Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies

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The outcomes of patients with acute myeloid leukemia (AML) are steadily improving with better understanding of disease biology (1), the introduction of novel agents (2–4), along with more precise monitoring of measurable residual disease (MRD; refs. 5, 6). However, outcomes of patients with high-risk (HR) and relapsed/refractory (R/R) myelodysplastic syndrome (MDS)/AML, especially in those who progress after exposure to a hypomethylating agent (HMA) or venetoclax, is guarded (7, 8). In addition, patients with certain subtypes of AML, for example, those with MECOM gene rearrangement, have exceedingly poor responses with conventional chemotherapy and venetoclax based regimens alike, and warrant the evaluation of newer agents and treatment combinations (9).

Bromodomain and extra-terminal domain (BET) family proteins (made up of BRD2, BRD3, BRD4, BRDT) represent a novel therapeutic class of agents for patients with myeloid malignancies. These BET proteins function to bind acetylation motifs to promote and enhance genetic transcription (10). Oncogenesis via this pathway is hypothesized to occur from the dysregulated transcription of oncogenes by BET protein action (11). Pharmacologic inhibition of BET proteins transcriptionally downregulates critical prosurvival and antiapoptotic genes (12–14). Furthermore, preclinical and early clinical studies of BET inhibitor (BETi) agents have been successfully used in the treatment of MDS and AML (15–19). HMA, such as decitabine and azacitidine, have also been successfully used as both monotherapy and in combination for treatment of AML and MDS (20–22). In preclinical studies, synergy has been demonstrated between BETi and other apoptosis-promoting agents like BCL2 and MCL1 inhibitors against myeloid blast progenitor cells (16, 23). In the setting of myelofibrosis, a combination of BETi (pelabresib) with ruxolitinib has shown promising results in symptoms and spleen reduction as well as some possible early disease-modifying potential (24). On the basis of our hypothesis that combination of BETi with azacitidine would lead to clinical benefit, we conducted a phase I study of this combination in patients with R/R MDS and AML. The study was enriched with patients having chromosome 3 aberrations (and/or MECOM rearrangements) given the dearth of treatment options in these patients and preclinical data showing evidence of activity of BETi in these patients (25).

We conducted an investigator-initiated, single-center, phase I, 3+3 dose escalation and cohort expansion study of PLX51107 (BETi) + azacitidine in patients with R/R HR MDS (by intermediate-2 score on revised international prognostic scoring for MDS or >10% blasts on bone marrow morphology) or R/R AML, with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, and adequate cardiac, liver, and renal function. Details of patient inclusion and exclusion criteria are mentioned in the supplemental clinical trial protocol. Written informed consent was procured from all patients enrolled on the study, the study was approved by the Institutional Review Board (IRB) of the University of Texas MD Anderson Cancer Center (Houston, TX), and was conducted in accordance with the Declaration of Helsinki. The trial is registered with ClinicalTrials.gov (NCT04022785).

PLX51107 was administered orally on days 1 to 21 along with azacitidine 75 mg/m², i.v., on days 8 to 14 of a 28-day cycle. Azacitidine was started from day 8 to better elucidate any safety signal from the preceding PLX51107 monotherapy phase. Also, preclinical data have shown that pretreatment with BETi can activate the DNA damage response pathways and sensitize leukemic cells to DNA methyltransferase inhibitors (HMA; refs. 26, 27).

Therapy was planned until clinically significant disease progression or any unacceptable toxicity. Dose-escalation phase of PLX51107 included: 40 mg (n = 3), 80 mg (n = 6), and 120 mg (n = 6). A 3+3 Bayesian design was used for studying the incidence of toxicity of PLX51107 at each dose level. Ultimately, no formal maximum tolerated dose (MTD) was reached; therefore, the 120-mg dose was administered to the remaining 22 patients treated on study. Details of the drug dosing, dose escalation, and dose modifications are mentioned in the Supplementary Data.

