Myeloid Neoplasms- Secondary

It includes following entities:

• Myeloid neoplasm post cytotoxic therapy
• Myeloid neoplasms associated with germline predisposition
• Myeloid proliferations associated with Down syndrome (Discussed separately)

Disease qualifiers such as “post cytotoxic therapy” or “with ____ germline mutation” must be appended to the names of relevant myeloid disease types whose criteria are fulfilled as defined elsewhere in the classification.

Ex: AML with KMT2A rearrangement, post cytotoxic therapy.

Myeloid neoplasms post cytotoxic therapy (MN-pCT)

AML, MDS, and MDS/MPN that arise in a patient with a history of exposure to DNA-damaging cytotoxic chemotherapy and/or large-field radiation therapy.

3 subtypes

• Alkylating agent / radiation related  (Occur 5-6 years following exposure)
• Topoisomerase II inhibitor related (After 12-130 months)
• Exposure to PARP1 inhibitors

Epidemiology:

• Accounts for 10-20% of all cases of AML, MDS and MDS/MPN

Predisposing factors:

• Pre-existing clonal haematopoiesis in genes such as TP53, PPM1D, DNMT3A, ASXL1, TET2
• Polymorphisms in genes such as NQO1 that affect drug metabolism

Investigations:

• Hemogram: 
  • Pancytopenia
  • RBC: anisopoikilocytosis and macrocytosis, nRBCs seen
  • WBC: Dysplastic changes, monocytosis may be present
• Bone marrow aspiration and biopsy:
  • Multilineage dysplasia is a consistent feature
  • Classification into MDS or AML is based on number of blasts (20%)
• Flow cytometry
• Cytogenetics
  • Complex karyotypes predominate, with loss of 5q, 7q, and 17p
  • MLL gene on 11q23 is often involved
• Molecular
  • Mutations in TP53 are often present

Clinical features:

• Persistent cytopenia

Criteria for diagnosis:

Essential:

• Fulfils criteria for one of the myeloid neoplasms (myelodysplastic neoplasms, myelodysplastic/ myeloproliferative neoplasms/ acute myeloid leukaemia)
• History of Cytotoxic therapy and/or large field radiation
  • Alkylating agents: Melphalan, cyclophosphamide, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, dacarbazine, procarbazine, carmustine, mitomycin C, thiotepa, lomustine
  • Ionizing radiation therapy: Large fields containing active bone marrow
  • Topoisomerase II inhibitors: Etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, actinomycin
  • Others
    • Antimetabolites: thiopurines, mycophenolate mofetil, fludarabine
    • Antitubulin agents (usually in combination with other agents): vincristine, vinblastine, vindesine, paclitaxel, docetaxel
    • PARP1 inhibitors
• Not meeting diagnostic criteria of myeloproliferative neoplasm

Desirable:

• Detection of clonal molecular and/or chromosomal alterations

Pretreatment workup:

• History
• Examination
• WHO P. S.
• BSA
• BMA and Bx (May be avoided in old patients with high counts)
• Flow cytometry
• AML Subtype
• Haemoglobin
• TLC, DLC
• Platelet count
• Coagulation tests: PT:             APPT:         Fibrinogen:
• LFT: Bili- T/D                         SGPT:                                 SGOT:
• Creatinine
• Electrolytes: Na:      K:              Ca:    Mg:              PO4:
• Uric acid
• LDH
• HIV
• HBsAg
• HCV
• UPT
• Cytogenetics
• Multi-target NGS panel including minimum of: IDH1/2, TP53, ASXL1, and RUNX1 (Preferably: NPM1, CEBPA, RUNX1, FLT3, IDH1, IDH2, KIT, WT1, ASXL1, SRSF2, STAG2, RAD21, TP53, KRAS, NRAS, MLL (KMT2A)-PTD, and PPM1D)
• Testing for copy-neutral loss-for-heterozygosity (specifically for determination of TP53 allele state) using SNP arrays or NGS-based analysis
• FLT3ITD analysis
• ECHO/ MUGA Scan: LVEF-               %
• Number of siblings
• HLA typing for HSCT fit patient
• MRI Brain with contrast (in suspected case of leukemic meningitis)
• Day 14 BM study
• Remission BM study
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Prognosis: 

• Very bad, refractory to anti leukemia therapy
• Poor prognostic markers include: 
  • Aberrations of chromosome 5 and/or 7
  • TP53 mutations
  • complex karyotype

Treatment:

• Medically fit: Intensive chemotherapy/ HMA+ Venetoclax followed by allo-HSCT in CR1
• Medically unfit: Palliative therapy with use of hypomethylating agents/ Low dose cytarabine +/- Venetoclax

Myeloid neoplasms associated with germline predisposition

• AML, MDS, MPN, and MDS/MPN that arise in individuals with genetic conditions associated with increased risk of myeloid malignancies.
• Includes myeloid neoplasms arising in individuals with
  • CEBPA-associated familial AML
  • Myeloid leukaemia predisposition associated with thrombocytopenia: Familial mutations of RUNX1, ETV6, and ANKRD26
  • Germline TP53/LP variant (Li- Fraumeni syndrome)
  • Germline predisposition due to DDX41 P/LP variants
  • GATA2-related MDS
  • Germline predisposition due to SAMD9 P/LP variants
  • Germline predisposition due to CHEK2 P/LP variants
  • Germline predisposition due to MPLP/LP variants
  • Germline predisposition due to RECQL4 P/LP variants
  • Fanconi anemia, dyskeratosis congenital, Shwachman Diamond Syndrome
  • Hereditary breast and ovarian cancer- BRCA1 and BRCA2
  • Down syndrome
  • Noonan syndrome, Bloom Syndrome, Lynch Syndrome, Nijmegen breakage syndrome, Wiskott-Aldrich syndrome
  • CBL Syndrome
  • Neurofibromatosis type I
  • RASopathies
• Prognosis: Depends on
  • Specific germline predisposition
  • Characteristics of the myeloid malignancy