OpenOnco v0.1.2 · 2026-04-30
OpenOnco · DIS-AML · BIO-FLT3-D835 (ESCAT IB)
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Treatment plan — DIS-AML
PLAN-BMA-FLT3_D835_AML-V1 · v1 · 2026-05-04
Patient
BMA-FLT3_D835_AML · Algorithm: ALGO-AML-1L

Clinical significance of mutations (ESCAT)

Tumor-board context — the engine does not use these tiers to rank tracks
BiomarkerVariantESCATEvidenceClinical significanceDrugsSources
BIO-FLT3-D835TKD point mutation (D835Y/V/H/F; ~7% AML, often co-occurs with ITD)IBFLT3-D835 (TKD) in newly-diagnosed AML: midostaurin + 7+3 was studied in FLT3-mutant (ITD or TKD) AML in RATIFY (Stone 2017) — benefit driven primarily by ITD subset, with smaller magnitude in TKD. Quizartinib (type II FLT3i) is INACTIVE against TKD D835 (target alternate conformation). Gilteritinib (type I) and midostaurin retain activity. ELN 2022 prognostic impact of D835 alone is intermediate.midostaurin + 7+3 + HiDAC consolidation + midostaurin maintenance
consider gilteritinib (off-label intensification or post-induction maintenance, trial)
  • SRC-RATIFY-STONE-2017
  • SRC-NCCN-AML-2025
  • SRC-ELN-AML-2022
BIO-FLT3-D835TKD point mutation (D835Y/V; relapsed/refractory)IAFLT3-D835 in R/R AML: gilteritinib superior to salvage chemo (ADMIRAL, Perl 2019 — pre-specified subset analysis showed activity across both ITD and D835/TKD; D835 subset response rates similar to ITD overall). Gilteritinib is preferred type-I FLT3i for D835-mutant R/R disease. Quizartinib remains contraindicated (no D835 activity).gilteritinib monotherapy (2L bridge to allo-SCT)
gilteritinib + venetoclax + azacitidine (off-label, trial)
  • SRC-ADMIRAL-PERL-2019
  • SRC-NCCN-AML-2025
  • SRC-ELN-AML-2022
BIO-FLT3-D835F691L gatekeeper resistance mutation (post-FLT3i)IIAFLT3-F691L is a gatekeeper mutation arising under FLT3-TKI selective pressure (gilteritinib, quizartinib). Confers cross-resistance to most current FLT3i. Crenolanib (investigational type-I) and next-gen FLT3i retain partial activity. No approved targeted option — clinical trial enrollment or salvage chemo + allo-SCT.salvage chemo + allo-SCT (preferred when fit)
clinical trial (next-gen FLT3i, crenolanib, FF-10101)
venetoclax + azacitidine (off-label salvage)
  • SRC-ADMIRAL-PERL-2019
  • SRC-ELN-AML-2022
BIO-FLT3-ITDinternal tandem duplication (juxtamembrane domain — ~25% of AML)IAFLT3-ITD in newly-diagnosed AML: midostaurin + 7+3 induction + high-dose cytarabine consolidation + maintenance improved OS vs chemo alone in fit adults (RATIFY, Stone NEJM 2017 — 4-yr OS HR 0.78). Quizartinib + 7+3 + maintenance also superior in QuANTUM-First (Erba Lancet 2023 — 4-yr OS HR 0.78). FLT3-ITD remains a poor-risk marker (ELN 2022) when allelic ratio high; allo-SCT in CR1 indicated.midostaurin + 7+3 induction + HiDAC consolidation + midostaurin maintenance
quizartinib + 7+3 induction + HiDAC consolidation + quizartinib maintenance (FLT3-ITD specifically)
allo-SCT in CR1 (high-allelic-ratio FLT3-ITD or other adverse-risk features)
  • SRC-RATIFY-STONE-2017
  • SRC-QUANTUM-FIRST-ERBA-2023
  • SRC-NCCN-AML-2025
  • SRC-ELN-AML-2022
  • SRC-ESMO-AML-2020
BIO-FLT3-ITDinternal tandem duplication (relapsed/refractory AML)IAFLT3-ITD in relapsed/refractory AML: gilteritinib monotherapy superior to salvage chemo (ADMIRAL, Perl NEJM 2019 — OS 9.3 vs 5.6 mo, HR 0.64). Gilteritinib is preferred 2L for FLT3-mutant R/R AML and is a bridge to allo-SCT. Quizartinib also active R/R (QuANTUM-R) but FDA label is 1L only (R/R label withdrawn).gilteritinib monotherapy (2L bridge to allo-SCT)
gilteritinib + venetoclax + azacitidine (off-label intensification, trial)
  • SRC-ADMIRAL-PERL-2019
  • SRC-NCCN-AML-2025
  • SRC-ELN-AML-2022

