Chemotherapy Free Regimen of Inotuzumab Ozogamicin and Blinatumomab in Frontline Therapy of Older Patients with Philadelphia Negative B-Cell Acute Lymphoblastic Leukemia
Authors: Senapati Jayastu , Jabbour Elias , Short Nicholas J. , Jain Nitin , Haddad Fadi G. , Kadia Tapan M. , Sasaki Koji , Alvarado-Valero Yesid , Takahashi Koichi , DiNardo Courtney D. , Daver Naval , Garcia-Manero Guillermo , Ravandi Farhad , Jacob Jovitta , Garris Rebecca , Kantarjian Hagop 
Published: December 2024

Background:
Older patients (pts) (≥70 years of age) with acute lymphoblastic leukemia (ALL) are particularly vulnerable to the effects of chemotherapy. Non relapse mortality from therapy related toxicity is an important cause of compromised survival in this age group. With Mini-HyperCVD-Inotuzumab (InO) with/without blinatumomab (Blina) in pts with Philadelphia (Ph) negative B-cell ALL, pts ≥70 years of age had high rates of death in remission, despite the low-intensity chemotherapy backbone (Jabbour et al. Lancet Haematology 2023). Two-year overall survival (OS) was 64%. Additionally, chemotherapy exposure can increase the risk of secondary myeloid neoplasms, as patients with B-cell ALL now live longer due to chemoimmunotherapy approaches compared to historical survival outcomes, providing time for evolution of clonal hematopoiesis. We report a chemotherapy minimized InO/Blina based treatment approach for frontline therapy in older pts with Ph-ve B-cell ALL.
Methods:
Pts ≥70 years of age (or 60-70 yrs unfit) with Ph-ve B-cell ALL, ECOG performance status ≤3 and adequate organ function were eligible. Treatment consisted of Dexamethasone intravenous (IV) 20 mg (Day) D1-D4 and vincristine 1 mg IV on D4 with fractionated InO 0.6 mg/m2 on D1 and 0.3 mg/m2 on D8, in Cycle (C) 1. Blina was administered as a continuous IV infusion from D15 for 14 days (9ug/day x 2 days followed by 28 ug/day). Consolidation cycles (C2-C5) consists of Blina 28 ug/day x D1-D28/42 days cycle and InO on D1, D8 at 0.6 mg/m2 (only C2-C4; cumulative max dose of InO=2.7 mg/m2). This was followed by 4 cycles of maintenance with single agent Blina continuous IV at 28 ug/day D1-D28/42-day cycles. Pts with CD20 positive disease could receive rituximab 375 mg/m2 IV per standard of care on D2 and D9 for C1-4 for a total of 8 doses. CNS prophylaxis with alternating IT methotrexate and cytarabine was administered for 12 doses. Antibiotic prophylaxis was as per institutional practice and Blina dose reduction for toxicity was as per standard guidelines. All pts received ursodeoxycholic acid prophylaxis.
Results:
From Apr 2021-May 2024, 14 pts at a median age of 76 yrs (65-84 yrs) were treated, 7 (50%) of who were female. 13/14 pts were ≥70 yrs at therapy initiation. 11 pts (79%) received rituximab. 6/13 pts evaluated pts (46%) had high-risk cytogenetics (KMT2A rearranged=2, hypoploidy=2, near triploidy=1, complex=1) and 7 pts (50%) had a TP53 mutation at ALL diagnosis. Two pts had KMT2A rearrangement and one pt had had CRLF2 positive B-cell ALL. A best response of CRc was attained in 13 pts (93%) (CR=12, CRi=1) and one pt has persistent disease after one cycle of therapy and awaiting response assessment after C2. All 13 responders (100%) became measurable residual disease (MRD) negative by flow cytometry (11 after 1 cycle, 2 after 2 cycles) and 11 of 12 pts (92%) evaluated by NGS based MRD became negative at sensitivity of 10-6 (6 of 8 evaluated after C1 were negative).
At a median follow up of 15 months (mos) (95% CI 2.3-31 mos), 2 pts have relapsed; the median PFS, CRD and OS have not been reached, and 1-year rates are 64%, 70% and 73% respectively. One pt underwent an allogeneic SCT (alive in CR, 30 months after SCT) and 2 pts relapsed (KMT2A rearrangement=1, hypoploidy+ TP53 mutation=1). Both relapsed pts had previously become negative on NGS based MRD assessment. At data cutoff, 5 pts have died, 2 after relapse and 3 in remission (pneumonia, myocardial infarction, non-infectious respiratory failure; none in the setting of neutropenia). The median time on study was 10 mos (1.3-14.8 mos), 3 pts completed protocol therapy and 5 pts are on active therapy. One pt had grade 3 ALT elevation and no pt developed a hepatic sinusoidal obstruction syndrome. One pt had grade 3 Blina related encephalopathy which resolved with holding Blina and treatment with steroids and Blina could be reintroduced; 5 pts (36%) had grade 1-2 confusion, 3 pts (21%) had grade 1-2 tremors and one pt had grade 2 cytokine release syndrome. No pt has developed a secondary myeloid neoplasm.
Conclusion:
A chemotherapy minimized combination of InO and Blina leads to promising response and survival outcomes in older pts with newly diagnosed B-ALL and appears tolerable. Longer follow up to assess safety, continued efficacy and incidence of secondary myeloid neoplasms is needed in this population.