Updated on: 28.08.25

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. Click here)

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

Subtypes

• Alkylating agent / radiation related: Occur 5-6 years following exposure to Cyclophosphamide, Melphalan, Chlorambucil, Ifosfamide, Bendamustine, Carmustine, Lomustine, or Busulfan.
• Topoisomerase II inhibitor related: Occur 12-130 months following exposure to etoposide, teniposide, doxorubicin, idarubicin, epirubicin, and mitoxantrone
• Exposure to PARP1 inhibitors which are mostly used in ovarian cancers (Olaparib, Rucaparib, Niraparib)

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

Clinical features:

• Persistent cytopenia

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

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

Prognosis: 

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

Pretreatment workup:

• History
• Examination
• WHO P. S.
• BSA
• BMA and Bx (May be avoided in old patients with high counts)
• Flow cytometry
• AML/ MDS 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

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

Introduction:

• AML, MDS, MPN, and MDS/MPN that arise in individuals with genetic conditions associated with increased risk of myeloid malignancies.
• In contrast to sporadic leukemia, where only the leukemic cells carry genetic variants, in familial leukemia all cells of the body carry a germline variant.
• Most are inherited in an autosomal dominant pattern
• Not every individual carrying the germline variant will develop disease, some might have no symptoms or only show mild cytopenia (this is called reduced penetrance)

Epidemiology:

• Although 10% of patients with MDS/AML have genetic predisposition, it is not recognized in many patients due to lack of awareness and testing facilities.
• They must be considered in all patients regardless of age at diagnosis. However, better to do in all patients of MDS/AML below age of 40 years.

Diseases included in this category:

• 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

History suggesting germline predisposition:

• Long-standing cytopenias or previous history of transfusions (eg, RUNX1, Diamond-Blackfan anemia, Shwachman Diamond syndrome)
• History of previous malignancy (eg, Li-Fraumeni syndrome)
• Frequent or atypical infections suggestive of an underlying immunodeficiency  (eg, GATA2, SAMD9/9L, and short telomere disorders)
• Brittle/abnormal hair or nails or premature gray hair or pulmonary/ hepatic fibrosis (eg, short telomere disorders)
• Long history of mild/moderate thrombocytopenia and aspirin-like platelet dysfunction/easy bleeding (Suggests germline RUNX1 familial platelet disorder)
• Family history of hematological or solid malignancy
• AML or MDS with monosomy 7, del(7q) or der(1;7)

Indications for germline predisposition testing

• Personal history of ≥2 cancers, 1 of which is a hematopoietic malignancy (order does not matter)
• Personal history of a hematopoietic malignancy plus:
  • Another relative within two generations with another hematopoietic malignancy, or
  • Another relative within two generations with a solid tumor diagnosed at age 50 or younger, or
  • Another relative within two generations with other hematopoietic abnormalities
• Presence of a deleterious gene variant in tumor profiling that could be a germline allele, especially if that variant is present during remission: Certain gene alleles (eg, CHEK2 I200T and truncating DDX41 variants) are overwhelmingly likely to be germline and should prompt consideration of germline testing when identified even once
• Age of diagnosis of hematopoietic malignancy at an earlier age than average (eg, MDS diagnosed < 40 y)

Key points to note before ordering germline predisposition testing:

• Somatic tumor testing via NGS panels is not a replacement for comprehensive germline genetic testing. Although it is true that the identification of a pathogenic DNA variant at near-heterozygous frequency in a gene that can be inherited should alert the provider to consider a germline etiology, the lack of any such alleles does not rule out an inherited cancer syndrome because
• Not all genes that can be inherited are included in NGS panels
• NGS often fails to detect small deletions that are frequent in certain genes (eg, RUNX1, GATA2, and TP53)
• NGS often do not sequence promoter or intronic regions, which are also frequent in certain genes(eg, promoter variants in ANKRD26, intronic GATA2 alleles)
• Genetic counseling and consent are must prior to genetic testing of patient and healthy relatives.
• Sample from healthy tissue should be tested to enable delineation of germline from somatic mutations. Buccal swab is heavily contaminated with hematopoietic cells, hence should never be used. Small cresent skin punch biopsy can be done at bone marrow biopsy incision site.
• Testing of any potential family member donors is strongly recommended, as related donors may be affected with the same inherited cancer syndrome, and such transplants have been associated with higher risks of graft failure and donor-derived leukemias.
• Family members who are tested positive must undergo regular surveillance for early detection of hematological malignancy.

Germline status of a variant is confirmed by:

• Its presence in DNA derived from a tissue source not likely to undergo somatic mutation frequently (eg, cultured skin fibroblasts obtained by skin punch biopsy or hair follicles) AND at a variant allele frequency consistent with the germline (generally considered between 30-60%), or
• Its presence in at least two relatives at a variant allele frequency consistent with the germline

Reasons to identify these predispositions:

• Patients with germline DDX41 mutations are highly sensitive to venetoclax-based therapies and they experience severe GVHD in the absence of post-transplant cyclophosphamide.
• Some of them have excessive treatment toxicities, delay count recovery after chemotherapy or poor stem cell mobilization
• Prognosis and treatment outcomes can be predicted in some cases

Prognosis: Depends on

• Specific germline predisposition
• Characteristics of the myeloid malignancy

Treatment: Allogeneic HSCT

• It is difficult to decide about timing of transplant. Too early may lead to unnecessary morbidity or mortality. Too late may lead to a completely evolved disease which is resistant to chemotherapy and has high risk of relapse.
• Early referral to transplant center is must, to identify potential related donor.