Tuspetinib Plus Venetoclax and Azacitidine Is Safe and Effective Across Molecular Subgroups in Newly Diagnosed AML

Tuspetinib (formerly HM43239) added to standard-of-care (SOC) venetoclax (Venclexta) and azacitidine produced high rates of complete remission (CR) and minimal residual disease (MRD) negativity with a manageable safety profile in older or unfit patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy, according to updated data from the triplet arm of the phase 1/2 TUSCANY trial (NCT03850574) presented at the 2026 EHA Congress.¹

Among 32 patients treated with tuspetinib plus venetoclax and azacitidine across 4 dose levels, as of a data cutoff of May 28, 2026, the overall response rate was 81.3%, and the composite CR (cCR) rate was 78.1%. CR was achieved in 50.0% of patients, and CR/CR with partial hematologic recovery (CRh) was achieved in 68.8% of patients. Among the 29 response-evaluable patients, CRc was achieved in 86.2%. MRD negativity was achieved in 62.5% of all patients, and in 86.4% of the patients who achieved CR/CRh. The median treatment duration was 5.2 months.

High response rates were observed across diverse AML molecular subgroups. CRc was achieved in 100% of patients with FLT3-mutated disease (n = 7/7), 70.0% of those with TP53-mutated/complex karyotype (n = 7/10), and 80.0% of those with NPM1-mutated disease (n = 4/5).

Safety data were filtered through April 26, 2026 (n = 32). Any treatment-emergent adverse effects (TEAEs) were reported in 93.8% of patients, grade 3 or higher TEAEs were seen in in 90.6% of patients, and serious AEs were observed in 59.4% of patients. One patient discontinued treatment due to a TEAE, and no treatment-related deaths occurred.

Two dose-limiting toxicities occurred at the 160-mg dose level: 1 case of reversible grade 3 myositis and weakness with normal creatine phosphokinase (CPK) and aldolase levels in the setting of sepsis and hyponatremia, and 1 case of persistent grade 4 neutropenia at cycle 1 day 42. Notably, no related QTc prolongation, differentiation syndrome, or CPK elevations were observed across any dose level.

“Safe and effective inhibitors targeting multiple growth factor signaling pathways that can be combined with the current SOC regimen of azacitidine plus venetoclax have the potential to improve outcomes in [patients with] newly diagnosed AML in a mutation-agnostic manner,” Nikolai Podoltsev, MD, PhD, said to OncLive^®. “Based on its mechanism of action, the safety profile and clinical activity observed in early-phase studies in relapsed/refractory AML, and the TUSCANY trial data presented at EHA 2026, I consider tuspetinib to be a strong candidate for frontline combination therapy in AML.”

Podoltsev is an associate professor of medical oncology & hematology in the Department of Internal Medicine, clinical director of Malignant Hematology, and associate program director of the Hematology/Medical Oncology Fellowship Program at the Yale School of Medicine in New Haven, Connecticut.

What was the rationale for adding tuspetinib to venetoclax and azacitidine in newly diagnosed AML?

Tuspetinib is an oral multi-kinase inhibitor that targets multiple oncogenic signaling pathways involved in AML, including FLT3, SYK, JAK, c-KIT, RSK, and TAK1-TAB1. Because acute leukemias upregulate multiple growth factor signaling pathways even in the absence of targetable driver mutations, a safe inhibitor of these pathways could improve AML management outcomes in a mutation-agnostic manner.

In prior completed arms of the TUSCANY study, tuspetinib monotherapy generated a CRc rate of 28.0% (n = 7/25) at target dose levels of 80 mg to 160 mg in venetoclax-naive patients with relapsed/refractory AML. Additionally, the tuspetinib-plus-venetoclax doublet yielded a CRc rate of 25.0% (n = 9/36) at a tuspetinib dose of 80 mg in evaluable patients with relapsed/refractory AML.

What patients were enrolled in the triplet arm of the TUSCANY trial?

TUSCANY enrolled patients with newly diagnosed primary or secondary AML who were 75 years of age or older, or under 75 years of age with 1 or more comorbidities precluding intensive chemotherapy. Patients could not have received prior hypomethylating agent or venetoclax treatment, could not have acute promyelocytic leukemia, and could not have BCR::ABL1 rearrangements. The eligibility criteria were designed to be similar to those of the pivotal phase 3 VIALE-A trial (NCT02993523), findings from which supported the 2020 regular FDA approval of venetoclax plus azacitidine, decitabine (Dacogen), or low-dose cytarabine for the treatment of patients with newly diagnosed AML who are at least 75 years of age or who have comorbidities precluding intensive induction chemotherapy.²

Among the 32 patients enrolled in the TUSCANY triplet arm, the mean age was 75.7 years (range, 63-82).¹ In total, 25.0% of patients had an ECOG performance status of 2 or higher, and the mean baseline bone marrow blast percentage was 50.2%. Key molecular features included FLT3-ITD, FLT3-TKD, or other mutations in 28.1% of patients; TP53 mutations and/or complex karyotype in 31.3% of patients; and NPM1 mutations in 15.6% of patients.

