Low Intensity Mini-Hypercvd (mHCVD), Inotuzumab Ozogamicin (Ino) with/without Blinatumomab (Blina) in Older Patients with Newly Diagnosed Philadelphia Negative B-Cell Acute Lymphoblastic Leukemia (B-ALL): 10 Years Update
Authors: Senapati Jayastu , Jabbour Elias , Jain Nitin , Haddad Fadi G. , Garcia-Manero Guillermo , Daver Naval , Kadia Tapan M. , Ravandi Farhad , Sasaki Koji , DiNardo Courtney D. , Takahashi Koichi , Garris Rebecca , Jacob Jovitta , Alvarado Valero Yesid , Montalban-Bravo Guillermo , Short Nicholas J. , Kantarjian Hagop 
Published: December 2024

Background:
Older patients (pts) with B-ALL have historically had poor outcomes from adverse disease biology and inability to tolerate intensive chemotherapy and asparaginase. Addition of B-cell targeted agents to low-intensity chemotherapy could lead to tolerable regimens with possibility of improved outcomes in these pts. Herein we are reporting the long-term safety and efficacy of InO with/without Blina added to mHCVD regimen as frontline therapy in older adults (≥60 yrs) with Philadelphia (Ph) negative B-ALL with 10-year follow-up.
Methods:
Pts ≥60 yrs with Ph-ve B-ALL were eligible if untreated or had received ≤2 cycles of previous therapy, ECOG PS ≤3 and adequate organ function. The chemotherapy backbone was mHCVD (mHCVD: cyclophosphamide 150mg/m2 q12h [day] D1-3, dexamethasone 20mg/day D1-4, 11-14, and vincristine 2 mg D1, 8; alternating with methotrexate (MTX) 250mg/m2 D1 & cytarabine 500mg/m2 q12h D2, 3) for up to 8 cycles (C). 12 doses of intrathecal IT MTX /cytarabine were given for CNS prophylaxis; pts with CNS disease had IT hydrocortisone, MTX, and cytarabine 2/week till CNS clearance, then weekly x 4. 8 doses of rituximab 375mg/m2 were given on D1, 8 of C1-4 if CD20 was ≥20% by flow cytometry (FCM). Initially, InO was dosed at 1.3-1.8mg/m2 on D3 of C1 and 1.0-1.3mg/m2 on D3 in C2-4. After protocol amendment from pt#50 onwards in Mar 2017, InO was administered in fractionated doses with a max cumulative dose of 2.7mg/m2 (0.6 mg/m2 on D2 of C1, 0.3 mg/m2 on D8 of C1, 0.3 mg/m2 on D2/D8 of C2-4). Ursodeoxycholic acid was given to all pts. 4 cycles of Blina 28µg/day replaced C5-8 of mHCVD. Maintenance was initially with vincristine 2mg D1, prednisolone 50mg daily D1-5, 6-mercaptopurine 50mg BID & MTX 10mg/m2 weekly (POMP) for 3 years. After the mentioned protocol amendment, this was reduced to 12 cycles of POMP, with 1 cycle of Blina given after every 3 POMP cycles (total 4 Blina cycles).
Results:
From Dec 2011-Aug 2022, 83 pts at a median (med) age of 67 years (60-88 years) were treated (28 [34%] ≥70 yrs], 6 of whom were in complete remission (CR) at start (5 of 6 were MRD+ve) at enrollment. 49 (59%) were male. Amongst 48 evaluated pts, 7 (14%) had CRLF2 positive and amongst 64 evaluated pts 25 (39%) had a TP53 mutation. 5 pts (65) had prior multiple myeloma. Cytogenetic (CTG) data was available in 67/83 pt; 27 had a diploid karyotype and 19 pts (28%) had high-risk (HR) CTG (12 hypodiploid, 4 tetraploid, 4 complex, 1 KMT2A rearranged). Four pts (5%) had CNS disease at baseline. A best response of CRc was attained in 76 of 77 pts not in CR at enrollment (99%) (CR=69, CRi=7) and a best response of MRD negativity by FCM was attained in 75 of 81 (5 CR-MRD+ve at enrollment + 76 CRc on study) evaluable pts (93%). MRD-ve rate after course 1 was 75% (56/75 evaluable). Amongst 17 pts evaluated by NGS for MRD (sensitivity= 10-6), 16 (94%) became undetectable, none of whom relapsed, at a med FU of 37 mos; the NGS MRD+ pt was consolidated with SCT. Amongst blina treated pts 3/38 (8%) had MRD+ve by FCM before Blina initiation.
At a med estimated F/U of 121 mos (95% CI 61-129 mos), (129 mos pre-amendment and 46 mos post-amendment pts), the med PFS was 47 mos (95%CI 22-71 mos), OS 62 mos (95%CI 22-72 mos) and continuous remission duration (CRD) not reached (95% CI NR-NR). 5-year rates were 46%, 50% and 79% resp. The 3-year PFS and OS pre and post amendment were 49% vs. 65% (p=0.56) and 57% vs. 65% (p=0.88) respectively. Med PFS and OS in pts 60-69 yrs and ≥70 yrs was 70 vs. 34 mos (p=0.1) and 75 vs. 36 mos (p=0.09) resp. 5 pts (7%) underwent an SCT in CR, 4 for HR-genomics and 1 for persistent MRD+ disease. 9 pts (11%) developed a secondary myeloid neoplasm after a med of 33 mos from therapy initiation (range, 3-66 mos), 6 on ALL therapy and 2 post ALL therapy; 5 of 8 evaluated had a TP53 mutation at ALL diagnosis which persisted.
6 pts (7%) developed hepatic SOS (4 pre, 1 post amendment), one after SCT and 5 without. 7 pts (8%) had grade 3 CNS events with Blina, but no seizures. At data cutoff, 33 pts (40%) are alive; of 50 pts who died, 1 was a non-responder, 11 died after relapse, and 38 in CR (secondary myeloid neoplasms=9, infectious complications=9 [6 on study, 3 off-study], SOS=4, miscellaneous=16).
Conclusion:
mHCVD-InO ± Blina is an efficacious and tolerable regimen with promising PFS and OS benefit even on long-term F/U. Further reduction of chemo doses and assessment of mutations that increase risk of myeloid neoplasms, especially in pts ≥70 years of age, is prudent to reduce non-relapse mortality.