Treatment options (4 tracks)

Aggressive plan
★ DEFAULT
Indication
IND-AML-1L-7-3
Regimen
7+3 Induction (cytarabine + daunorubicin/idarubicin) ± midostaurin
Drugs + NSZU
  • Cytarabine (DRUG-CYTARABINE) 100-200 mg/m²/day · continuous IV infusion days 1-7 · IV ✓ NSZU covered
  • Daunorubicin (DRUG-DAUNORUBICIN) 60-90 mg/m² (or idarubicin 12 mg/m² as alternative) · IV bolus days 1-3 · IV ✓ NSZU covered
  • Midostaurin (DRUG-MIDOSTAURIN) 50 mg PO BID — ONLY if FLT3-ITD/TKD positive · days 8-21 of induction (and continuation through consolidation + maintenance) · PO ⚠ NSZU — not for this indication
Supportive care
SUP-TLS-PROPHYLAXIS, SUP-PJP-PROPHYLAXIS, SUP-HSV-PROPHYLAXIS, SUP-HBV-PROPHYLAXIS
Reason
Engine default per algorithm ALGO-AML-1L: {'step': 7, 'outcome': False, 'branch': {'result': 'IND-AML-1L-7-3'}, 'fired_red_flags': [], 'winner_red_flag': None}
Standard plan
Indication
IND-AML-1L-VEN-AZA
Regimen
Venetoclax + Azacitidine (AML, unfit) — VIALE-A schedule
Drugs + NSZU
  • Venetoclax (DRUG-VENETOCLAX) Cycle 1 ramp: day 1 = 100 mg, day 2 = 200 mg, day 3 = 400 mg → days 4-28 = 400 mg PO daily; subsequent cycles = 400 mg daily continuously · PO daily; reduce to ~70-100 mg if combined with strong CYP3A4 inhibitor (posaconazole) · PO ⚠ NSZU — not for this indication
  • Azacitidine (DRUG-AZACITIDINE) 75 mg/m²/day · SC or IV days 1-7 of each 28-day cycle · SC ⚠ NSZU — not for this indication
Supportive care
SUP-TLS-PROPHYLAXIS, SUP-PJP-PROPHYLAXIS, SUP-HSV-PROPHYLAXIS, SUP-HBV-PROPHYLAXIS
Reason
Alternative track presented for HCP consideration
Aggressive plan
Indication
IND-AML-1L-7-3-GO-CBF
Regimen
7+3 + fractionated gemtuzumab ozogamicin (CD33+ AML, 1L; ALFA-0701)
Drugs + NSZU
  • Cytarabine (DRUG-CYTARABINE) 100-200 mg/m²/day · Continuous IV infusion days 1-7 · IV ✓ NSZU covered
  • Daunorubicin (DRUG-DAUNORUBICIN) 60 mg/m² (per ALFA-0701; 90 mg/m² acceptable when GO not added per ECOG-ACRIN — but 60 mg/m² standard with concurrent GO due to additive cardiotoxicity / mortality concern) · IV bolus days 1-3 · IV ✓ NSZU covered
  • Gemtuzumab ozogamicin (DRUG-GEMTUZUMAB-OZOGAMICIN) 3 mg/m² (max 4.5 mg total per dose) IV — fractionated · Days 1, 4, 7 of induction · IV ✗ Not registered in UA
Supportive care
SUP-TLS-PROPHYLAXIS, SUP-PJP-PROPHYLAXIS, SUP-HSV-PROPHYLAXIS, SUP-HBV-PROPHYLAXIS
Hard contraindications
CI-LVEF-LOW-FOR-ANTHRACYCLINE
Reason
Alternative track presented for HCP consideration
Aggressive plan
Indication
IND-AML-1L-CPX351-SECONDARY
Regimen
CPX-351 (Vyxeos) for tAML / AML-MRC 1L
Drugs + NSZU
  • Liposomal cytarabine-daunorubicin (DRUG-CPX-351) Induction 100 units/m² IV (= cytarabine 100 mg/m² + daunorubicin 44 mg/m²) days 1, 3, 5 · Cycle 1; re-induction days 1, 3 if needed · IV ✗ Not registered in UA
  • Liposomal cytarabine-daunorubicin (DRUG-CPX-351) Consolidation 65 units/m² IV days 1, 3 · Up to 2 consolidation cycles, every 5-8 weeks after count recovery · IV ✗ Not registered in UA
Supportive care
SUP-TLS-PROPHYLAXIS, SUP-PJP-PROPHYLAXIS, SUP-HSV-PROPHYLAXIS, SUP-HBV-PROPHYLAXIS
Hard contraindications
CI-LVEF-LOW-FOR-ANTHRACYCLINE
Reason
Alternative track presented for HCP consideration