Dose-limiting toxicity (DLT) was defined as clinically significant nonhematologic adverse event or abnormal laboratory value that is ≥ grade 3 (as per CTCAE version 4) and at least possibly related to the study drugs, with some exceptions (for details, see Supplementary Data). A >30% DLT rate was considered unacceptable. Hematologic DLT was defined as grade ≥ 3 neutropenia and/or thrombocytopenia with a hypocellular bone marrow lasting for 6 weeks or more after the start of a course in the absence of residual leukemia. DLT also included any grade toxicity that required patient to miss 15% or more doses during the DLT period; that is, the inability to tolerate at least 18 of 21 planned doses of PLX51107 per 28-day cycle. Specific guidelines were also set for the diagnosis and management of possible BETi-induced differentiation syndrome.

Response to therapy was as per the International Working Group definition for MDS (28) and as per the European LeukemiaNet 2017 recommendations for AML (29). First response bone marrow (BM) assessment was planned at cycle 1 day 28 (±7 days). Additional baseline evaluation included conventional G-banded karyotyping, myeloid-directed FISH, and an 81-panel myeloid gene next-generation sequencing (NGS) in our in-house Clinical Laboratory Improvement Amendments–certified lab.

The primary objective of the study was to assess the safety profile and determine the minimum safe and biologically effective dose of the combination agents PLX51107 and azacitidine. The total number of patients was determined to be 37 with up to 18 patients in dose escalation part and the remainder patients in the dose expansion cohort including 6 patients in the recommended phase II dose (RP2D) level.

The efficacy endpoint of the expansion cohort was overall response rate (ORR) defined as hematologic improvement (with or without a blast response), morphologic leukemia free state (MLFS), CR (complete remission), CRi (CR with incomplete count recovery), CRp (CR with incomplete platelet recovery) by three cycles of treatment. The response definitions are elaborated in the Supplementary Data.

Survival outcomes were estimated using the method of Kaplan and Meier. Toxicity type and severity were summarized for each patient cohort using frequency tables. All patients who received one or more dose of the study drugs were included in the safety analysis and intention-to-treat analysis for response assessment. The duration of response (DOR) refers to the duration from initial response to the date of first documented disease progression/relapse or death, whichever occurred first; for the patients who did not progress/relapse or die, the DOR was censored at the last follow-up date. Overall survival (OS) was calculated from therapy initiation to death and censored at last follow-up.

Comprehensive correlative analysis through mRNA expression and proteomic assessments from BM or peripheral blood (PB) of patients were done to study biological factors associated with response to the combination regimen.

Data not included in the article and its supplementary files may be made available on an individual basis after discussion with the corresponding author.

A total of 43 patients were screened and 37 patients were eligible, enrolled, and treated with PLX51107 + azacitidine [R/R AML (n = 33); R/R HR MDS (n = 4)]. Baseline characteristics are included in Table 1 and representativeness of study participants are presented in Supplementary Table S1. Median age of the study cohort was 64 years (range, 18–85 years) and 51% of patients were female. The median follow-up of the study patients was 25.2 months (range, 0–25.2 months).

A total of 18 patients (51%) had chromosome 3 abnormalities (either alone or as part of a complex karyotype). Cumulatively, 16 patients (43%) were positive for EVI1/MECOM gene rearrangement by FISH; 15 of these patients had a chromosome 3 abnormality on conventional karyotyping and one patient without a chromosome 3 aberration (Fig. 1). 81-Gene panel sequencing showed relevant mutations as follows: NRAS/KRAS (n = 15); TP53 (n = 9); SF3B1 (n = 7) and ASXL1, PTPN11, RUNX1, and WT1 (n = 6 each). The median variant allele frequency for the TP53 mutation was 64% (range, 22%–95%). Only 2 patients with TP53 mutation had concurrent MECOM rearrangement. Most of the patients were heavily pretreated with the median prior number of therapies being three (range, 1–9); 97% of patients had received prior HMA-based therapy, and 84% had prior venetoclax. Furthermore, 17 (46%) patients had prior stem cell transplant (SCT), seven of whom were on concurrent active immunosuppressive therapy for graft-versus-host disease (GVHD) prophylaxis at the time of enrollment (n = 6 tacrolimus; n = 1 sirolimus), and this also continued while on study. All 4 patients with HR MDS were HMA exposed, and 2 patients had undergone prior SCT. Two of the 4 patients with MDS had ≥10% BM blasts. Nine of 33 (27%) patients with AML had prior diagnosis of an MPN or MDS preceding AML, and overall, 16 of 37 (43%) had a diagnosis of another prior nonmyeloid malignancy. Considering the patients treated on the dose escalation and dose expansion cohort, cumulatively 28 of 37 (76%) patients received the maximum dose (120 mg) of PLX51107 with azacitidine.

