Leukemias In Children

What is Leukemia?

“The leukemias may be defined as a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to an unregulated clonal proliferation of cells.” 

They are characterized by 

1. Excessively high proliferation rates. 
2. Decreased rates of spontaneous apoptosis. 

Due to the above two factors, cell proliferation in the bone marrow (BM) causes bone marrow infiltration. This leads to overwhelming peripheral circulation and inside the bone marrow, leading to bone marrow failure. So the manifestations arise due to BM failure and dissemination through the circulation of the monoclonal abnormal proliferating cells.

Leukaemia is the most common childhood malignancy overall. In the age group 0–15 years, leukemias have a 31-38% occurrence rate.

Types of Leukaemias

Acute leukemias

comprise 95% of total leukemias. The most common acute leukaemia is acute lymphoblastic leukemia (ALL), 70–75% of the cases. The second most common is acute myeloid leukemia (AML), 11% of the total cases. Other rare acute forms are not classified, including mixed lineage forms and unclassified forms.

Chronic leukemias

5% of total leukemias. This can be divided into two forms: 

1. CML: Chronic myeloid leukemia is associated with the Philadelphia chromosome (translocation of chromosomes 9, 22 BCR-ABL gene). 
2. JMML: Juvenile myelomonocytic leukemia.

Also read: Mitochondrial Hepatopathies

Acute Lymphoblastic Leukaemia Epidemiology

The peak age for ALL is 2–5 years. Gender: across all age groups. (M>F). Influence in siblings: This can be of two types: 

In monochorionic twins or monozygotic twins, if the 1st twin has ALL before the age of 1, then the risk of getting ALL in the second twin is >70%. (Infantile leukemia). 

If a child gets ALL between the twin chances of 0-5 years, getting ALL is 20%. (non-infantile leukemia)

Leukemia has a strong genetic association with its occurrence; however, many times a child might have the genetic influence that can cause leukemia but never does in his life. This shows that, along with genetics, other factors influence the occurrence of leukemia in a child. 

Classification of ALL

Many classification systems are used to classify ALL. They are 

Immunophenotypic Classification: 

Based on surface markers and the morphology of the malignant cells. There are 3 types 

1. B-lymphoblastic leukemia (Pre-B cell): They are precursor B-cells and comprise 80-85%. Known as the classic variety of ALL. 
2. B. T-lymphoblastic leukemia (T cell): comprise of the 15% cases. Tends to occur at an older age, including adolescence. High risk of developing extramedullary disease. Very high TLC in the peripheral blood. 
3. C. Mature B-cells (Burkitt's Leukaemia) comprise 1% of the cases. 

FAB Classification: 

French American British classification. It is based on the morphology of the type of cells that are present. These are of 3 types - L1, L2, and L3.

Also read: Principles Of Therapy In Children

Clinical Features of ALL

The clinic features are widespread and generally start with common symptoms like fever, anorexia, irritability, etc and later constitute symptoms of bone marrow involvement and various other metastasis. According to Lanzkowsky, the distribution of the clinical features is given in the table below :

• Constitutional features: Initially the child will have nonspecific features like
  • Low-grade fever - intermittent in nature. 
  • Anorexia 
  • Irritability 
  • +/- Loss of weight: This is not very significant.
• Bone marrow involvement features: These features occur because the blast cells will replace the normal hematopoietic lineages. These include: 

• Anaemia: It includes pallor, fatigue, dyspnea, and CCFlike manifestations. 
• Leukopenia: It is not consistently seen, but if serious and involves neutrophils, then the child will have recurrent infections with high-grade fever. 
• Thrombocytopenia: Petechiae, purpura, epistaxis, gum bleeds, subcutaneous bleeds, black eyes, and rarely GIT bleeds and CNS bleeds. 
• Pancytopenia 
• Bone involvement features: occur due to bone marrow infiltration and periosteal involvement. subperiosteal deposits of the leukaemic cells or frank infiltration of the periosteum. These include
  • Bone pain is more severe at night. 
  • Increased risk of developing pathological fractures. 
• Organ involvement/infiltration features: These include 

• Hepatomegaly 
• Splenomegaly 
• Hepatosplenomegaly 
• Lymphadenopathy 

Superior vena cava syndrome occurs due to mediastinal mass due to mediastinal lymph node involvement. causes obstruction of the SVC. Common in T-cell ALL.