Pre-treatment investigations

Investigations before treatment start · critical / standard / desired · merged across tracks
IDNamePriorityCategoryWhere to orderNeeded for
TEST-BM-ASPIRATEBone Marrow AspirateCriticalhistologyall tracks
TEST-BM-TREPHINEBone Marrow TrephineCriticalhistologyall tracks
TEST-CBCComplete Blood Count with DifferentialCriticallaball tracks
TEST-CMPComprehensive Metabolic PanelCriticallaball tracks
TEST-COAG-PANELCoagulation PanelCriticallaball tracks
TEST-FISH-PANELFISH (Fluorescence In Situ Hybridization)CriticalgenomicCSD Lab ✓ (code TBC)all tracks
TEST-FLOW-CYTOMETRYFlow CytometryCriticalhistologyCSD Lab ✓ (code TBC)all tracks
TEST-HBV-SEROLOGYHepatitis B Serology Panel (HBsAg, anti-HBc total, anti-HBs)Criticallaball tracks
TEST-HCV-ANTIBODYHCV AntibodyCriticallaball tracks
TEST-HIV-SEROLOGYHIV Antibody/AntigenCriticallaball tracks
TEST-KARYOTYPEKaryotypeCriticalgenomicCSD Lab ✓ (code TBC)all tracks
TEST-LDHLactate DehydrogenaseCriticallaball tracks
TEST-LFTLiver Function Tests (ALT, AST, bilirubin, ALP, GGT, albumin)Criticallaball tracks
TEST-NGS-MYELOID-PANELMyeloid NGS PanelCriticalgenomicCSD Lab ✓ (code TBC)all tracks
TEST-PERIPHERAL-SMEARPeripheral Blood SmearCriticallabCSD Lab ✓ (code TBC)all tracks
TEST-PREGNANCYBeta-HCGCriticallabaggressive
TEST-CMV-SEROLOGYCMV IgG/IgMStandardlabaggressive
TEST-ECHOEchocardiographyStandardimagingaggressive
TEST-URIC-ACIDSerum Uric AcidStandardlaball tracks
TEST-D-DIMERD-DimerDesiredlabaggressive