Median number of cycles on therapy was two (range: 1–20). Fourteen patients (38%) received ≥ 3 cycles of therapy. No patient had a DLT in the escalation phase and thus the RP2D of PLX51107 was chosen as the 120 mg/day dose. Hematologic toxicities experienced by patients were anemia (n = 7; 4 = grade 3, 3 = grade 4), thrombocytopenia (n = 6; all grade 4), and neutropenia (n = 3; 2 = grade 3, 1 = grade 4) as would be expected in this patient population.

Table 2 shows the nonhematologic therapy–emergent adverse events, irrespective of attribution seen in at least 10% of the patients and all ≥ grade 3 adverse events. The most common nonhematologic adverse events, irrespective of attribution, were febrile neutropenia and lung infection in 11 patients (30%) each, followed by hyperbilirubinemia in 7 patients (19%) and sepsis in 6 patients (16%). Six of the 7 patients with hyperbilirubinemia had grade 3 events and two of these patients were taken off the study for the persisting grade 3 hyperbilirubinemia (Supplementary Table S2). Both these patients were on the 120 mg of PLX51107 and were post SCT; one patient was 4 months after the SCT and had prior history of gastrointestinal GVHD and another patient was 14 months after SCT with no prior GVHD but had gallstone related pancreatitis and need for cholecystostomy due to cholecystitis just prior to the development of the hyperbilirubinemia. At the peak of the hyperbilirubinemia, three patients had pure indirect hyperbilirubinemia, 1 patient had mixed hyperbilirubinemia, and 2 patients had direct predominant hyperbilirubinemia.

None of the grade 5 adverse events were attributable to the study drugs. The most common cause of discontinuing study therapy was an absence of response in 19 patients (51%), followed by disease progression/relapse in 7 patients (19%). At the time of last follow-up of the study, only one patient is alive and on an alternate line of therapy. The median duration of the patients on study was 1.8 months (range, 1.1–21 months).

Eight of 37 (22%) patients had an ORR; CRp (n = 1); MLFS (n = 2; both MLFS responders had chromosome 3 abnormality); hematologic improvement with/without blast improvement (HI; n = 5). Of the 8 responders, 7 had AML and one patient (with HI) had MDS. In addition, 4 other patients had >50% BM blast reduction without hematologic improvement (AML n = 3, MDS n = 1). Thus, overall response was attained in 7 of 33 (21%) patients with AML and in one of 4 (25%) patients with MDS. Among the 8 patients with an ORR, 5 (62%) were on 120 mg of PLX51107. Four patients were able to stay on study ≥6 months, with one patient having received 20 cycles of therapy with hematologic improvement spanning over 14 months. Overall, 7 of 8 patients with an ORR had received prior venetoclax and 3 of the 8 responders had undergone a prior SCT. All 3 patients with a marrow response (CRp and MLFS) had prior HMA and venetoclax exposure; 2 patients had chromosome 3 aberration (one patient had confirmed MECOM rearrangement). The median duration of marrow response was 1.1, 11, and 5 months in these 3 patients. The median duration of hematologic improvement in the 5 patients with a best response of HI (with/without blast response) were 1.5, 2.6, 3.6, 6, and 14 months. The median OS of all the patients on the study was 2.9 months [95% confidence interval (CI), 1.9–4.8 months] and of the 8 patients with an ORR was 5.1 months (95% CI, NE–19 months; Fig. 2A and B). None of the patients could proceed to a subsequent SCT.

