WELCOME TO �THE EXTENDED CLINICAL MEETING

Presenter:

Dr.Olivia Akter

Dr. Tandra Chakma

Resident , Phase B

Pediatric Hematology and Oncology

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Salient feature

Jamil, 9months male baby , 2^nd issue of non-consanguinous parents hailing from Gafargaon , Mymensingh got admitted in BSMMU on 26^th September’22 with the complaints of high grade intermittent fever for 1 month and progressive pallor for same duration. Jamil developed multiple blackish spots all over the body but bleeding from any other sites were absent.

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Salient feature(cont’d..)

Mother also gave history of poor feeding, poor physical activity and occasional vomiting . There was no history of convulsion, unconsciousness, cough and breathing difficulty. Jamil has been treated with antibiotics , blood products , Tab.Allopurinol, Tab.Oradexon and other supportive treatment.

Salient feature(cont’d..)

On examination, the baby was ill looking, fretful, mildly pale, multiple petechial rash over trunk and abdomen, vitally stable, anthropometrically well thriving. Liver- enlarged, 8cm from the right costal margin along the mid clavicular line, spleen-4cm along its long axis . Other systemic examinations revealed nothing abnormality.

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Provisional Diagnosis ?

Infant Acute Leukemia

Differential diagnosis

• Juvenile myelomonocytic leukemia (JMML)

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�Infant Acute Leukemia�

Juvenile Myelomonocytic Leukemia(JMML)�

Plan of investigation

• CBC
• Bone Marrow Study
• Morphology
• Immunophenotyping
• Cytogenetics

• Chest X ray
• CSF Study
• S. LDH
• S. Electrolytes
• S. Ca

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• S. Inorganic Phosphate
• S. Uric Acid
• SGPT
• S. Creatinine
• PT, APTT
• HBsAg
• Echocardiography

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• CBC: 13.09.22
• Hb%- 5.8 gm/dl.
• TC of WBC: 40,400/cumm ( Blast 45%)
• PLT- 25,000/cu mm.

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• CBC: 26.09.22 ( Admission)
• Hb%- 11 gm/dl(PRBC given)
• TC of WBC: 19,890/cumm
• PLT- 22,000/cu mm.

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Bone marrow study

• Morphology : Acute Leukemia ( ALL )
• Immunophenotyping :

Cd 10 pos : 68.32 %

Cd19pos : 98.32%

cCd79apos : 85.25%

HLADR pos : 99.15%

Comment : Acute lymphoblastic leukemia ( B cell lineage)

CXR

� Investigations

• S LDH :659 U/L
• S creatinine : 0.44 mg/dl
• Uric acid : 2.7 mg/dl
• S . Electrolyte : Na 137 mmol/L, K : 4 mmol/L, Cl :97 mmol/L, TCO2 : 26.3 mmol/L
• S Ca : 2.6 mmol/L
• PT : 12 sec (control 12 sec ; INR 1)
• APTT: 30sec( Control 32 sec)
• SGPT : 56U/L
• HBsAg : Negative

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Management

Management on admission

Counselling

Supportive Care

Breastfeeding and neutropenic diet

Hydration

Tab Allopurinol

Syp. Aluminium Hydrochloride

Acriflavin hip bath

Nystatin oral suspension

Blood Transfusion

Specific Treatment :

Interfant 99 Protocol for Infant Leukemia(Started from 28.09.22)

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CSF study(28.09.22) :

Total count < 5/cmm, mostly lymphocyte

Blasts : 00%

Final diagnosis

Infant acute lymphoblastic Leukemia ( B cell lineage) with CNS I.

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Infant acute lymphoblastic leukemia �

Definition :

“Infant leukemia” refers to acute leukemia diagnosed prior to 1 year of age.

Epidemiology :

• There is no population based data in Bangladesh.
• The estimated incidence of acute leukemia in infants is 41 cases per million in the United States, which equates to ∼ 160 cases of infant leukemia per year.

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• Infant leukemia demonstrates a female predominance, in contrast to the male predominance in leukemia.
• Infant ALL accounts for 2-5% of pediatric ALL cases .
• Infant AML accounts for 6-20% of pediatric AML.

Blood. 2019;133(3):205-214

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Clinical features

Compared with older children, infants with acute leukemia tend to present with more aggressive features, including ---

• High WBC counts
• Hepatosplenomegaly
• Central nervous system (CNS) involvement
• Leukemia cutis (skin infiltration).

