Acute Myeloid Leukemia (AML) with Myelodysplasia-Related Gene Mutations
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Acute Myeloid Leukemia (AML) with Myelodysplasia-Related Gene Mutations
Clinical Summary
AML with MDS-related gene mutations was diagnosed in November 2025 in the context of a Pancytopenia workup. Ishamma T M presented with progressive cytopenias (hemoglobin 6.8 g/dL, WBC 2,500, platelets 45K), prompting bone marrow biopsy and molecular testing that confirmed the diagnosis. The disease is classified as adverse-risk by molecular profiling.
WHO/ICC 2022 Classification
AML with myelodysplasia-related gene mutations, adverse-risk molecular category. This classification is based on the presence of multiple MDS-related gene mutations (ASXL1, BCOR, SRSF2, STAG2) identified on next-generation sequencing. The adverse-risk designation reflects the unfavorable molecular profile, particularly the RUNX1, ASXL1, and SRSF2 mutations.
Molecular Profile (NGS — Oncomine Myeloid Assay GX V2)
Sample: Bone marrow, drawn 2025-11-22, reported 2025-11-27
Lab: Agilus Diagnostics Ltd, Reference Lab, Gurugram, Haryana (ULR 666000016219917-0009)
Ordering physician: Ashwin V Nair
Accession: 4182YK008935 | Patient ID: ISHAF2211444182 | Client ID: L085863525
QC: DNA 21.4 ng/µl, RNA 74.0 ng/µl | Coverage 3345x | Uniformity 99.54% | PASSED
Panel: 69 genes (28 hotspot + 17 full-length + 34 fusion drivers + 10 expression/control)
Analytical sensitivity: ≥5% VAF for DNA alterations (at 1000x coverage with min 10ng input)
| Gene | Nucleotide Change | Protein Change | Genomic Locus | VAF | Transcript | AMP/ASCO/CAP Tier |
|---|---|---|---|---|---|---|
| RUNX1 | c.277_278insGAAACGGG (frameshift) | p.(Asp93GlyfsTer32) | chr21:36259213 | 4% | NM_001754.5 | Tier I — Strong |
| ASXL1 | c.4232G>A (nonsense) | p.(Trp1411Ter) | chr20:31024747 | 28% | NM_015338.6 | Tier I — Strong |
| BCOR | c.2428C>T (nonsense) | p.(Arg810Ter) | chrX:39932171 | 17% | NM_001123385.2 | Tier I — Strong |
| SRSF2 | c.284C>A (missense) | p.(Pro95His) | chr17:74732959 | 31% | NM_003016.4 | Tier I — Strong |
| STAG2 | c.3303_3304insT (frameshift) | p.(Met1102TyrfsTer34) | chrX:123224449 | 16% | NM_001042749.2 | Tier I — Strong |
| NRAS | c.35G>A (missense) | p.(Gly12Asp) | chr1:115258747 | 3% | NM_002524.5 | Tier II — Potential |
RNA Fusion Panel: No clinically significant gene rearrangements/fusions detected.
Variant Interpretation Summary
- RUNX1 p.(Asp93GlyfsTer32) — Frameshift truncating (loss-of-function) in N-terminal region. Critical transcription factor for definitive hematopoiesis. Defines adverse-risk AML per WHO/ICC/ELN 2022. Can serve as leukemia-specific MRD marker. No direct targeted drug. Pushes patient into adverse ELN risk and supports early consideration of allogeneic HSCT in CR1 if feasible.
- ASXL1 p.(Trp1411Ter) — Nonsense, premature stop in C-terminal PHD domain. Epigenetic regulator (PRC2/ASXL1–BAP1 axis). Alters histone modification (H3K27me3). Associated with inferior OS, higher relapse, resistance to intensive chemo and HMA-based regimens. Not ideal as sole MRD marker.
- BCOR p.(Arg810Ter) — Nonsense, loss-of-function of BCL6 corepressor. Alters transcriptional repression and epigenetic control. Often founding/co-founding clone. Useful in composite MRD panel but persistence at low VAF may represent residual clonal hematopoiesis.
- SRSF2 p.(Pro95His) — Canonical hotspot missense at Pro95. Alters RNA-binding preference and global splicing. Strong association with adverse prognosis, older age, secondary evolution. No specific SRSF2 inhibitor in routine clinical use.
- STAG2 p.(Met1102TyrfsTer34) — Frameshift truncating loss-of-function of cohesin complex component (X-linked). Involved in chromatid cohesion, DNA repair, 3D genome architecture. Induces genomic instability.