The only patient on study who attained a CRp was a 70-year-old woman with R/R AML and extensive leukemia cutis, [refractory AML with prior exposure to azacitidine and fludarabine, idarubicin, cytarabine, and G-CSF (FLAG-IDA) + venetoclax], had almost complete resolution of all skin lesions with no major toxicities after three cycles of therapy, and received a total of six cycles of therapy. The patient had a diploid karyotype with no high-risk myeloid mutations or MECOM rearrangement on FISH. This exceptional patient response was published previously (30).

The patient who had the longest duration of response (HI of 14 months with transfusion independence) had received seven prior lines of therapy including venetoclax and had a MECOM rearrangement along with a PTPN11 mutation. Although the patient did not have a marrow response, her BM blasts remained stable for around 16 months and she received a total of 20 cycles on therapy before disease progression and death.

In parallel correlative studies, we determined mRNA and protein expressions in AML cells harvested pretreatment and on-treatment from the BM aspirates (BMA; pretreatment) or PB (pretreatment and day 3 on-treatment) collected from patients enrolled on the trial. Data generated from one patient each, who responded or was unresponsive to PLX51107 treatment, are presented in Fig. 3. RNA-sequencing (RNA-seq) analysis showed that treatment with PLX51107 caused >1.25-fold depletion or induction of significantly greater number of mRNAs in the sample from the treatment-responsive versus unresponsive patient (Fig. 3A). The heat map of the log₂ fold decline or upregulation of mRNA expressions on day 3, compared with pretreatment (day 1), showed markedly diverse gene expression perturbations between the samples from the responder versus nonresponder (Fig. 3B). Gene-set enrichment analysis (GSEA) of the mRNA perturbations in the sample from the responder demonstrated significant positive enrichment of inflammatory response and TNFα signaling by NF-κB, but negative enrichment of MYC targets, IL7 signaling, ribosomal RNA processing, protein translation initiation and elongation, and of stem-cell mRNA expression (Fig. 3C and D). RNA-seq analysis also highlighted significantly greater log₂ fold decline in BCL2, IL7 receptor, and CDK6, but greater induction of HEXIM1, RAD51, NOXA, SPI1, CDKN1A, and DCXR in the sample from the responder versus nonresponder (Fig. 3E). These mRNAs have been previously reported to be induced by BETi treatment (16, 18, 31, 32). Western blot analysis of cell lysates shown in Fig. 3F demonstrated that in vivo treatment with PLX51107 (day 3 vs. day 1 samples) induced the protein levels of BRD4 and HEXIM1 while reducing c-Myc, CDK6, BcL-xL, and BCL2 levels in the sample from responder compared with nonresponder. Regrettably, lack of adequate numbers of viable AML cell numbers that were harvested from BMA and/or PB samples from the other enrolled patients on the trial, either on day 3 and/or day 1, precluded the conduct of these analyses on their samples.

In this phase I dose escalation and expansion study of a novel BETi in combination with azacitidine, we demonstrate tolerability and safety of the combination therapy, with a modest ORR of 22%, noted to be in a setting with heavily pretreated patients (prior HMA and venetoclax exposure in  ∼90% patients and three median prior lines of therapy), 15 of 37 (40%) study patients had a proven MECOM rearrangement, 9 patients were TP53-mutated (7 of whom did not have the MECOM rearrangement), and 46% had prior SCT. The study was enriched with patients having chromosome 3/MECOM aberrations given preclinical evidence suggesting the potential benefit of BETi in this historically poor prognosis group of patients (16–18). Although most of these responses on our study were not durable, the majority of the patients who had an ORR in our study (7/8 patients) have had prior exposure to venetoclax. Another interesting finding of this study was the remarkable cutaneous response along with CRp in the patient with leukemia cutis, who had refractory AML after two prior lines of therapy, including prior exposure to venetoclax.

