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1510 Chemotherapy-Sparing Induction Followed By Consolidation and Maintenance with Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy for Newly-Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Primary Endpoint Results from the Blissphall Study

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
clinical trials, Research, Lymphoid Leukemias, ALL, Biological therapies, adult, Clinical Research, Combination therapy, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies, young adult , Study Population, Human, Minimal Residual Disease
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Mark Blaine Geyer, MD1,2, John Mascarenhas, MD3*, Marissa Smith4*, Shakira Pascual2*, Anmol Shah2*, Michael R. Silvestrone2*, Tina Czaplinska3*, Kathryn Johnson, DNP, MSc, FNP-BC5*, Meghan C. Thompson, MD6 and Jae H. Park, MD6,7

1Department of Medicine, Cell Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
2Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
4Department of Nursing, Memorial Sloan Kettering Cancer Center, New York, NY
5Department of Nursing, Icahn School of Medicine at Mount Sinai, New York, NY
6Memorial Sloan Kettering Cancer Center, New York, NY
7Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Oral ABL-targeted kinase inhibitors (TKIs) have transformed treatment of BCR::ABL+ (Philadelphia chromosome-positive, Ph+) acute lymphoblastic leukemia (ALL). Induction (IND) w/ corticosteroids (CS) and dasatinib (DAS) alone results in morphologic complete response (mCR) rates approaching 100% but low rates of measurable residual disease (MRD) negativity; addition of intensive chemotherapy to TKIs adds risks of myelosuppression. DAS + the CD3/CD19 bispecific T-cell engager blinatumomab (BLIN) is effective consolidation (CONSOL) for Ph+ ALL, though ABL kinase mutations conferring resistance can arise early in therapy (Foà, NEJM, 2020). We designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in mCR, w/ aim of expediting MRD clearance and suppressing resistant clones early in disease course, and including a maintenance (MAINT) phase of BLIN + TKI for pts in molecular response.

Methods: We conducted a multicenter trial of TKI + CS IND and TKI + BLIN CONSOL + MAINT in adults (≥18 yrs) w/ newly-diagnosed (ND) Ph+ ALL (NCT04329325). Study schema is depicted in Figure 1. Pts received CS pre-phase w/ prednisone (PRED) or dexamethasone (DEX) followed by modified GIMEMA LAL1205 IND (DEX + DAS 140 mg/d w/ DAS dose adjustments or TKI change per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) MRD assessments including FACS and BCR::ABL1 PCR. Pts in mCR on d43 could proceed to CONSOL w/ 3 cycles (C) of TKI + BLIN 28 mcg/d IVCI, d1-28, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. TKI was given continuously including between BLIN cycles. Pts in protocol-defined complete molecular response (CMR; MRD negative by FACS and no detectable BCR::ABL1 transcripts) after CONSOL could proceed to MAINT (C4-7 BLIN + TKI, 28d off between cycles). The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of CONSOL (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Toxicities were defined by CTCAE v5.0.

Results: 17 pts enrolled (12 women, 5 men) w/ median age 50 yrs (range 22-87); BCR::ABL1 transcript type p190 (n=15) or p210 (n=2). Median follow-up 11.7 months (range 3-24). All began DAS 140 mg/d as initial TKI; 4 changed TKI for DAS intolerance per protocol (bosutinib, n=2; ponatinib [PON], n=2) and remained on study; TKI was changed to PON in 1 other pt to optimize BCR::ABL1 transcript suppression pre-allogeneic transplant (alloHCT) and that pt was withdrawn from study. Two had interruption or delay of BLIN due to toxicity (grade [G] 3 transaminase elevation, n=1; G2 cytokine release syndrome, n=1); BLIN was resumed in both. Figure 2 lists nonhematologic adverse effects (AEs) seen in ≥2 pts at least possibly related to TKI or BLIN while on study. One pt developed G3 pancreatitis after DAS was changed to PON; TKI was changed back to DAS. There were no G4-5 AEs.