- NRAS p.(Gly12Asp) — Classic RAS hotspot G12D. Constitutive MAPK/ERK and PI3K/AKT pathway activation. Subclonal (3% VAF). Cooperating lesion; unstable — can appear/disappear between diagnosis and relapse. Not reliable sole MRD target. No approved NRAS-specific inhibitor; MEK inhibitors under trial.
Integrated Molecular Summary (from Agilus report)
This constellation of ASXL1, BCOR, RUNX1, SRSF2, STAG2, and NRAS is characteristic of AML with myelodysplasia-related gene mutations / secondary-type AML, corresponding to an adverse-risk molecular category. Truncating ASXL1 and BCOR support antecedent myelodysplastic/secondary myeloid neoplasm with epigenetic deregulation. RUNX1 truncating mutation defines adverse-risk biology with impaired hematopoietic differentiation. SRSF2 and STAG2 further underline a secondary AML pattern through widespread aberrant RNA splicing and cohesin dysfunction. Subclonal NRAS provides additional proliferative drive via constitutive RAS–MAPK pathway activation. The report supports consideration of allogeneic HSCT in first CR where clinically appropriate, with RUNX1 as the preferred leukemia-specific marker for molecular MRD monitoring.
Reviewed by: Haristuti Verma (Sr. Technical Supervisor), Dr. Shrinidhi Nathany (Consultant)
Cytogenetics
Karyotype (2025-11-29, DDRC Agilus): 46,XX[10] — normal female karyotype. Ten metaphases analyzed; no structural or numerical chromosomal abnormalities identified.
Flow Cytometry (2025-11-28)
Approximately 5% blasts identified in the blast window. Sample was dilute. Previous bone marrow flow cytometry report (FC/139/25) was correlated. See Flow Cytometry 2025 11 28 for full details.
Bone Marrow Biopsy #1 (2025-11-20, KIMS)
See Bone Marrow Biopsy 2025 11 20 for full details.
- Cellularity: 60%
- Findings: Atypical mononuclear cell infiltrate admixed with normal hematopoietic precursors
- Reticulin: Grade 1–2
- Interpretation: Suspicious for infiltrative process; flow cytometry recommended
Bone Marrow Biopsy #2 (2025-11-28, Dr. Bijay)
See Bone Marrow Biopsy 2025 11 28 for full details.
- Performed by: Dr. Bijay Prabhakaran Nair
- Cores: 2 good cores obtained
- Aspirate: Hemodilute (again)
- Post-procedure: Tolerated well. Paracetamol advised. Expected more soreness than first biopsy.
- Results discussed: 2025-12-04 (22-min voice call with Sameer). Report: ISHAMMA T M (MR000384802).pdf (7 pages).
- Associated studies: Flow cytometry (Flow Cytometry 2025 11 28) and karyotype (Karyotype 2025 11 29) from this sample.
Bone Marrow Biopsy #3 (2025-12-31, Day 21 Aza-Ven)
See Bone Marrow Biopsy 2025 12 31 for full details.
- Cellularity: 25–30% (decreased from 60%)
- Findings: Erythroid predominance, few plasma cell aggregates, occasional myeloid collection with left shift
- Reticulin: Grade 1 (improved from Grade 1–2)
- Iron stores: Perls Grade 3
- Interpretation: Findings suggest treatment response with reduced cellularity and decreased reticulin fibrosis
Treatment
Regimen: Azacitidine + Venetoclax (Aza-Ven)
Started: 2025-12-09 or 2025-12-10 (port placed Dec 9; treatment discussed for same evening or next morning)
Port Placement (2025-12-09)
See Port Placement 2025 12 09. Port placed at KIMS radiology suite. Delayed due to thrombocytopenia — platelet transfusion given first. Central line was not required for Aza-Ven (Dr. Bijay confirmed), port placed for long-term convenience.
Documented Treatment Cycles
| Cycle | Start Date | End Date | Duration | Notes |
|---|---|---|---|---|
| Cycle 4+ (est.) | 2026-04-06 | 2026-04-13 | 7 days | AZA 5 days + VEN 5 days (both reduced). Azacitidine given IV this cycle. Mar 30 visit: CBC "very good," patient fatigued, given week off, chemo planned for following Monday. |
| Cycle 3 | 2026-03-02 | ~2026-03-08 (est.) | 7 days (est.) | Start date confirmed by patient. Per Dr. Bijay (Feb 25): "Platelets are better. We could proceed with cycle 3 of chemo next week starting Monday and monitor cbc closely. Best not to wait too long." Pegfilgrastim (G-CSF) given this cycle — caused significant bone pain. |
| Cycle 2 | 2026-01-19 | ~2026-01-28 (est.) | ~10 days | AZA 5 days + VEN 10 days. Start date confirmed by patient. |
| Cycle 1 | 2025-12-09 or 12-10 | ~2025-12-16 (est.) | 7 days (est.) | Port placed Dec 9. Treatment could start same evening or next morning per Dr. Bijay. Day 21 BMBx on 2025-12-31 showed response. |
[!note] Cycle numbering established from WhatsApp correspondence with Dr. Bijay (Feb 25, 2026): "proceed with cycle 3 of chemo next week starting Monday." Cycle 2 (Jan 19), Cycle 3 (Mar 2), and Cycle 4+ (Apr 6–13) have confirmed start dates. Only Cycle 1 start date remains approximate.