The trial tested tuspetinib at 40 mg, 80 mg, 120 mg, and 160 mg once daily in 28-day cycles in combination with venetoclax at 400 mg once daily on days 21 through 28 and azacitidine at 75 mg/m² once daily for 7 days per 28-day cycle. A day-18 bone marrow assessment guided cycle 1 venetoclax interruption. In cycle 1, venetoclax was held from day 18 onward if bone marrow blasts were less than 5% or aplastic with cytopenias, pending a day-22 response decision. Pharmacokinetic data confirmed dose-proportional tuspetinib exposure from 40 mg to 160 mg in the triplet setting. Patients achieving remission could resume tuspetinib as monotherapy 30 to 90 days after hematopoietic stem cell transplantation.

What were the full TUSCANY trial efficacy results by dose level and mutation group?

Across the tuspetinib dose levels, the CRc rates were 75.0% at 40 mg (n = 3/4), 75.0% at 80 mg (n = 9/12), 100% at 120 mg (n = 3/3), and 76.9% at 160 mg (n = 10/13). CR was achieved in 75.0%, 33.3%, 100%, and 46.2% of patients at these respective dose levels. The MRD-negativity rates at these respective dose levels in patients with CRc were 100% (n = 3/3), 77.8% (n = 7/9), 66.7% (n = 2/3), and 70% (n = 7/10), translating to an overall MRD-negativity rate of 76.0% (n = 19/25) in this population.

Across mutation subgroups, CRc was achieved in 72.0% of patients with FLT3-unmutated disease (n = 18/25), 100% of those with FLT3-mutated disease (n = 7/7), 80.0% of those with NPM1-mutated disease (n = 4/5), and 70.0% of those with TP53-mutated/complex karyotype disease (n = 7/10). The swimmer plot demonstrated durable, ongoing responses across all dose levels, with multiple patients remaining on study for more than 48 weeks.

What were the additional safety data with tuspetinib plus venetoclax and azacitidine in TUSCANY?

Some of the most frequent TEAEs (reported in > 15% of patients) included decreased platelet counts (65.6%), decreased white blood cell (WBC) counts (59.4%), anemia (56.3%), decreased neutrophil counts (53.1%), diarrhea (43.8%), nausea (37.5%), constipation (37.5%), vomiting (28.1%), hypophosphatemia (28.1%), and febrile neutropenia (21.9%). Of the tuspetinib-related grade 3 or higher TEAEs, decreased platelet counts occurred in 40.6% of patients, decreased WBC counts were seen in 34.4% of patients, decreased neutrophil counts were observed in 34.4% of patients, and anemia was reported in 25.0% of patients.

Among patients who achieved remission during cycle 1, the median time to absolute neutrophil count (ANC) recovery to at least 0.5 K/µL was 35 days, and the median time to ANC recovery to at least 1.0 K/µL was 36 days. The median time to platelet count recovery to at least 50 K/µL was 27 days, and the median time to platelet count recovery to at least 100 K/µL was 39 days.

“We’re looking forward to the randomized phase 2 part of this trial,” Podoltsev concluded in the presentation. “A couple tuspetinib dose levels will be carried in a controlled fashion to be randomized against the SOC venetoclax/azacitidine.”

The TUSCANY findings add to a rapidly evolving paradigm of frontline combination regimens in newly diagnosed AML; separately at EHA 2026, azacitidine plus venetoclax and ivosidenib (Tibsovo) produced robust MRD-negative responses in patients with IDH1-mutated newly diagnosed AML in a phase 1b/2 trial (NCT03471260).³ Additionally, ziftomenib (Komzifti) plus 7+3 induction yielded high CR and MRD-negativity rates in patients with newly diagnosed NPM1-mutant and KMT2A-rearranged AML in long-term data from the phase 1a/b KOMET-007 trial (NCT05735184).⁴

References

1. Podoltsev NA, Mannis G, Watts JM, et al. TUSCANY study of safety and efficacy of tuspetinib plus standard of care venetoclax and azacitidine in study participants with newly diagnosed AML ineligible for induction chemotherapy. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S134.
2. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia in adults unable to receive intensive chemotherapy. News release. ASCO. November 3, 2020. Accessed June 14, 2026. https://www.asco.org/practice-policy/policy-issues-statements/asco-in-action/fda-grants-regular-approval-venetoclax
3. Wahner A. Azacitidine/ivosidenib/venetoclax generates high ORRs in IDH1-mutant newly diagnosed AML. OncLive.com. June 11, 2026. Accessed June 14, 2026. https://www.onclive.com/view/azacitidine-ivosidenib-venetoclax-generates-high-orrs-in-idh1-mutant-newly-diagnosed-aml
4. Rosa K. Ziftomenib plus 7+3 elicits durable responses in newly diagnosed NPM1-mutant and KMT2A-rearranged AML. OncLive.com. June 14, 2026. Accessed June 14, 2026. https://www.onclive.com/view/ziftomenib-plus-7-3-elicits-durable-responses-in-newly-diagnosed-npm1-mutant-and-kmt2a-rearranged-aml