Impact of High-Risk Cytogenetics (HR-CTG) on the Outcome of Newly Diagnosed Adult Patients with Philadelphia Negative B-Cell Acute Lymphoblastic Leukemia (B-ALL) Treated with Frontline Blinatumomab (Blina) and/or Inotuzumab Ozogamicin (Ino) Containing Hypercvad (HCVAD) Therapy
Authors: Senapati Jayastu , Jabbour Elias , Short Nicholas J. , Tang Guilin , Haddad Fadi G. , Jain Nitin , Issa Ghayas C. , Kadia Tapan M. , Daver Naval , Ferrajoli Alessandra , Kwari Monica , Garcia-Manero Guillermo , Montalban-Bravo Guillermo , Nasnas Patrice Eric , Pemmaraju Naveen , Garris Rebecca , Ravandi Farhad , Kantarjian Hagop M. 
Published: December 2023

Introduction:
HR-CTG in B-ALL is considered an adverse prognostic factor along with age and measurable residual disease (MRD) status. The use of potent B-cell targeted drugs like InO and Blina as part of frontline therapy has improved outcomes in adult pts with B-ALL ( Jabbour et al, Lancet Haematology 2022 and 2023) but the impact of baseline HR-CTG needs to be further elucidated .
Methods:
From Oct 2014-Feb 2023 we identified 71 consecutive patients (pts) with Philadelphia (Ph)-negative B-ALL and adequate CTG data who were treated on frontline therapy that included InO and/or Blina along with HCVAD chemotherapy. The intensive phase of treatment protocol consisted of HCVAD 4 courses followed by 4 courses of blina which could be initiated post HCVAD course 2 for high-risk or MRD positive pts and has been published before (Jabbour et al, Lancet Haematology 2022). The protocol was later amended to include fractionated InO from course 2 of HCVAD at a cumulative dose of 2.4 mg/m 2(Short et al, ASCO 2023).
Pts with confirmed Ph-like ALL were excluded. CTG was evaluated and graded as HR based on a combination of conventional karyotyping and fluorescent in situ hybridization data and included low-hypoploidy or near triploidy (Ho-Tr), complex karyotype (CK; ≥5 abnormalities), 14q32 rearrangement ( IGH) and KMT2A re-arrangement as described before (Issa et al, Cancer 2017).
Results:
31 of 71 pts (44%) with Ph- B-ALL had HR-CTG; 14 pts (45%) with Ho-Tr, 8 (26%) pts with KMT2A rearrangement, 6 pts (19%) with CK and 3 pts (10%) with IGH rearrangement (Table 1). The median age of the whole cohort was 33 years (range, 18-60 years); median age was 29 yrs in HR-CTG group compared to 34 yrs in non-HR-CTG group. 12 pts (39%) in the HR group compared to 5 pts (12%) in the non-HR group had a TP53 mutation ( p=0.01). 5/12 (42%) pts in the HR group with TP53 mutation had low-hypoploidy. 7 pts (23%) and 13 (32%) pts in the HR-CTG and non-HR-CTG group respectively had RAS mutations, with 1 pt in each group having both TP53 and RAS mutation. 17 pts (55%) received Blina and 14 pts (45%) received both InO and Blina in the HR group compared to 20 pts (50%) each who received Blina and Blina+ InO in the non-HR group.
A best response of complete remission (CR)/CR with incomplete count recovery (CRi) was obtained in 100% pts (CR=30, CRi=1) in the HR-CTG group, 17 (55%) of whom had concurrent MRD negativity ; in the non-HR-CTG group 39 pts (98%) attained CR and one pt a partial remission, with concurrent MRD negativity attained in 21/39 (54%) pts with CR. At a median follow-up of 31 months (mos) for the full cohort (43 mos for HR pts and 28 mos for the non-HR group) the median overall survival (OS) was not reached (NR) and 3-yr OS was 85% (95% CI, 78-92%); median OS and 3-yr OS were NR and 89% in the HR-CTG group and 74.7 mos and 82% in the non-HR-CTG group ( p=0.64). The median relapse free survival (RFS) was NR in the HR-CTG group and 74 mos in the non-HR group ( p=0.73) while the 3-yr RFS were 74% and 80% respectively. There was no intergroup difference in RFS and OS based on the MRD status at response assessment. 11 HR-CTG pts (35%) underwent allogeneic stem cell transplantation (SCT) (5 Ho-Tr, 4 KMT2Ar, 1 CK, 1 IGHr) in continued remission at a median of 4.8 mos from therapy initiation (IQR 4.5-8.2 mos), 9 of whom went directly to SCT without introduction of a new therapy between the frontline therapy and SCT. Two pts received additional lines of therapy for MRD relapse/progression without morphological relapse before SCT. The 3-year OS in the HR-CTG pts who underwent SCT was 87% and similar to HR pts who did not undergo SCT (89%, p=0.78). 5 pts (12%) underwent SCT in the non-HR-CTG group, 4 for persistent or recurrent MRD positivity and one with Down's syndrome. No pts in either groups developed hepatic sinusoidal obstruction syndrome or a secondary myeloid neoplasm.
Conclusion:
In our analysis, in a prospectively maintained dataset where &gt;90% pts were treated on clinical trial, HR-CTG did not have any significant impact on B-ALL survival outcomes when treated with frontline therapy containing B-cell targeted agents. Further analysis is underway.