All pts (100%) achieved mCR during IND (median d22). Ten achieved CMR to date (5 during IND, 5 during CONSOL) and 6 did not achieve CMR; determination pending in 1 pt. By FACS, 16/17 achieved BM MRD negativity; 13/14 evaluable pts had no evidence of malignant clonal IgH rearrangement (IgHR) by next generation sequencing (NGS). Notably, 3 pts w/ persistent low-level BCR::ABL1 transcripts had no evidence of malignant clonal IgHR by NGS but were withdrawn post-CONSOL as protocol required BCR::ABL1 PCR negativity to proceed to MAINT. Two pts relapsed, both after achieving CMR (one declined CONSOL and self-discontinued TKI; one had extramedullary (EM) relapse w/ ABL T315I mutation). Four pts underwent alloHCT in CR1 (rising MRD levels on study leading to change in therapy, n=1; persistent BCR::ABL1 PCR positivity, n=2; IKZF1plus phenotype, n=1); one underwent alloHCT in CR2 following EM relapse.

Conclusions: DAS + CS IND w/ addition of BLIN to TKI in mCR leads to high rates of deep molecular response w/ low risk of early relapse and low rates of severe regimen-related toxicity in pts w/ ND Ph+ ALL. Use of PON (vs DAS) as initial TKI w/ BLIN may further suppress resistant clones. Further f/u is needed to confirm durability of CMR w/ BLIN + TKI CONSOL ± MAINT in absence of alloHCT and whether pts w/ persistent BCR::ABL1 PCR positivity and no malignant clonal IgHR by NGS exhibit similar outcomes to those in CMR.

Disclosures: Geyer: Actinium Pharmaceuticals, Inc: Research Funding; Novartis: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding. Mascarenhas: Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Janssen, Kartos Therapeutics, Merck, Novartis, PharmaEssentia, Roche; Participated in consulting or advisory committees – AbbVie, Bristol Myers Squibb, Celgene, Constellation Pharmac: Research Funding; Incyte, Novartis, Roche, Geron, GSK, Celgene/BMS, Kartos, AbbVie, Karyopharm, PharmaEssentia, Galecto, Imago, Sierra Oncology, Pfizer, MorphoSys, CTI Bio: Consultancy; Bristol Myers Squibb, Celgene, Constellation Pharmaceuticals/MorphoSys, CTI BioPharma, Galecto, Geron, GSK, Incyte Corporation, Karyopharm Therapeutics, Novartis, PharmaEssentia, Prelude Therapeutics, Pfizer, Merck, Roche, AbbVie, Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Novartis, Janssen, Kartos Therapeutics, Merck, PharmaEssentia, Roche: Research Funding; GSK: Honoraria; AbbVie, CTI BioPharma Corp, a Sobi company, Geron, GlaxoSmithKline, Imago, Incyte, Kartos, Kayropharm, MorphoSys, Novartis, Pfizer, PharmaEssentia, Sierra: Consultancy. Thompson: Beigene: Consultancy, Research Funding; VJHemOnc: Honoraria; Loxo Oncology at Lilly: Consultancy; Janssen: Consultancy; Massachusetts Medical Society: Honoraria; Dava Oncology: Honoraria, Other: Travel ; Genmab: Research Funding; Curio Science: Honoraria; MJH Life Sciences: Honoraria; Intellisphere LLC: Honoraria; Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH): Honoraria; Genentech: Research Funding; Abbvie: Consultancy, Research Funding; Nurix Therapeutics: Other: travel support, Research Funding; AstraZeneca: Consultancy, Research Funding; Philips Group Oncology Communications: Honoraria. Park: BeiGene: Consultancy; Servier: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Genentech, Inc.: Research Funding; Incyte: Research Funding; GC Cell: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Autolus Therapeutics: Research Funding; Kite: Consultancy; Minerva Bio: Consultancy; Be Biopharma: Consultancy; Intella: Consultancy; Amgen: Consultancy; Bright Pharmacetuicals: Consultancy; Curocell: Consultancy; Artiva Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Affyimmune: Consultancy.

OffLabel Disclosure: Dasatinib (not FDA approved for newly-diagnosed acute lymphoblastic leukemia); blinatumomab (not FDA approved as consolidation for acute lymphoblastic leukemia without minimal residual disease, or in combination with tyrosine kinase inhibitor)

*signifies non-member of ASH