Over the last two decades, important efforts have been led by different groups to understand the role of BRD proteins and BET in oncogenesis, and pharmacologic BET inhibition as therapy in myeloid disorders and other malignancies (16, 23, 33–35). Overexpression of BET proteins have been linked to pathogenesis and growth of both hematologic and solid tumor malignancies (14). The novel BETi agent, PLX51107, is an oral agent with moderate selectivity for BD1, the N-terminal of two bromodomains of BET family proteins, with the potential to suppress oncogenesis (13). The BETi class of agents has also been linked to MYC oncogene targeting in the treatment of cancer (14). Furthermore, BET inhibition has been shown to downregulate genes that promote cancer cell-cycle progression and propagation, thereby suppressing the growth of malignant cells (12).

A phase Ib clinical trial with another oral BETi (PLX2853) as monotherapy in myeloid AML and MDS showed an acceptable safety profile but without promising efficacy (19). Preclinical and early clinical studies have shown synergism of BETi with antiapoptotic agents like venetoclax and MCL1 inhibitors in AML (16, 23, 36). In preclinical studies, PLX51107 was shown to have a synergistic effect with BCL2 inhibitors (VEN) leading to BIM dependent apoptosis in MYC-driven lymphomas (37). In a phase I study, mivabresib, a BETi, with or without venetoclax, showed promising clinical responses in patients with R/R AML (18). Notably, even in blastic plasmacytic dendritic cell neoplasm (BPDCN), BETi have demonstrated to induce tumor cell apoptosis through disruption of oncogenic pathways regulated by TCF4 and by reversing corticosteroid resistance in preclinical studies (38, 39). These studies along with the prominent cutaneous response anecdotally seen in one of our study patients warrants further evaluation of BETi-based combinations in patients with myeloid sarcoma/leukemia cutis and BPDCN (40, 41).

The biomarkers associated with a clinical response identified in our study clearly need to be validated in a larger cohort of samples from patients who are prospectively treated with PLX51107. Our findings demonstrated that treatment with PLX51107, in the responding patient [without chromosomal alteration in inv (3)/t(3;3)], exhibited positive enrichment of gene sets of inflammatory response and TNFα signaling by NF-κB. If these findings are confirmed in future clinical trials, the cytokines induced and highlighted in these gene expression perturbations may have relevance for modulating the immune microenvironment in AML (42). As has been previously reported, treatment with PLX51107 also negatively enriched gene sets of MYC targets and IL7 signaling (35, 43).This is consistent with PLX51107-mediated reduction in c-Myc protein levels shown here and of IL7R levels in a previous report (35). Concomitant upregulation of p21 protein levels is also consistent with the previous observation that c-Myc represses p21 (44). Our findings also showed that treatment with PLX51107 negatively enriched gene sets for ribosomal RNA processing, protein translation initiation, and elongation, suggesting a potential for therapeutic benefit from cotreatment with PLX51107 and a protein synthesis inhibitor, for example, omacetaxine (45). PLX51107 mediated log₂ fold induction in the mRNA expressions of HEXIM1, NOXA, SPI1, DCXR, RAD51, and CDKN1A in the responder sample, with concomitant log₂ fold decline in mRNA levels of BCL2, IL7R, and CDK6 are also consistent with the previously reported effects of BETi (31, 35, 43). While PLX51107 treatment reduced MYC mRNA level, the protein levels of c-Myc were unaffected in the nonresponder sample. This discrepancy may be due to increased stability of c-Myc (46). Finally, our findings demonstrating that in the AML cell sample from the PLX51107 responder versus nonresponder, the upregulation of BRD4, HEXIM1, and p21 protein levels, with concomitant downregulation of c-Myc, CDK6, BCL-2, and BcL-xL are also same as those previously reported with respect to the in vitro and in vivo effects of BETi (47, 48). Therefore, collectively, these findings highlight gene expression perturbations that could potentially serve as correlates of PLX51107-induced clinical responses.