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Blood. 2019;133(3):205-214

Pathophysiology and Cytogenetics

A high proportion of cases are characterized cytogenetically by balanced chromosomal translocations involving the histone lysine methyltransferase 2A gene (KMT2A, formerly known as mixed lineage leukemia [MLL] gene) at chromosome 11q23.

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• MLL rearrangements (MLL-r) occur in < 5% of�childhood ALL cases overall, but in 70% to 80% of ALL in infants.
• In childhood AML, MLL-r is more common overall�(15%-20%), but is also particularly common in the infant age group ( 50%).

Biologically and clinically, infant ALL consists of two distinct subtypes:

• KMT2A rearrangement (KMT2A-r) ( also called MLL)
• Wild type KMT2A (wt-KMT2A).

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Blood. 2019;133(3):205-214

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• Infant ALL with rearranged MLL (MLL-r) is a highly aggressive leukemia with high white blood cell (WBC) count and frequent involvement of extramedullary sites including the central nervous system (CNS) at diagnosis.

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• In addition, MLL-r ALL has a very immature CD10-negative B-cell precursor phenotype in approximately two-thirds of cases and is frequently associated with co-expression of myeloid-specific antigens. �

Risk stratification of infant ALL

Blood. 2019;133(3):205-214

Chemotherapy �

• Leukemic cells with MLL-r ALL are more resistant in vitro to prednisolone and L-asparaginase, which are the key drugs for treating ALL.
• In contrast, infant ALL cells are more sensitive to cytarabine (Ara-C) irrespective of MLL status.
• From these observations, a “hybrid chemotherapy” combining ALL-oriented drugs (e.g. corticosteroids, vincristine, L-asparaginase, and MTX) and AML-oriented drugs (e.g. anthracyclines, etoposide, and especially Ara-C) is considered effective . ��

Interfant 99

Chemotherapy �

• Remission induction chemotherapy results in a high complete remission (CR) rate ≥90% in general, but a high incidence of relapse occurs 4–5 months after�achieving CR .
• The current ongoing Interfant-06 is investigating whether early intensification with AML-oriented chemotherapy with Ara-C, daunorubicin or mitoxantrone, and etoposide will be superior to ALL-oriented chemotherapy with cyclophosphamide, Ara-C, and 6-mercaputopurine in MLL-r infants . ��

HSCT in infant leukemia�

• The use of HSCT in infant leukemia is variable, reflecting uncertainty regarding the risk/benefit ratio of HSCT in this population.
• There does appear to be a small minority of KMT2A-r patients at high risk of relapse (very young age, very high WBCs, and persistence of MRD) who may benefit from HSCT in first remission.

Novel therapies �

• Intensification of conventional cytotoxic chemotherapeutic drugs with or without HSCT has enabled cure in approximately 50% of the infants with ALL, but this is far from satisfactory outcome.
• Novel therapies are urgently required, especially for those with MLL rearrangements .��

• Nucleoside analogues :Clofarabine
• FLT3 inhibitors :Lestaurtinib , Midostaurin ,Quizartinib
• Epigenetic modifiers :Demethylating agents ( Azacitidine ,Decitabine , Zebularine) , Histone deacetylase inhibitors.
• Immunotherapy :CD19 BiTE (Blinatumomab), CD19 CAR T-cells � ���� ����

Prognostic factors �

• Among all the known prognostic factors, presence of KMT2A-r(MLL rearrangement) is the strongest predictor
• Other factors such as high WBC, CNS involvement, and absence of CD10 expression on leukemic cells are also prognostic but are highly correlated with MLL rearrangement .
• Infants younger than 3 or 6months is extremely poor compared with older infants.
• Treatment response evaluated in the early phase .����

The prognosis of infant differs between ALL and AML.

• In ALL, The 4-year event free survival (EFS) in Interfant-99, the largest trial of infant ALL to date, was 47%.
• Conversely, outcomes for infants with AML are similar to those for older children.

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Blood. 2019;133(3):205-214

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Take Home Messages

• Leukemia in infants is rare but generates tremendous interest due to its aggressive clinical presentation .
• There is marked heterogenicity in pathogenesis, management & outcome.
• Current treatment practices are not satisfactory at all.
• Availability of Immune therapy, novel targeted therapies based on the unique biology of the type of leukaemia and collaboration among the groups is an urgent need. �

THANK YOU