Red flags — PRO / CONTRA aggressive

PRO-AGGRESSIVE

Triggers that push toward the aggressive track
  • AML with core-binding-factor (CBF) cytogenetics: t(8;21)(q22;q22.1) with RUNX1::RUNX1T1 fusion OR inv(16)(p13.1q22) / t(16;16)(p13.1;q22) with CBFB::MYH11 fusion. ~10-15% of de novo adult AML, ~25% of pediatric AML. ELN 2022 favorable risk; standard 7+3 induction + 3-4 cycles HiDAC consolidation is curative-intent in CR1 (5-year OS 60-75%); upfront alloHCT is NOT recommended in CR1 default. Adding gemtuzumab ozogamicin to induction (ALFA-0701, AML-19) further improves OS specifically in CBF AML (HR 0.69). c-KIT mutations (D816, exon-8) co-occur in ~25% of CBF AML and may downgrade favorability — warrant MRD-directed approach. RF-AML-CORE-BINDING-FACTOR-FAVORABLE
  • AML emergency triad: hyperleukocytosis (WBC ≥100 K/μL), tumor lysis syndrome (LDH >2× ULN, uric acid >7.5 mg/dL, K+ rising, phosphate rising, Ca2+ falling), or symptomatic leukostasis (dyspnea, altered mental status, retinal hemorrhage)RF-AML-EMERGENCY-TLS-LEUKOSTASIS
  • AML with FLT3-ITD or FLT3-TKD mutation — addition of midostaurin (or gilteritinib in r/r) to induction is required (RATIFY trial)RF-AML-FLT3-ACTIONABLE
  • AML with adverse-risk biology per ELN 2022: TP53 mutation, complex / monosomal karyotype, RUNX1 / ASXL1 mutation, KMT2A rearrangement (other than t(9;11)), inv(3) / t(3;3), -5/del(5q), -7, FLT3-ITD without NPM1, or therapy-relatedRF-AML-HIGH-RISK-BIOLOGY
  • AML patient with positive HBV / HCV / HIV serology, latent TB, or active uncontrolled infection — needs antiviral prophylaxis (HBV-active prophylaxis with entecavir/tenofovir; HCV expert consult; ART optimization for HIV; TB treatment) before inductionRF-AML-INFECTION-SCREENING
  • NPM1 mutation (most commonly type-A: c.860_863dupTCTG / p.W288fs) in AML — ~30% of adult AML; ~50% of cytogenetically normal AML. ELN-2022 favorable risk when NPM1-mutated WITHOUT FLT3-ITD; standard 7+3 induction first-line (no upfront alloHCT in CR1; consolidation HiDAC × 3-4 cycles is curative-intent). MRD qPCR (NPM1-mut transcript) for monitoring. RF-AML-NPM1-MUT-FAVORABLE
  • AML eligible for CPX-351 (Vyxeos) liposomal cytarabine+daunorubicin per the FDA-approved subset: therapy-related AML (t-AML, post-cytotoxic / post-radiation), AML with myelodysplasia-related changes (AML-MRC) per WHO criteria (multilineage dysplasia OR MDS-related cytogenetics OR antecedent MDS/CMML). Phase-3 Lancet 2018 (Lancet 2018;392:2088; Lancet Haematology 2020;7:e552 5-yr follow-up): mOS 9.56 vs 5.95 mo for 7+3, HR 0.69; 5-yr OS 18% vs 8%. Eligibility window age 60-75 + fit-for-intensive-chemo. Routes 1L AML to CPX-351-SECONDARY indication over standard 7+3 when this RF fires. RF-AML-SECONDARY-AML-MRC-CPX351-ELIGIBLE
  • AML refractory or relapsed: <5% blast clearance after induction, or relapse after CR (early relapse <6 mo, late relapse ≥6 mo). Switch to salvage chemotherapy (FLAG-IDA, MEC) ± targeted (FLT3+: gilteritinib; IDH+: ivosidenib/enasidenib) + alloHCT bridgeRF-AML-TRANSFORMATION-PROGRESSION

CONTRA-AGGRESSIVE

Hard contraindications to escalation
  • Pre-treatment LVEF <50% is an absolute contraindication to anthracycline-containing regimens (R-CHOP, Pola-R-CHP, ABVD, BV-AVD, etc.). Cardiotoxicity from doxorubicin is dose-cumulative and often irreversible; starting with already-impaired function risks acute decompensation.CI-LVEF-LOW-FOR-ANTHRACYCLINE
  • Pre-treatment LVEF <50% is an absolute contraindication to anthracycline-containing regimens (R-CHOP, Pola-R-CHP, ABVD, BV-AVD, etc.). Cardiotoxicity from doxorubicin is dose-cumulative and often irreversible; starting with already-impaired function risks acute decompensation.CI-LVEF-LOW-FOR-ANTHRACYCLINE