Also read: What's New In Paediatric Oncology

Diagnosis of ALL 

There should be a clinical suspicion of ALL. Then investigations are done. These are 

Complete blood count (CBC)

Decreased hemoglobin: normocytic normochromic type of anaemia. If Hb level is relatively preserved, indicate an aggressive form of ALL, as ALL developed in such a short period of time that Hb levels were still near normal. TLC variable. In >50% of the patients, TLC is <10,000/mm3, some have 10,000-50,000/mm3, and only 5-7% of cases have >50,000/mm3. Decreased platelet count causes various degrees of thrombocytopenia. On PBF, blast cells may/may not be seen. Present if TLC is >20,000/mm3. 

Bone marrow studies

A bone marrow biopsy is preferred, but aspiration can also be done. Immunohistochemistry analysis (IHC) and cytogenetic analysis of the bone marrow are also done. A sufficient sample of the bone marrow should be taken. The hallmark of ALL bones is the presence of lymphoblasts comprising >25% of the total bone marrow cells.

Other investigations: These include 

Chest X-ray: mediastinal mass; Routine LFT and RFT; Urine analysis—microscopic haematuria

CSF analysis. The staging lumbar puncture (LP) may be performed in conjunction with the first dose of intrathecal chemotherapy if leukaemia is diagnosed from bone marrow (BM) studies.

Acute Myeloid Leukemia

Acute myelogenous leukemia and acute non-lymphoblastic leukemia (ANLL). AML is the second most common childhood leukemia after ALL. Comprises 10-15% of all childhood leukemias. Occurs throughout childhood, with a slightly higher incidence in the neonatal period. Also common in adolescence, 36% of all leukemias in the 15–19-year age group. AML is more complex and disease-resistant than ALL. Characterized by monoclonal proliferation of hematopoietic precursors of myeloid, erythroid, or megakaryocytic lineage. 

Also read: High-Yield NEET SS Pediatric Oncology Questions

Syndromes Increase the Risk of AML 

• Down syndrome 
• Bloom syndrome 
• Fanconi anaemia 
• Diamond blackfan anemia 
• Kostmann syndrome 
• Schwachman-Diamond syndrome 
• Li- Fraumeni syndrome, NF-1 

Causes of Secondary AML 

Induced by pre-occurrence of myelodysplasia and other myeloproliferative disorders. Induced by exposure to ionizing radiation. Chemotherapeutic agents: 

• Cyclophosphamide, Ifosfamide 
• Chlorambucil 
• Nitrogen mustard, Melphalan 
• Etoposide 

Clinical Features of AML 

It is like ALL except for the following points: 

• Higher risk of infections. 
• Higher TLC levels at presentation can cause leukostasis, pulmonary infiltrates with respiratory distress, and even stroke. 
• HSM and LAP are less common in AML except in M4 and M5. 
• Gum hypertrophy is very common in the M4 form. 
• DIC is common in M3/APML form. 
• Blueberry muffin-type skin lesions are seen in infants with M3/APML. 
• Overall CNS involvement is seen in 15% of cases. 
• Occurrence of chloromas, especially in the M2 variety.

Also read: Neuroblastoma -Investigation, Staging and Treatment

What are Chloromas?

Also called Granulocytic Sarcoma or Myeloid Sarcoma. Represent an extra-medullary collection of myeloblasts. Most seen in AML M2. Can occur at any age, but > 60% occur below 15 years of age. Common sites are skin, gums, bones, GIT, and neck. It can produce proptosis. Diagnosis of chloromas can be confirmed by biopsy of the mass and IHC. Treatment is a systemic manifestation of AML and is managed with chemotherapy as for AML M2.

Diagnosis 

Peripheral blood film—Hb will be lower, TLC will be higher, blast cells may or may not be present, and platelet count is low. Bone marrow aspiration and biopsy: hallmark - presence of 20% blast cells in BM. IHC stains need to be applied ≥ for looking at their characteristics. Cytogenic analysis for underlying specific abnormalities. Flow cytometry: identify the various tumour characteristics. 

Management of AML Problems 

Higher relapse rates and lower remission rates. Higher risk of death in remission due to infections and hemorrhage. Risk-based approaches. Patients with favourable factors - chemotherapy alone. Patients with unfavourable factors - chemotherapy for remission followed by SCT. 

