Dr.Venkatesh Kumar, Dr.Rema( Hematology),Dr.C.Jayakumar, Dr.Praveena, Dr.Preethi, AIMS,Kochi.
Five year old male child second child of non-consanguinous marriage presented with high grade intermittent fever ,vomiting , irritability and poor oral intake of 4 days duration after initial treatment from another hospital with parenteral antibiotics ,
As the symptoms were persisting despite treatment and labs done showed high total counts and peripheral smear showed atypical cells he was referred
History of mild speech delay and was on therapy for the same and Immunised upto age .
On examination,Child was febrile, irritable and tired looking with stable vitals..
Auxology revealed weight at 3rd percentile. Systemic examination revealed Hepatomegaly.
Differntial diagnosis considered at this point were:
1Acute bacterial infection
2Infectious mononucleosis.
3Evolving juvenile idiopathic arthritis
4Hematological malignancies- Leukaemia
5Myelodysplastic syndrome.
Investigations:
Hemogram: TC- 53.73 K/uL, N/L: 12/9%, Atypical forms- 71%, Hb – 9.03 gm/dl, Plt- 1.2 lakh
Peripheral smear: Marked leuckocytosis with left shift and monocytosis
Normocytic normochromic anemia and thrombocytopenia
PT-INR: 23.9/1.67
Inflammatory markers are elevated.
CRP: 96.65 mg/L, LDH: 835 U/L, Ferritin: 1961 ng/ml, Uric acid: 2.8 mg/dl , Procal : 7.85 ng/ml.
C3: 180.4 mg/dl, C4: 9.7 mg/dl.
Calcium: 9.34 mg/dl, Phosphorous: 3.3 mg/dl, Magnesium; 1.9 mg/dl.
Urine routine showed 1+ proteins.
Bone marrow aspiration:
Aparticulate hemodilluted marrow aspirate shows markedly left shifted myeloid predominance comprising of promyelocytes and myelocytes.
In view of acute history along with leukocytosis and thrombocytopenia ,possibility of acute promyelocytic leukemia to be considered.
FISH for Promyelocytic Laeukaemia Retinoic acid receptor Alfa gene (PML-RARA):
FISH analysis with the t(15;17) dual color, dual fusion (PML/RARA) probe showed evidence of a PML/RARA gene rearrangement in 134 (67%) of 200 interphase nuclei scored.
Translocation (15;17) resulting in a PML/RARA gene rearrangement is a recurrent, nonrandom finding consistent with a diagnosis of acute promyelocytic leukemia.
Flow cytometry: shows 72% of the gated events with CD45 dim & high SSC, CD117 positive, CD34 negative, HLA-DR negative, MPO positive. Together with clinical details & morphology possibility of Acute Promyelocytic leukemia to be considered.
Bone Marrow Biopsy : Hypercellular bone marrow biopsy suggestive of Acute Leukemia
Karyotyping from bone marrow: 46,XY,del(5q),t(15;17)(q22;q21)[18]/46,XY[2]
Child was then started on Inj.Dexamethasone and given ATRA.
Impression: ACUTE PROMYELOCYTIC LEUKEMIA .
Discussion:
Acute promyelocytic leukemia (APL) is a biologically and clinically distinct category of acute myeloid leukemia (AML) in which abnormal promyelocytes predominate. APL represents a medical emergency with a high rate of early mortality that requires initiation of treatment as soon as the diagnosis is suspected (ie, even before genetic confirmation of the diagnosis). APL accounts for 5 to 20 percent of AML. It is uncommon in the first decade of life, the incidence increases during early adulthood and it remains at a plateau until it decreases after age 60 years.
●Clinical presentation – APL most often presents with weakness/fatigue from anemia, infections due to neutropenia, and/or hemorrhage due to thrombocytopenia or disseminated intravascular coagulation (DIC).
●Pathology – Characteristic malignant promyelocytes are present in blood and marrow.
•Blood – Atypical promyelocytes, which are large myeloid precursors with variable morphology, are seen on blood smear.There are two categories of APL:
-Hypergranular APL – The cardinal feature is numerous violet cytoplasmic granules with a dense or coarse pattern that often obscures the nucleus-Microgranular variant – One-quarter of cases correspond to the microgranular variant of APL, in which malignant promyelocytes have a bilobed nucleus and no apparent granules on light microscopy the promyelocytes may be resemble monocytic cells.Patients with APL, particularly the hypergranular variant, can have a low white cell (WBC) count at diagnosis.
•Bone marrow – Infiltration of marrow malignant promyelocytes.
●Genetics – Most (≥95 percent) cases of APL have the t(15;17)(q24.1;q21.2) chromosomal translocation, which is associated with PML::RARA fusion gene that links retinoic acid receptor alpha (RARA) on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. Rare APL variants include: t(11;17)/ZBTB16::RARA, t(5;17)/NPM1::RARA, t(11;17)/NuMA::RARA, and t(17;17)/STAT5b::RARA.
●Immunophenotype – Malignant cells typically express CD13 and CD33, are usually negative or weakly positive for CD34, and do not express or only dimly express CD15, CD117, HLA-DR, and CD11b.
●Diagnosis – The diagnosis of APL is confirmed detection of PML::RARA reverse transcriptase polymerase chain reaction (RT-PCR) or the associated translocation t(15;17) chromosomal translocation conventional cytogenetics or fluorescence in situ hybridization (FISH). Some cases have cytogenetic or molecular findings associated with a rare variant of APL.
Treatment with all-trans retinoic acid (ATRA) should be initiated when the diagnosis of APL is suspected the clinical presentation, morphology, cytochemistry, and/or flow cytometry, even before genetic confirmation of the disease
*Factors Affecting Prognosis:*
– Low-risk:
WBC <10,000/μL and platelet count >40,000/μL
– Intermediate-risk:
WBC 10,000-50,000/μL or platelet count <40,000/μL
– High-risk: WBC >50,000/μL
2. *Genetic Abnormalities:
PML-RARA fusion gene, influences prognosis.
3.Early and complete response to induction therapy is a positive prognostic factor.
4.Patients who experience relapse have a poorer prognosis.
5. Presence of other health conditions, such as diabetes or cardiovascular disease, can impact prognosis.
Good prognostic factors
1. *All-trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO):* Combination therapy has significantly improved outcomes.
2. *Chemotherapy:* Anthracycline-based regimens are commonly used.
3. *Hematopoietic Stem Cell Transplantation (HSCT):* Considered for high-risk patients or those with relapse.
*Survival Rates:*
– 5-year overall survival rate: approximately 70-80%
– 5-year event-free survival rate: approximately 50-60%
*Complications and Challenges:*
1. *Bleeding and Coagulopathy:* Common complications due to disseminated intravascular coagulation (DIC).
2. *Differentiation Syndrome:* Life-threatening complication associated with ATRA therapy.
3. *Relapse:* Occurs in approximately 10-20% of patients.