Myeloid Neoplasm Classification 

1. Myeloproliferative neoplasms (MPN)
2. Myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRAPDGFRB, or FGFR1
3. Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
4. Myelodysplastic syndrome (MDS)
5. Acute myeloid leukemia and related neoplasms
6. Acute leukemias of ambiguous lineage
7. B lymphoblastic leukemia/lymphoma
8. T lymphoblastic leukemia/lymphoma 

5 AML: Classification
  1. Acute myeloid leukemia with recurrent genetic abnormalities
    • AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
    • AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 APL with t(15;17)(q22;q12); PML-RARA
    • AML with t(9;11)(p22;q23); MLLT3-MLL
    • AML with t(6;9)(p23;q34); DEK-NUP214
    • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
    • AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 
    • Provisional entity: AML with mutated NPM1
    • Provisional entity: AML with mutated CEBPA restricted to balletic mutation
  2. Acute myeloid leukemia with myelodysplasia-related changes 
  3. Therapy-related myeloid neoplasms
    • 2 types 
      • Drugs targeting topoisomerase II like anthracyclines, epipodophylotoxins (within months to 2 years of exposure)
      • Alkylating agent (5-6 years after exposure)
  4. Acute myeloid leukemia, not otherwise specified
    • AML with minimal differentiation
    • AML without maturation
    • AML with maturation
    • Acute myelomonocytic leukemia
    • Acute monoblastic/monocytic leukemia 
    • Acute erythroid leukemia
      • Pure erythroid leukemia
      • Erythroleukemia, erythroid/myeloid 
    • Acute megakaryoblastic leukemia 
    • Acute basophilic leukemia
    • Acute panmyelosis with myelofibrosis
  5. Myeloid sarcoma
  6. Myeloid proliferations related to Down syndrome
    • Transient abnormal myelopoiesis
    • Myeloid leukemia associated with Down syndrome
  7.  Blastic plasmacytoid dendritic cell neoplasm (Separate entity in 2016 classification) 

2016 Classification

AML is clinically and biologically heterogenous disease with different morphological and cytogenetic presentations
A revision of this WHO 2008 classification is currently underway, specifically regarding underlined item below 

Additional References:

Based on this there is a proposed genomic classification of AML NEJM 2016

What are the 8 Functional Categories of genes that are affected in AML 

Clonal evolution and patterns of AML. 

Clinical Relevance of molecular 

Prognostic factors of AML are 
  • patient-associated factors
  • disease-related factors 
    • 3 molecular markers currently most commonly used are 
      • NMP1
      • CEBPA
      • FLT3

AML is now cured in 35 to 40% of adult patients who are 60 years of age or younger and in 5 to 15% of patients who are older than 60 years of age NEJM 2015
  • Induction and Consolidation regimen as below 
  • AIM:
    • Induction Therapy: achieve complete remission (CR)
      • CR: 
        • BM blasts less than 5 %  in a normocelluar BM, absence of extra medullary leukemia, N > 1000 / uL, plt > 100K/uL. 
        • More sensitive ways to define CR using Flowcytometry may be used in future if it correlates with clinical outcome 
      • CR with incomplete hematological recovery
        • CR but Plt or N count do not reach the taget of 100K or 1000 / uL. 
    • Consolidatoin Therapy: eliminate residual leukemia cells that persists after induction therapy

Acute Myeloid Leukemia NEJM 2015

Anthracyclin for AML induction therapy 

BM transplant in AML 

Newer concepts in AML treatment

Epigenetic changes in AML and treatment strategies to target epigenetic changes 

AML Treatment Complications: 

Case Discussion 1 
47 yo F is seen for weakness and gum bleeding of 3 days associated with Fever of 101.3 degree F. CBC shows the following. CMP is essentially normal. 

What is the DDx?
  • AML or CML
  • ALL or CLL less likely as lymphocyte population was rare
Diagnosis of AML was made, and not CML due to the presence of blasts of 52 % in peripheral smear. 

How is AML diagnosed? 
Presence of blasts > 20 % in periphery or in BM 

What is the next best step? Determine if it is APML as it is treated. How to do so? PBS

PBS is above shows all blasts with no visible aur rods. Hence, AML not likely APML was diagnosed. 