Management of Acute Promyelocytic Leukemia (APML)

The drug of choice is oral Tretinoin, also called ATRA (all transretinoic acid). Acts by inducing differentiation of leukemic cells with t (15;17). Can be combined with other agents. Problem: APML syndrome/differentiation syndrome within 3 weeks in some patients. These drugs differentiate leukemic cells and leukemic cells adhere to the pulmonary vascular endothelium and produce complications like dyspnea, pulmonary edema, pleural effusion, pericardial effusion, etc. 10% of cases can have mortality also. Treatment is supportive. 

                                    Steroids + fluid management + Stop ATRA. 

Alternative is arsenic trioxide, also called ATO. Combination of ATO and ATRA used may be superior to any other chemotherapy regimen in patients of M3 ML. But it is theoretical data. 

Also read: DM Medical Oncology Preparation for NEET SS 2023

Down Syndrome and Transient Leukemia 

10% of children with Down tend to develop transient leukemia or transient myeloproliferative disorder in the neonatal period. Characterized: high TLC levels, blast cells in circulation, anaemia, and hepatosplenomegaly. Called transient because most of the characteristic features will involute spontaneously, there will be improvement of patients within three months.

Chronic Myeloid Leukaemia

Also called chronic myelogenous leukemia, adult-type CML. Comprises 2-3% of all cases of childhood leukemia. CML originates in a hematopoietic stem cell and is characterized by myeloid hyperplasia of BM, extramedullary hematopoiesis, and raised peripheral TLC with myeloid cells at all stages of differentiation. Cause- unknown, Seen in children >4 years age. A peak around 10 years of age. Ionizing radiation has been implicated in pathogenesis. 

Diagnosis of CML

• Very high TLC. 
• Presence of mature and immature granulocytes. 
• Proliferation of the precursors in the bone marrow and 
• In cytogenetic analysis, Philadelphia chromosomes can be seen. 
• The Philadelphia chromosome is present in 99% of patients with CML. 

Management of CHML

• Drug of choice: tyrosine kinase inhibitors
  • Imatinib mesylate is approved for children. 
• In adults, 2 tyrosine kinase inhibitors (Dasatinib) are used.
  • Not used in children. 
• In untreated/blast crisis/accelerated – Die within 1 year.
• Most patients have mutations in the genes involved in the RAS syndrome pathway, e.g., PTPN-11, NRAS, and NF-1. Two strong associations of JMML are neurofibromatosis-I and Noonan syndrome. Monosomy 7 in 30% of patients.

Also read: Neonatal Respiratory Monitoring

Juvenile Myelomonocytic Leukemia (JMML)

Clinical Features

Acute presentation with fever, anemia, HSM, LAP, bleeding manifestations, and skin features—Xanthomas, Eczematous, Rash, and Cafe-au-lait macules. Raise TLC with significant monocytosis and occasional erythroblasts. Anemia and thrombocytopenia are seen. LAP score is normal to low. Bone marrow is a myelodysplastic pattern with <20% blast cells. Philadelphia Chromosome is negative. 

Management

Aggressive tumor. Poor prognosis. Strong chemotherapeutic agents followed by allogeneic stem cell transplant. JMML in Noonan syndrome shows spontaneous regression. 

Congenital Leukemias 

It is leukemia diagnosed between birth and 6 weeks of age. Rare disease incidence is 1 in 5 million. Risk factors 

• Down syndrome 
• Turner syndrome. 
• Mosaic Trisomy 9 
• Mosaic monosomy 7 
• Advanced maternal age

Clinical features

Lethargy, poor feeding, pallor, HSM, Petechiae/purpurae. Nodular skin infiltrates, bluish nodules, or leukemia cutis. Usually resembles AML-M5, rarely Pre-B cell ALL type.

Treatment

If it occurs in Down syndrome, wait and watch for spontaneous remission. If it doesn't happen in 2-3 months, treat it as AML. IV Cytarabine with or without Anthracyclines is used. Other forms/isolated forms/ALL types start with intensive chemotherapy. Poor prognosis, except if it occurs in Down syndrome. 

Also read: NEET SS Preparation Strategy No One Talks About!

Important Question 

Q. What are the risk factors for testicular involvement in ALL? 

Ans. 

• T cell ALL 
• Leucocytosis >20000/mm3 
• Mediastinal mass 
• Moderate to severe hepatosplenomegaly and lymphadenopathy. 
• Thrombocytopenia with platelet <30000/mm3 

Hope you found this blog helpful for your NEET SS Pediatrics Oncology preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.