Dr.Venkatesh Kumar, Dr.Praveena Bhaskar Dr.C.Jayakumar, AIMS,Kochi.
Eight month old male child- presented with complaints of erythematous rashes which were initially noticed mother on face,hands and over the trunk of days duration associated with high grade intermittent fever and rhinitis of 3 days duration.As the symptoms persisted and labs done outside showed leucopenia with thrombocytopenia,he was referred here for further management
History of getting phototherapy for Neonatal hyperbilirubinemia in the neonatal period.
Auxology revealed normal growth parameters.
General examination revealed pallor, erythematous rashes over the face. And brown to black macule on left side of abdomen. Abdominal examination revealed tenderness in the right lumbar region and hepatosplenomegaly( Liver –palpable 2 cm below right subcostal margin, spleen palpable 2 cm below left subcostal margin).
Differential diagnoses considered at this point:
•Viral exanthems- dengue, parvo virus, rubella, exanthem subitum, Adenovirus
•Infectious mononucleosis
•Drug rashes
•Kawasaki disease
•Hematological malignancies
Investigations:
Hemogram- Pancytopenia: Anemia (Hb-9.8), TC: 5800, Neutropenia(Neutrophils of 6%, ANC-348) and severe thrombocytopenia(Plt: 28000).
Peripheral smear: Normocytic normochromic anemia anemia , leucopenia, thrombocytopenia with suspicious 2% blasts.
•LFT, RFT : Normal
LDH: 375 U/L (elevated)
•Iron studies: Normal
•Dengue panel(NS1Ag,IgM,IgG)- Negative
• Parvo virus IgM: Negative
•Respiratory Viral Panel – Rhinovirus detected.
Clinical hematology consultation availed in view of decreasing trend in total counts and platelets and advised Bone marrow study.
Bone Marrow Aspiration showed Pauci particulate fairly cellular marrow shows erythroid preponderance, markedly reduced myeloid maturation,few megakaryocytes and approximately 24 % blasts/ Hematogones
Bone marrow flowcytometry: Acute Myeloid Leukemia with monocytoid differentiation ( CD38 +, CD58+ ).
Parents were counselled regarding the diagnosis and explained high risk nature of disease,with need for chemotherapy followed possibly Bone marrow transplantation, chances of about 30% response explained.
Impression: Acute Myeloid Leukemia with monocytoid differentiation.
Discussion:
Heterogeneous disease – accounts for 15-20% of all acute leukemias in children.
Inherited and acquired diseased have been associated with development of AML.
Inherited conditions- Downs syndrome, Fanconi anemia, Congenital neutropenia, inherited bone marrow failure syndromes. Acquired causes – Myelodysplastic conditions, environmental factors, drugs and ionizing radiations.AML is characterized >20% blast cells in bone marrow.
PATHOGENESIS: Multiple genetic mutations have been associated with the pathogenesis of AML.Broadly classified as Class 1 and 2 mutations.
Class 1 : include lesions that confer a proliferative and/or survival advantage aberrant activation of protein kinases such as FLT3, cKIT and RAS
Class 2 : impairs cell differentiation and confer self renewal properties.
Pediatric AML can have varied presentations.Patient can present with: fever, pallor, bleeding, hepatosplenomegaly, infections. Children with high leukocyte counts may have symptoms due to CNS or pulmonary leukostasis. 10-20% AML- present with extramedullary myeloid tumours due to infiltration of tissue with leukemic blasts. Common sites-lymph nodes, skin(leukemic cutis), gums and orbits. Subcutaneous nodules or “BLUEBERRY MUFFIN” lesions (especially in infants). Infiltration of the gingiva (especially in monocytic subtypes). Discrete masses ( chloromas or granulocytic sarcomas) associated with t(8;21) translocation.
Diagnosis:
Initial step- examination of CBC and peripheral smear- pancytopenia and circulating blasts. Other lab features- electrolyte abnormalities s/o tumour lysis(hyperuricemia, hyperkalemia, hyperphosphatemia). Small proportion – present with coagulopathies- DIC like picture can be seen most commonly in acute promyelocytic leukemia. Definitive diagnosis – Bone marrow aspiration and trephine biopsy.For diagnosis of AML- 20% or more myeloblasts in the peripheral blood or bone marrow. Certain types of translocations such as t(8;21), t(15;7)- also diagnostic of AML irrespective of blast percentage. Morphology- myeloblasts are classically described as large and uniform with finely dispersed chromatin with 1-4 nucleoli , granular cytoplasm and the presence of Auer Rods in 60-70% cases. Bone marrow trephine biopsy – required in cases where :
• BM aspirate smears are acellular or dry tap, diluted with peripheral blood
• Partially treated cases where blood transfusion/ treatment with steroids or other drugs alter the morphological picture
• Cases in which samples are degenerated
• Myeloperoxidase stain- specific for AML diagnosis- positivity of >3% of blasts- considered diagnostic.
• Immunophenotyping- detects antigen on AML cells – should be used at the time of initial diagnostic workup.
TREATMENT:
INDUCTION THERAPY
• Primary goal- achieve a significant reduction in leukemia burden(i.e. achievement of remission defined as a normal peripheral blood cell count), normocellular marrow with <5% blasts in the marrow
• Most treatment regimen – intensive combination of anthracycline and cytarabine
• CLASSIC 3 + 7 regimen – Daunorubicin 45mg/m2 per day for 3 days and Cytarabine 200mg/m2 as continuous infusion for 7 days.
• DOSE INTENSIFICATION:
• CCG-2891 study: 4 day treatment courses with 6 dayintervals showed better event free survival
• MRC-10 trial: Extended Cytarabine infusion to 10 daysimproved outcomes
• Anthracyclines(daunorubicin, mitoxantrone)- chosen for their anti- leukemic effect and lower cardiotoxicity
• POST REMISSION THERAPY:
• CONSOLIDATION THERAPY: often includes high dose cytarabine
• Other strategies- continuous delivery of multi agent low dose chemotherapy (thioguanine, vincristine) delivery of repeated cycles of myelosuppressive therapy with or without stem cell rescue and allogenic stem cell transplantation.
Prognosis:
5 year survival rates in children < 20 yrs is more than 60%.60-70% of Pediatric AML are long term survivors.Refractory disease occurs in 20%,Recurrence occurs in 30-40% who achieve remission.APML and DS-ML has better outcomes with survival rates of >95% and 80% .
85% of AML achieve 1st remission.Relapse rates ranges between 20% and 40%.
Carry home message:
Any child presenting with fever and rashes should not only be evaluated for viral illness, atleast peripheral smear should be done to suspect malignancies.
Prognosis is not generally good for Laeukaemia below one year of age