancies and graft versus host disease.

*signifies non-member of ASH