Targeting Mutant Calreticulin in Essential Thrombocythemia

INCA033989 · EHA 2026 (PS1983, Mascarenhas et al.)

Ashwin Kishtagari, MBBS, MSCI

Division of Hematology/Oncology, Vanderbilt University Medical Center

2026-08-18

Background

The unmet need in CALR-mutant ET

Essential thrombocythemia (ET) features megakaryocyte hyperplasia and clustering, thrombocytosis, and a raised risk of thrombosis, hemorrhage, and transformation to myelofibrosis (MF).

  • Calreticulin (CALR) exon 9 mutations occur in ~25–30% of ET
  • mutant CALR (mutCALR) ET tends to present younger and carries a higher risk of MF transformation than JAK2 V617F disease
  • Current cytoreductive drugs are broadly myelosuppressive, not mutant-targeted, and do little to lower mutCALR allele burden

INCA033989 — a mutCALR-targeted antibody

A novel, first-in-class, fully human, Fc-silenced IgG1 monoclonal antibody.

  • Selectively binds mutCALR with high affinity when it is in complex with the thrombopoietin receptor (TPO-R / MPL)
  • Blocks mutCALR-driven TPO-R dimerization and the resulting constitutive JAK-STAT signaling
  • Aim: shut down oncogenic signaling and proliferation of the mutant clone

Note

This is an investigational agent — early-phase, not FDA-approved. The data here are from a phase 1, first-in-human program presented at EHA 2026.

Study Design

Phase 1, first-in-human

Two parallel studies: INCA033989-101 (NCT05936359; ex-US) and INCA033989-102 (NCT06034002; US).

  • Multicenter, open-label, in patients with a CALR exon-9 mutation and high-risk ET or MF (monotherapy or combined with ruxolitinib)
  • Administered IV every 2 weeks, dose range 24–2500 mg (alternative schedules also tested)

Key ET eligibility

  • ET by 2022 WHO criteria, with mutCALR exon 9
  • High risk (age ≥60, or prior thrombosis / major bleeding / extreme thrombocytosis)
  • Resistance/intolerance to ≥1 prior cytoreductive therapy; platelets >450 G/L
  • Concurrent hydroxyurea or anagrelide permitted

Endpoints

Primary

  • Dose-limiting toxicities (DLTs)
  • Treatment-emergent adverse events (TEAEs)

Secondary

  • Response by ELN and clinically established criteria
  • Symptom improvement (MPN-SAF TSS)
  • Change in mutCALR allele burden (VAF)
  • Pharmacokinetics

Patients (N = 114)

Characteristic Value
Median age, years (range) 62 (23–89)
Female 60.5%
Median time from diagnosis, years 6.9
CALR Type 1 / non–Type 1 43.9% / 56.1%
Median CALR VAF 34% (10–75)
Median platelets, G/L 913 (444–3152)
Prior hydroxycarbamide 87.7%
Prior anagrelide / interferon 31.6% / 30.7%
On aspirin at baseline 60.5%

Safety

Well tolerated

  • 95% (108/114) remained on treatment; only 5% discontinued
  • Median exposure 8.1 months (up to 27)
  • No dose-limiting toxicities; no fatal TEAEs
  • Grade ≥3 cytopenia TEAEs in 6% (7/114)
  • No grade ≥3 thrombocytopenia — and most cytopenias occurred alongside concurrent hydroxyurea
  • Lipase/amylase elevations were transient with no clinical sequelae

Most common TEAEs (≥10%)

Note

Overall TEAE rate 91%; treatment-related 61%; grade ≥3 19%; serious 4.4%.

Efficacy

Rapid, durable hematologic responses

Across all doses, response rates were high.

Response by mutCALR type and dose

  • Median duration of CHR/PHR: 23 weeks (up to 107)
  • Median time to durable CHR: 2.1 weeks — responses came on fast
  • Type 1 mutCALR at ≥750 mg: durable CHR 81% (21/26)
  • Non–Type 1 at 2500 mg: durable CHR/PHR 50% (3/6)

Dose titration brought patients started at lower doses into response — supporting an escalation strategy.

Molecular responses

The antibody lowered the malignant clone, not just the platelet count.

  • A ≥25% reduction in mutCALR VAF correlated with durable CHR (nominal P < 0.0001, n = 103)
  • Among patients with durable CHR and a post-baseline VAF reading, 73% (33/45) achieved a ≥25% VAF reduction
  • Durable molecular responses occurred in both Type 1 and non–Type 1 disease

Mechanism of clonal response

The molecular response tracked to the mutant clone itself.

  • Driven by loss of mutCALR myeloid cells and a rise in wild-type cells
  • Bone marrow showed reduced total and mutCALR⁺ megakaryocytes from baseline to cycle 7
  • Consistent with a disease-modifying, clone-directed effect rather than generic myelosuppression

Conclusions

Summary

  • INCA033989 is a first-in-class antibody selectively targeting mutCALR in ET
  • In pretreated, high-risk patients it was well tolerated — no DLTs, no grade ≥3 thrombocytopenia, 95% still on treatment
  • Produced rapid, durable hematologic responses (CHR 70%; CHR/PHR 87%)
  • Drove molecular responses that correlated with clinical benefit and reflected reduction of the mutant clone

What’s next

These data support a planned phase 3 program in ET:

EXCALIBUR-ET2 — NCT07623200

Warning

Early-phase, investigational data from a single EHA 2026 poster. Figures and framing are summarized for educational use and should be checked against the primary presentation; this agent is not approved and conclusions are preliminary pending phase 3.