What NOT to do

Explicit prohibitive rules, each grounded in a regimen / supportive care / contraindication entity
Aggressive plan (IND-AML-1L-7-3)
  • Do not start induction without baseline echo / LVEF if there is any cardiac suspicion — cumulative anthracycline cardiotoxicity can be fatal.
  • Do not wait for FLT3 results to start d1-d7 cytarabine + anthracycline — midostaurin starts on day 8, so induction is not delayed.
  • Do not skip TLS prophylaxis (allopurinol ± rasburicase) in patients with high WBC or high tumor activity.
  • Do not skip HBV/HCV/HIV screening before induction — HBV reactivation on chemotherapy can be fatal.
  • Do not prescribe without discussing fertility in young patients — anabolic-induced gonadotoxicity is often irreversible.
  • Do not start without a validated donor search for ELN-adverse-risk patients — the alloHCT window closes quickly.
Standard plan (IND-AML-1L-VEN-AZA)
  • Do not skip the 3-day venetoclax ramp + TLS prophylaxis — fatal TLS cases described when skipping the ramp.
  • Do not use full-dose venetoclax (400 mg) with a strong CYP3A4 inhibitor (azole) — reduction to ~70-100 mg required.
  • Do not skip HBV screening + prophylaxis — reactivation on HMA + venetoclax described.
  • Do not expect a rapid response — azacitidine requires 4-6 cycles; do not stop earlier without progression.
  • Do not skip G-CSF in febrile neutropenia — cumulative cytopenias expected; antimicrobial prophylaxis is mandatory.
Aggressive plan (IND-AML-1L-7-3-GO-CBF)
  • Do not add GO in adverse-risk AML (TP53-mutant, complex karyotype, monosomy 7) — no benefit + toxicity persists.
  • Do not use daunorubicin 90 mg/m² with GO — cardiotoxicity + early mortality signal in SWOG-S0106 was specifically due to this combination.
  • Do not add GO without CD33 validation — CD33-flow ≥20% blasts required; CD33-low/negative AML — no benefit signal.
  • Do not give GO within 90 days before planned alloHCT — VOD/SOS risk in the post-transplant window is dramatically increased.
  • Do not skip baseline LFT + daily monitoring of bilirubin / weight gain during GO — VOD/SOS is the dominant safety concern.
  • Do not skip ECHO — anthracycline cardiotoxicity + GO-specific cardiac signal require LVEF tracking.
  • Do not skip TLS prophylaxis + HBV/HCV/HIV screening — standard 7+3 vigilance.
Aggressive plan (IND-AML-1L-CPX351-SECONDARY)
  • Do NOT use CPX-351 in patients with de novo AML without MRC-features — FDA approval is narrow: only tAML / AML-MRC / antecedent MDS-CMML.
  • Do NOT mix or substitute with free cytarabine + daunorubicin — fatal dosing errors documented (units/m² vs mg/m²).
  • Do NOT prescribe with LVEF <50% — liposomal anthracycline is still cardiotoxic.
  • Do NOT skip pre-cycle ECHO + cumulative-anthracycline tracking.
  • Do NOT start without alloHCT-pathway planning — survival benefit predominantly via bridge to HCT.
  • Do NOT stop on delayed recovery (>day 35) — this is expected for the liposomal formulation; G-CSF + transfusion support.
  • Do NOT skip TLS prophylaxis in high WBC or high tumor activity.

Timeline

Treatment timeline — derived from regimen + monitoring schedule

Aggressive plan

Induction · 7+3 Induction (cytarabine + da
28-day cycles × 1 induction (re-induction if not in CR after day 14 BM); then 3-4 consolidation HiDAC cycles for younger fit; alloHCT for adverse-risk or post-CR1 in adverse / intermediate

Standard plan

Induction · Venetoclax + Azacitidine (AML,
28-day cycles × Continue until progression / unacceptable toxicity (median ~12 cycles in VIALE-A; ~25-30% achieve durable remission)

Aggressive plan

Induction · 7+3 + fractionated gemtuzumab
28-day cycles × 1 induction; consolidation HiDAC × 3-4 cycles ± additional fractionated GO 3 mg/m² day 1 of consolidation cycles 1-2 (per ALFA-0701 protocol). No upfront alloHCT in CR1 for favorable-risk per ELN 2022.

