AUTHORS
Guillermo Montalban-Bravo, MD, Sanam Loghavi, MD2, Wanheng Zhang3, Chong Wu4, Naval Daver, MD5, Nicholas Short, MD6, Kelly Sharon Chien, MD7, Gautam Borthakur, MD8, Ghayas C. Issa, MD9, Elias Jabbour, MD10, Abhishek Maiti, MBBS11, Danielle Hammond, MD12, Alex Bataller, MD, PhD13, Wei Ying Jen, BM BCh, FRCPath14, Alexandre Bazinet, MD15, Pezhman Hosseinpoor16, Rashmi Kanagal-Shamanna, MD17, Sa Wang, MD18, Keyur P. Patel, MD19, Guilin Tang, MD, PhD,FACMG20, L. Jeffrey Medeiros, MD21, Hui Yang, MD, PhD22, Guillermo Garcia-Manero, MD23, Courtney DiNardo, MD, MSCE24, Tapan Kadia I, MD25
AFFILIATIONS
1 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
2 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
3 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
4 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
5 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
6 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
7 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
8 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
9 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
10 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
11 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
12 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
13 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
14 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
15 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
16 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
17 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
18 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
19 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
20 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
21 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
22 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
23 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
24 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
25 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
ABSTRACT
Introduction: Although the BCL2 inhibitor venetoclax (ven) has improved outcomes in acute myeloid leukemia (AML), therapeutic resistance remains a clinical challenge. Ven resistance is driven by: (1) monocytic clones which frequently harbor RAS pathway (RASp) mutations and rely on MCL-1 and purine/pyrimidine metabolism; (2) BCL-XL-dependent TP53 mutant (TP53MT) clones. We have previously reported the efficacy of the purine analog cladribine (CLAD) combined with cytarabine and ven in AML. Here we sought to determine which AML biological subsets preferentially benefit from this combination and whether CLAD improves outcomes in RASp mutant (RASpMT) AML.
Methods: We evaluated 270 patients (pts) with newly diagnosed AML treated on two prospective trials at MD Anderson Cancer Center: CLAD, cytarabine and ven (CLAD-Ven; n=173; NCT03586609) or decitabine and ven (DAC-Ven; n=97; NCT03404193). Next-generation sequencing was performed at diagnosis in all pts and at response assessment in 139 (51%). To dissect genomic architecture and the differential impact of CLAD-based therapy, we performed unsupervised clustering of genomic alterations using partitioning around medoids (PAM). MRD and monocyte and immature monocyte subsets were evaluated with flow cytometry.
Results: Clustering revealed three major genomic clusters defined by enrichment of NPM1/IDH2/SRSF2 (n=113), DNMT3A/ASXL1/RUNX1 (n=88), and TP53 mutations or complex karyotype (TP53-complex, n=69). Survival differed across these clusters but not by treatment regimen in a multivariate survival model using Cox regression with SCT as a time-dependent variable. Subclustering identified 10 genomic clusters with distinct survival: TP53-complex (n=41), TET2/CEBPA (n=32), DNMT3A/TP53 (non-multihit, n=30), ASXL1/TET2/SRSF2 (n=28), NPM1/DNMT3A/FLT3/RASp (n=28), SRSF2/IDH2/RUNX1 (n=27), NPM1/IDH2 (n=24), DDX41 (n=24), DNMT3A/NRAS/trisomy 8 (n=21), and SF3B1/RUNX1 (n=15).
Because RASp mutations (BRAF, CBL, KRAS, NF1, NRAS and PTPN11) spanned multiple clusters rather than forming a single genomic group, we compared outcomes by therapy within RASpMT AML (n=82). Compared with DAC-Ven, CLAD-Ven improved CR/CRi (85% vs 66%, p=0.043) and MRD negativity rates (69% vs 43%, p=0.044), reduced cumulative incidence of relapse (CIR; HR 0.2, 95% CI 0.1-0.5, p=0.0004), and prolonged overall survival (OS; HR 0.4, 95% CI 0.2-0.7, p=0.0007) of RASpMT AML. These differences persisted after censoring at SCT (CIR: HR 0.2, 95% CI 0.1-0.6, p=0.0007; OS: HR 0.5, 95% CI 0.3-0.9, p=0.0334). Responses in RASpMT AML were observed among all 10 genomic clusters with most RASpMT cases not achieving response to therapy belonging to the TP53-complex cluster. CLAD-Ven also produced greater reductions in variant allele frequency (VAF) of clonally dominant (≥20% VAF) RASp mutant clones.
To evaluate the effect of therapy on monocytic populations, we performed longitudinal flow cytometry at diagnosis and response assessment in 40 pts with RASpMT AML with monocytic differentiation predominance (CLAD-Ven n=24; DAC-Ven n=16). CLAD-Ven produced deeper depletion of immature monocytes (ImMono) than DAC-Ven, particularly among RASpMT cases without NPM1 co-mutation, and RASp VAF declined significantly with CLAD-Ven but not DAC-Ven. Relapse occurred in 6/24 (25%) CLAD-Ven and 9/16 (56%) DAC-Ven pts; RASp mutations were stable at relapse in 1/4 (25%) and 9/9 (100%), respectively. Single-cell RNA sequencing and cytometry by Time-of-Flight (CyTOF) of paired baseline and response bone marrow samples to dissect the effects of CLAD-Ven on distinct cell populations are ongoing and will be presented at the meeting.
In contrast to our findings in RASpMT AML, among pts with RASp wildtype AML (n=143), no differences between therapies were observed in CR/CRi (95% vs 91%, p=0.469) or MRD negativity rates (85% vs 80%, p=0.393), CIR (HR 1.0, 95% CI 0.3-2.9, p=0.9979), or OS (HR 0.7, 95% CI 0.7-1.7, p=0.7153). TP53 mutant cases (n=58) were analyzed separately, with no differences in response or in allo-SCT-censored survival between therapies.
Conclusions: Together, these data from two large prospective clinical trials indicate that CLAD-based therapy improves clinical outcomes of RASpMT AML and more effectively depletes RASpMT and monocytic populations. These findings support future studies of CLAD-based approaches as treatment backbones for RASpMT AML.
DISCLOSURES
Guillermo Montalban-Bravo, MD: Solu Therapeutics - Research Funding; Rigel Pharmaceuticals - Research Funding; Takeda Oncology - Research Funding