What is the next step? 
  • Flow cytometry for lymphoma leukemia immunophenotyping
  • Leukemia cytogenetics
  • Also, BM biopsy should be considered even though diagnosis was made by PBS
  • Emperic abx can be started, but will be discussed later 
  • In the mean time, allopurinol can be started at 300 mg daily
  • Also, hydroxyurea can be started 1500 mg BID PO for initial cytoreduction until we can define definite chemotherapy based on cell typing
Despite using Hydroxyurea, cell count remained high as follow 

On day 4 of admission, Peripheral blood flow cytometry result is as follow 

Diagnostic of acute myelogenous leukemia, with monocytic differentiation. The blast express CD4 subset, subset CD11b, CD11c, CD13, CD33, subset CD34, CD38, CD45, HLA DR, CD 117 and CD 123 

BM Biopsy is also done and sample is sent for path only as flow and cytogenetics were done from peripheral blood 

Now that diagnosis is made, how should this be treated?
  • Induction chemotherapy day 1 with daunorubicin 90 mg/m² per day for 3 days and araC 100 mg/m² IV continuous infusion over 24 hours daily for 7 days. 
  • Also, Rasburicase is started prior to treatment. Allopurinol continued. IV Fluid continued 
  • What other tests should be typically ordered prior to start of chemotherapy?
    • ECHO: EF normal 
    • CMV  ab and PCR: both negative
    • EBV PCR: detected by PCR 
    • Aspergillus galactomannon ab test: negative 
    • Uric Acid
    • Cryptococcal Ag: Negative 

After treatment, on day 3 following is the response. 98 K down from 125 was still an effect of Hydroxyurea, after that is due to Chemo. 

After day 3 of treatment, allopurinol was stopped and IV fluid rate was decreased as patient was out of window for Tumor lysis syndrome

Cytogentics came as follow 

Cytogenetics normal 46 X,Y. NPM-1 mutated (favorable), Flt3-ITD positive (unfavorable), Flt3 D835 mutation positive (unfavorable), CEBPA mutation negative, kit mutation negative 

On day 14 of induction, patient continued to have some fever labs were as follow . Leukine 500 mcg subq daily was started . 
Day 14 marrow  was not done, though had rapid dramatic drop in WBC with treatment initiation 

ON day 19-20 patient started to have BM recovery, 

Patient continued to have fever on day 23 requiring BAL to evaluate for pulmonary infection 

On 11/5, i.e 35 days of induction chemo, BM Bxp was performed, shows CR in BM bxp

Another 30 days later, i.e 2 months after the day 1 of induction chemotherapy, patient was admitted again for Consolidation therapy 

high dose Ara-C 2 g/m2 IVB q12h d 1,3,5 (CALGB style consolidation). Used 2g/m2 rather than 3 g/m2 in light of patient's prior severe mucositis with induction. 

Another two months later patient was admitted for consolidation # 2  with high-dose araC 2 g/m² IVB every 12 hours days 1, 3, and 5

Another 6 weeks later, patient was admitted for consolidation # 3 midostaurin was planned in light of favorable trial data in FLT-3 abnormal patients .  araC 2 g/m² IVB every 12 hours days 1, 3, and 5 was given. 

6 weeks later, # 4 consolidation treatment was given 

After that, patient was given Midostaurin (two 25 mg capsules BID x 14 days

1 year later, patient was readmitted and was found to have relapse; 50% blasts WBC 14.25 

HLA-DNA typing was ordered and patient readmitted for reinduction rx.

Events summarized to date is as follow 

Labs at various stages of treatment and prior to relapse was as follow


After relapse, salvage chemotherapy was started with FLAG-Ida (G-CSF deleted) 
  • Fludrabine 56 mg IV q24 h for 3 days (Also anthracylin like Danarobucin given initially)
  • Cytarabine at 2 gm / m2 

Subsequently, patient had chemo and likely steroids induced pancreatitis 

Subsequently, patient had V tach. Anthracycline-induced cardiomyopathy. EF 30-35% was diagnosed 

Patient is currently working to get a BM transplant 

What is the stage for this patient?

What is the prognosis. 

What is the complication of AML and complications during treatment? How to manage them?
How should this patient be treated?