Schedule evolution: AZA has been 5 days since at least Cycle 2. VEN started at 10 days (Cycle 2) and was reduced to 5 days by Cycle 4+. Cycle 1 and Cycle 3 durations not yet confirmed by patient.
Route of Administration
Dr. Bijay discussed SC vs IV azacitidine with the patient on Mar 30, 2026. IV route was used for the most recent cycle (Cycle 4+, 2026-04-06 to 2026-04-13). Source: patient report, 2026-04-15.
Pegfilgrastim (G-CSF) Use
Pegfilgrastim was administered during Cycle 3 (started 2026-03-02) for neutropenia support. The patient experienced significant bone pain as an adverse reaction. On 2026-03-30, Dr. Bijay decided to avoid pegfilgrastim in subsequent cycles ("will avoid this time"). See Pegfilgrastim.
Transfusion Reaction (2025-12-10)
Patient experienced sudden chills and breathing difficulty during a blood transfusion on 2025-12-10. Reported urgently by family caretaker Nisha (who was at the bedside) to Sameer at 5:22 AM (Sameer's time zone), who immediately relayed to Dr. Bijay via WhatsApp. Dr. Bijay called back within ~37 minutes (2-min voice call at 5:59 AM). Outcome not documented in this conversation but reaction was managed.
Future transfusions should include pre-medication and close monitoring. Allergy/reaction list should be updated — see Allergy List.
Supportive Care Medications
The patient has been on prophylactic medications since AML diagnosis:
- Acyclovir — Antiviral prophylaxis (HSV/VZV) since diagnosis (~Nov 2025). Standard of care during venetoclax-based immunosuppressive therapy.
- Posaconazole — Antifungal prophylaxis. Also a strong CYP3A4 inhibitor, which necessitates and enables venetoclax dose reduction (typically 400 mg → 50–100 mg). The treating team uses this pharmacokinetic interaction intentionally as a cost-reduction strategy in Indian oncology practice. See Posaconazole and Venetoclax.
Antibiotics During Initial Treatment
Meropenem was discussed as an alternative to Zosyn (piperacillin/tazobactam) on 2025-12-10, suggesting the patient was on empiric broad-spectrum antibiotics during Cycle 1 — likely for febrile neutropenia prophylaxis or treatment.
Treatment Response
CBC trends show progressive improvement on Aza-Ven therapy:
| Date | Hemoglobin (g/dL) | WBC (/cumm) | Platelets (/cumm) | Status |
|---|---|---|---|---|
| 2025-11-19 | 8.3 (L) | 2,320 (L) | 70,000 (L) | Pre-treatment |
| 2025-11-28 | 6.8 (L) | 2,500 (L) | 45,000 (L) | Nadir / early treatment |
| 2026-04-06 | 11.6 (L) | 5,400 (N) | 131,000 (L) | Improving |
- Hemoglobin: 6.8 (Nov 2025) to 11.6 (Apr 2026) — significant improvement
- WBC: Normalizing — 5,400 as of April 2026
- Platelets: Recovering but still borderline low at 131,000 (ref 150,000–410,000)
Myeloma Workup (2025-11-19)
- SPEP: Inflammatory pattern, no M-spike. Total protein 7.42 g/dL, A/G ratio 1.20. Alpha-1 (5.4%) and Alpha-2 (11.7%) mildly increased (acute phase reactants). Gamma fraction normal (16.9%).
- Free Light Chains: Kappa 36.81 mg/L (H, ref 3.3–19.4), Lambda 26.73 mg/L (H, ref 5.71–26.3), K/L ratio 1.377 (normal, ref 0.26–1.65). Polyclonal elevation — monoclonal gammopathy ruled out.
- Copper, serum: 124.5 ug/dL (normal). Combined with normal Ceruloplasmin — Wilson's disease ruled out.
Related Conditions
- Pancytopenia — presenting manifestation
- Anemia — component of pancytopenia, improving on treatment
Updated automatically during ingest.