Outcomes of Adult Patients with Philadelphia Negative B-Cell Acute Lymphoblastic Leukemia (B-ALL) Having Myeloid Type Mutations Treated with Inotuzumab/Blinatumomab Containing Frontline Regimens
Authors: Senapati Jayastu , Kantarjian Hagop M. , Robinson Clark , Takahashi Koichi , Jain Nitin , Haddad Fadi G. , DiNardo Courtney D. , Loghavi Sanam , Tang Guilin , Montalban-Bravo Guillermo , Kadia Tapan M. , Daver Naval , Sasaki Koji , Komrokji Zena , Garris Rebecca , Garcia-Manero Guillermo , Ravandi Farhad , Short Nicholas J. , Jabbour Elias 
Published: December 2024

Background
Myeloid type mutations (MyM) are occasionally detected in patients (pts) with B-ALL with wider use of next generation sequencing. Recent data have shown that MyM in B-ALL can be associated with inferior outcomes. Targeted therapies like inotuzumab ozogamicin (InO) and blinatumomab (Blina) are often being used in frontline therapy (as consolidation or MRD directed approaches) for B-ALL and prognostic impact of MyM with such agents need further evaluation.
Methods:
We retrospectively analyzed adult pts (≥18 years) with B-ALL who received targeted therapy (InO, Blina or both) as part of frontline therapy at MD Anderson Cancer Center. Chemotherapy backbones included HyperCVAD or MiniHyperCVD. All pts had a baseline gene mutation assessment done from the bone marrow. MyM included somatic mutations in ASXL1, BCOR/BCORL1, DNMT3A, Cohesin complex genes (SMC3, SMC1A, STAG1/2, RAD21), EZH2, FLT3, IDH1/2, splicing factor genes (SRSF2, SF3B1, U2AF1, ZRSR2), RUNX1 and TET2 (Saygin et al, Blood Cancer Discov 2024). Baseline pt, disease and treatment factors were captured. High-risk cytogenetics (HR-CTG) included hypoploidy/near triploidy, tetraploidy, complex karyotype and KMT2A rearrangement. We compared outcomes of pts with and without MyM. Multivariate (MVA) Cox proportional hazard analysis was done to understand the independent prognostic impact of MyM. Progression free survival (PFS) was calculated from therapy initiation to relapse/change in therapy/death.
Results:
From Apr 2017- Apr 2024, 189 adults pts with B-ALL and adequate mutation data were included; 108 (57%) were male. The median (med) age of the pts was 43 years (18-70 years); 56 pts (30%) were ≥60 years of age, all of whom got MiniHyperCVD based regimens and 106/133 pts (80%) pts &lt;60 years of age got HyperCVAD based regimen. 28 pts (15%) had ≥1 MyM (MyM+) and 161 pts (85%) did not (MyM-). 11 pts (6%) had prior therapy for multiple myeloma, all in the ≥60 years age group. 35 pts (18.5%) were CRLF2 positive, and another 11 pts (17%) had fusions in ABL class or non-CRLF2 JAK class. 13 pts (7%) received InO, 44 pts (23%) received Blina, and 132 pts (70%) received both (20/28 [71%] in MyM+ and 112/161 [70%] MyM- received both agents, p= 0.9). InO or Blina was administered as part of MRD eradication/maintenance in 9 pts (5%).
18 (64%) MyM+ pts were ≥60 years of age compared to 38 (24%) MyM- pts (p&lt;0.01). 7 (25%) pts in the MyM+ group had a TP53 mutation versus 38 (24%) pts in the MyM- group (p= 0.8). 3 (11%) MyM+ pts were CRLF2 positive compared to 32 (20%) MyM- pts (p=0.77). Amongst 153 evaluated pts, 42 (27%) had HR-CTG (complex=13, hypoploidy=19, KMT2A rearranged= 10); 5/23 (22%) evaluated in MyM+ group compared to 37/130 (28%) evaluated in MyM- group (p=0.6). A best response of CRc (CR+CRi) was attained in 26 (93%) MyM+ pts and 158 (98%) MyM- pts; 17/26 (65%) and 104/158 (66%) attained MRD-ve as best response. At a med estimated follow up of 33 mos (95% CI 28-37 mos) the med RFS for MyM+ and MyM- pts were 45 mos and NR (3 year: 63% vs. 75%; p=0.03) and med OS 61 mos and NR (3year: 68% vs. 76%; p=0.11) resp. When stratified by age, the med PFS was NR for both groups &lt;60 years (3-year 88% vs. 75%, p=0.54) and 40 mos vs NR for pts ≥60 years (3 year=56% vs. 70%, p=0.20) for MyM+ and MyM- pts resp. 41 pts (22%) underwent allogeneic SCT in first remission (3 [11%] in MyM+ and 38 [24%] pts in the MyM- group); med time to SCT was 6.7 mos (2.6-30.1) mos from ALL therapy initiation.
On MVA Cox analysis adjusting for age (&lt;60/≥60 years), CRLF2 status, CTG (HR or not), use of both or single targeted therapy and SCT, presence of MyM did not have an independent impact on hazards of progression (Hazard ratio=1.2, 95%CI 0.5-2.6) or death (Hazard ratio=0.84, 95%CI 0.34-1.92). For both PFS and OS, lower age, use of both targeted agents versus any one agent was independently favorable while CRLF2 positivity and TP53 mutation were adverse. 4 pts developed a secondary myeloid neoplasm, 2 in each cohort and all ≥60 years; one pt had a baseline TP53 mutation. 19 pts (11 pts ≥60 years) died in remission at a med of 6 mos (1.0-78 mos), from therapy initiation without intervening SCT or a myeloid neoplasm, 6 (21%) MyM+ and 13 (8%) MyM-.
Conclusion:
Baseline MyM in pts with B-cell ALL are rare and more common in older pts. Though PFS and OS were inferior in MyM+ pts in the whole cohort, age stratified analysis and MVA diminished their independent impact on survival in pts treated with InO/Blina based frontline therapy. Further analysis is underway.