Rapid clonal selection within early hematopoietic cell compartments presages the outcome of ivosidenib combination therapy
Abstract
Abstract Acquired resistance to targeted, nonintensive therapies is common in myeloid malignancies. However, the kinetics of selection, the hematopoietic cell compartments in which selection occurs, and the molecular mechanisms underlying selection remain open questions. To address this, we studied the kinetics of clonal and transcriptional responses to combinational therapy with ivosidenib plus venetoclax, with or without azacitidine, across hematopoiesis in 8 patients with IDH1-mutant myeloid malignancy. All 8 patients initially responded to treatment, but 6 relapsed, whereas 2 remained in sustained remission for >4 years. We performed combined high-sensitivity single-cell genotyping and scRNA sequencing in index-sorted sequential patient samples. In all patients, clonal selection occurred rapidly, within 1 to 3 treatment cycles. Clonal selection preceded treatment failure by months to years. Relapse was associated with expansion of either clones harboring newly detected myeloid driver mutations or preexisting minor clones that underwent differentiation delay upon treatment exposure. In both cases, clonal selection occurred within immature cell populations previously shown to contain leukemic stem cell potential. Different genetic alterations within relapse-associated clones converged onto common upregulated transcriptional programs of stemness, branched-chain amino acid catabolism, and genes sensitive to menin inhibition. Importantly, this relapse-associated transcriptional signature was selected within 3 cycles of therapy. In contrast, in both patients remaining in remission, leukemic clones were rapidly eradicated, and replaced by clonal and wild-type hematopoiesis. Overall, in patients treated with ivosidenib combination therapy, rapid clonal selection occurs within the first treatment cycles. In those patients destined to relapse, genetically heterogeneous resistant clones are characterized by common transcriptional programs.
Article Details
Authors (24)
Sven Turkalj
Felix A. Radtke
Bilyana Stoilova
1Medical Research Council Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Rabea Mecklenbrauck
Angus J. Groom
1Medical Research Council Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Niels Asger Jakobsen
Curtis A. Lachowiez
Oregon Health & Science University, Portland, Oregon, United States
Marlen Metzner
1Medical Research Council Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Batchimeg Usukhbayar
1Medical Research Council Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Mirian Angulo Salazar
1Medical Research Council Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Zhihong Zeng
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Sanam Loghavi
Jennifer Marvin-Peek
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Verena Körber
Farhad Ravandi
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Ghayas Issa
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Tapan Kadia
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Vasiliki Symeonidou
1Medical Research Council Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Anne P. de Groot
1Medical Research Council Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Hagop Kantarjian
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Koichi Takahashi
Marina Konopleva
Courtney D. DiNardo
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Paresh Vyas