Among the pertinent negative prognostic factors in AML, TP53 mutation(s) are very relevant, especially when present at a high variable allele fraction, and portends an extremely guarded outcome with limited median OS usually short of 12 months (49–52). In addition, approximately 10% of patients with AML have dysregulated expression of the nuclear transcription factor ecotropic viral integration site 1 (EVI1), encoded by the MECOM locus on chromosome 3q26, which is also associated with a particularly poor prognosis (53). A common chromosomal alteration t(3:3)(q21:q26)/inv (3)(q21q26) leads to overexpression of this proto-oncogene EVI1 via GATA2 enhancer mediation, and preclinical data has shown that this could be pharmacologically targeted through BET inhibition (25). In a recent report from our institution, the 3-year OS in patients with inv (3)(q21q26.2)/t(3;3)(q21;q26.2) AML was <10% in both first-line and R/R settings (53). Our cohort included 16 patients (43%) with a confirmed MECOM rearrangement. Among these 16 patients, 3 patients had a response and another 3 patients had a >50% blast reduction. Although the response and survival with the azacitidine + PLX51107 combination was not ultimately durable in these patients, it opens avenues for further evaluation of BETi-based combination regimens in earlier lines of therapy for patients with MECOM-rearranged AML who have historical expectations of poor prognosis with conventional intensive chemotherapy as well as venetoclax-based low-intensity regimens (53).

A previous phase Ib/IIa study in patients with R/R solid tumors and advanced hematologic malignancies including AML, demonstrated an acceptable safety profile and preliminary efficacy for use of single-agent PLX51107 (15). Hyperbilirubinemia was a notable adverse event in our study, seen in 7 patients (19%), 6 who were grade 3. In two of these patients, the combination had to be discontinued because of this adverse event and in the remaining patients the hyperbilirubinemia resolved with supportive therapy while continuing therapy or transient withholding the PLX51107. In another phase Ib/II study with PLX51107 monotherapy that included patients with advanced hematologic and solid organ malignancies, hyperbilirubinemia was seen in 17% of the study cohort, with the final results not yet available (15). Notably, one feature of our clinical trial was the inclusion of patients post-SCT and on active GVHD/immunosuppressive therapy [n = 7 (19%)]. Potential toxicities from concurrently administered drugs in these situations could, however, increase the trial reported adverse events in such scenarios.

Despite the progress with BETi therapy in AML, further investigation is needed to better understand the clinical implications of combination therapies including a BETi and define the optimum genomic subset of patients with AML who are poised to benefit the most from these combinations. Given the limited treatment options in patients with MECOM-rearranged AML, BETi combinations should be studied in these patients, possibly as an earlier line of therapy before acquisition of resistance to proapoptotic agents like venetoclax. Our study is limited by a small sample size and being a single institution study but captures important clinical and biological insights about the potential of this combination in a very high risk and R/R population of patients with MDS/AML.

In a heavily pretreated group of patients with R/R HR MDS and AML, with approximately 90% having had prior HMA and venetoclax exposure, 46% post SCT, 43% with MECOM rearrangement, and 24% with TP53 mutation, we demonstrate that the combination of BETi and HMA is reasonably safe, but results in modest overall clinical benefit. A remarkable response in a patient with leukemia cutis and another long-term survivor with hematologic improvement and stable BM disease after seven prior lines of AML therapy were achieved on the study. Future directions should include investigation of novel BETi combinations in earlier lines of therapy, possibly before developing venetoclax and HMA-refractory disease. Further investigation into high-risk subsets of patients with MECOM rearrangements and further clinical/translational investigation of BETi activity in leukemia cutis/skin lesions in myeloid malignancies are warranted.