Aggressive plan

Induction · CPX-351 (Vyxeos) for tAML / AM
35-day cycles × 1-2 induction + up to 2 consolidation; alloHCT in CR1 if eligible

MDT brief

Skills (recommended) — for consideration (1)

  • Clinical pharmacist recommended
    Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication.
    skill: clinical_pharmacistv0.1.0reviewed 2026-04-25STUBsign-offs: 0lead: TBD

Open questions (1, 0 blocking)

  • OQ-LDH-CURRENT
    What is the current LDH? Marker of tumor burden and transformation.
    LDH is part of the prognostic indices of indolent lymphomas.
    → hematologist

Data quality

  • Unevaluated RedFlags: RF-AML-CD33-POS-GO-CANDIDATE, RF-AML-CORE-BINDING-FACTOR-FAVORABLE, RF-AML-EMERGENCY-TLS-LEUKOSTASIS, RF-AML-FLT3-ACTIONABLE, RF-AML-FRAILTY-AGE, RF-AML-HIGH-RISK-BIOLOGY, RF-AML-IDH1-MUT-ACTIONABLE, RF-AML-IDH2-MUT-ACTIONABLE, RF-AML-INFECTION-SCREENING, RF-AML-KMT2A-ACTIONABLE, RF-AML-MEASURABLE-RESIDUAL-DISEASE, RF-AML-NPM1-MUT-FAVORABLE, RF-AML-ORGAN-DYSFUNCTION, RF-AML-SECONDARY-AML-MRC-CPX351-ELIGIBLE, RF-AML-TP53-ADVERSE, RF-AML-TRANSFORMATION-PROGRESSION

Skill catalog (1/16 activated in this plan)

All registered virtual specialists. ✓ — activated for this case; ○ — not activated (available for other clinical scenarios).
Specialistskill_idVersionLast reviewedSign-offsDomain
Cellular therapy specialist (CAR-T)cellular_therapy_specialistv0.1.02026-04-250cellular_therapy
Clinical pharmacistclinical_pharmacistv0.1.02026-04-250clinical_pharmacy
Hematologist / oncohematologisthematologistv0.1.02026-04-250hematology_oncology
Hematopathologist (lymphoma / leukemia / myeloma)hematopathologistv0.1.02026-04-250hematopathology
Infectious disease / hepatologyinfectious_disease_hepatologyv0.1.02026-04-250infectious_diseases
Medical oncologist (solid-tumor chemotherapist)medical_oncologistv0.1.02026-04-250solid_oncology
Molecular geneticist / molecular oncologistmolecular_geneticistv0.1.02026-04-250molecular_oncology
Palliative carepalliative_carev0.1.02026-04-250palliative_care
Pathologist (general)pathologistv0.1.02026-04-250pathology
Primary care / family physicianprimary_carev0.1.02026-04-250primary_care
Psycho-oncologistpsychologistv0.1.02026-04-250psychosocial
Radiation oncologistradiation_oncologistv0.1.02026-04-250radiation_oncology
Radiologistradiologistv0.1.02026-04-250diagnostic_imaging
Social worker / case managersocial_worker_case_managerv0.1.02026-04-250psychosocial
Surgical oncologistsurgical_oncologistv0.1.02026-04-250surgical_oncology
Transplant specialist (BMT)transplant_specialistv0.1.02026-04-250cellular_therapy

Sources cited

Experimental options (clinical trials)

Last synced: 2026-05-04 · ctgov.

No active trials matched this scenario in ctgov.

Option availability in Ukraine

Per-track UA registration · NSZU · cost · access pathway. Render-time metadata; engine selection does not depend on these fields (CHARTER §8.3).
OptionUA registrationNSZUCost orientationAccess pathway
Aggressive plan
7+3 Induction (cytarabine + daunorubicin/idarubicin) ± midostaurin (REG-AML-7-3)
✓ registered✓ covered₴-? — verify pathwayNSZU formulary
Standard plan
Venetoclax + Azacitidine (AML, unfit) — VIALE-A schedule (REG-VEN-AZA-AML)
✓ registered✓ covered₴-? — verify pathwayNSZU formulary
Aggressive plan
7+3 + fractionated gemtuzumab ozogamicin (CD33+ AML, 1L; ALFA-0701) (REG-AML-7-3-GO)
1/3 component drug(s) not registered in Ukraine +1
✗ not registered✗ out-of-pocket₴-? — verify pathwaynot recorded
Aggressive plan
CPX-351 (Vyxeos) for tAML / AML-MRC 1L (REG-CPX351-AML)
2/2 component drug(s) not registered in Ukraine +1
✗ not registered✗ out-of-pocket₴-? — verify pathwaynot recorded

Cost information is orientation. Verify with a specific pharmacy / foundation / trial site. Status updated: 2026-05-04.