J. Senapati reports personal fees from Kite Pharma outside the submitted work. N.G. Daver reports grants from Daiichi-Sankyo, Bristol-Meyers Squibb, Pfizer, Gilead, Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, Trillium, Hanmi, Trovagene, FATE Therapeutics, Novimmune, Glycomimetics, and KITE; other support from Daiichi-Sankyo, Bristol-Meyers Squibb, Pfizer, Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, Trillium, Arog, Novartis, Jazz, Celgene, Syndax, Shattuck Labs, Agios, KITE, and Stemline/Menarini outside the submitted work. T.M. Kadia reports grants from Amgen, BMS, Astex, Pfizer, Glycomimetics, Regeneron, and Astellas; grants and personal fees from Genentech, Abbvie, Jazz, AstraZeneca; personal fees from Rigel, Novartis, Servier, and Agios outside the submitted work. C.D. DiNardo reports grants and personal fees from Abbvie, Servier, and Loxo outside the submitted work. J. Burger reports personal fees from Janssen; grants from Pharmacyclics, Abbvie, BeiGene, and AstraZeneca outside the submitted work. N. Jain reports grants, personal fees, and nonfinancial support from Abbvie, Pharmacyclics, Genentech, AstraZeneca, BMS, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Bio, Fate Therapeutics, Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Newave, Novartis, Sana Bio, Carna Bio, and Beigene outside the submitted work. K. Sasaki reports research funding and advisory board membership from Novartis; honoraria from Otsuka; advisory board membership from Daiichi-Sankyo and Pfizer; and research funding from EnLiven. M. Konopleva reports grants, personal fees, and other support from AbbVie, AstraZeneca, Genentech, Gilead, and Stemline-Menarini; grants from Allogene, Daiichi, Forty Seven, Precision BioSciences, Rafael Pharma, Sanofi; grants and other support from Cellectis; personal fees from Janssen and MEI; other support from Arcellx, Astellas, Baxk, Celgene, CRSP Therapeutics, Kite, Marker, Pfizer, Reata Pharma; Syndax Pharma, Syros Pharma, and TCR2 Therapeutics outside the submitted work. N. Pemmaraju reports grants from NIH/NCI and Strategic Alliance Program between MD Anderson Cancer Center and Daiichi-Sankyo during the conduct of the study; other support from Dan's House of Hope; personal fees from AbbVie, Aplastic Anemia & MDS International Foundation, Bristol-Myers Squibb Pharmaceuticals, CancerNet, CareDx, Celgene, Cimeio Therapeutics AG, ClearView Healthcare Partners, CTI BioPharma, Curio Science, Dava Oncology, EUSA Pharma, Harborside Press, Imedex, Immunogen, Intellisphere, Magdalen Medical Publishing, Medscape, Menarini Group, Neopharm, Novartis Pharmaceuticals, OncLive, Pacylex, Patient Power, PeerView Institute for Medical Education, Pharma Essentia, Physician Education Resource (PER), ASH Committee on Communications, ASCO Cancer.Net Editorial Board, Karger Publishers; grants from US Department of Defense (DOD); and other support from HemOnc Times/Oncology Times outside the submitted work. No disclosures were reported by the other authors.

J. Senapati: Data curation, software, formal analysis, investigation, methodology, writing–original draft, writing–review and editing. W.C. Fiskus: Formal analysis, investigation, writing–review and editing. N. Daver: Funding acquisition, validation, investigation, writing–review and editing. N.R. Wilson: Investigation, writing–original draft. F. Ravandi: Investigation, writing–review and editing. G. Garcia-Manero: Investigation, writing–review and editing. T. Kadia: Investigation, writing–review and editing. C.D. DiNardo: Investigation, writing–review and editing. E. Jabbour: Investigation, writing–review and editing. J. Burger: Investigation, writing–review and editing. N.J. Short: Investigation, writing–review and editing. Y. Alvarado: Investigation, writing–review and editing. N. Jain: Investigation, writing–review and editing. L. Masarova: Investigation, writing–review and editing. G.C. Issa: Investigation, writing–review and editing. W. Qiao: Formal analysis, investigation. J.D. Khoury: Investigation, writing–review and editing. S. Pierce: Data curation. D. Miller: Resources, data curation. K. Sasaki: Investigation, writing–review and editing. M. Konopleva: Investigation, writing–review and editing. K.N. Bhalla: Resources, formal analysis, supervision, validation, investigation, methodology, writing–original draft, writing–review and editing. G. Borthakur: Conceptualization, supervision, funding acquisition, validation, investigation, project administration, writing–review and editing. N. Pemmaraju: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration, writing–review and editing.

This study was supported and funded under the Strategic Alliance program between The Department of Leukemia University of Texas MD Anderson Cancer Center, and Daiichi Sankyo. Other funding sources include grants from the University of Texas MD Anderson Cancer Center (CA016672) and University of Texas MD Anderson SPORE (C1100632).

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