INTRODUCTION:

Acute Lymphoblastic Leukemia (ALL) occurs in both adults and children, but its incidence peak is between the ages of 3 to 5 years. Based on the patient’s details, the children who are affected by this leukemia are given proper treatment and also reducing the side effects, their survival rate has increased. The novel microscopic structural genetic alterations and sequence variations have been identified.¹ The factors like age, WBC count, and the outcome of the cancer treatment help to identify the right level of care and service for distinct subgroups of patients. If we are able to find out the recurring symptoms of a disease in a patient then it will be very useful in improving the progress of the patient and guiding the disease and treatment management. Geriatric patients do not have the capability to tolerate cancer treatment and so the rate of progression in their case is very low.^2,3

Acute lymphoblastic leukemia (ALL) is an increased cell growth of lymphoid progenitor cells in the bone marrow and the blood. Mostly the children are being affected by ALL at maximum rate as compared to that of adults. The treatment strategies for ALL have been worked out best in the children as compared to that of elderly patients.^4,5

Definition:

Acute lymphoblastic leukemia (ALL) is a disease that mainly affects the bone marrow's function. ALL constitutes one-fourth to one-third of all pediatric malignancies and 75% of all leukemias. In India, each year over 3000 - 4000 children less than 15 years of age are affected by acute lymphoblastic leukemia.⁶

Epidemiology:

Acute lymphoblastic leukemia like common cancer can be caused by the contact between exogenous or endogenous exposures. This may lead to the higher chances of getting affected. This mainly affects the pediatrics. Children are having ALL with the age below 1 year, are having rearrangement of the MLL gene. Monozygotic twins (with good concordance rate) have been suggested to develop leukemogenesis at birth. In contrast, the incidence of non – MLL rearranged B- ALL peaks at 2 and 5 years of age and a concordance rate of 10 – 15%, suggesting in vitro initiation in common, other “promotional” exposures are probably needed for the later emergence of disease. The peak age of developing acute lymphoblastic leukemia is 4-5 years of age with the most common age range being 2-6 years of age. Boys are more susceptible than girls (2:1). Globally, the incidence age distribution and subtypes of ALL exhibit marked geographic variations that may reflect variability in genetic susceptibility, environmental factors or both. Since childhood acute lymphoblastic leukemia accounts for 75% of all acute leukemias with a peak incidence between 2 to 5 years of age. Most commonly the children are being affected as compared to that of adults by chronic lymphocytic leukemia.^7,8

Etiology:

Childhood acute lymphoblastic leukemia, like most other cancers, remains a disease with few established etiologies and genetic and immunological factors. Patients with a high incidence of acute lymphoblastic leukemia in monozygotic twins (hereditary); with Bloom’s syndrome and Fanconi anemia (hereditary, defective DNA repair); Down’s and Klinefelter’s syndrome (hereditary). Environmental factors include radiation (nuclear bombs), benzene, pesticides, and herbicides. Epstein-Barr virus; HTLV I and II (Human T Lymphotropic Virus) and HIV (Non - Hodgkin’s lymphoma) are the viruses that cause a viral infection.^9,10

Morphology:

The classic morphologic features of ALL are well described in the literature and were best outlined by the original classification of ALL, the French American British (FAB) system, based primarily on the microscopic appearance of the leukemia cells, as seen on Wright – Giemsa dyed cotton swabs. The FAB classification outlines three morphologic groups of ALL, called L1, L2, and L3. The division was done on the basis of the size of the cell, nucleous and the cytoplasm. The WHO presented a collaborative division describing the morphology and cytogenetic profile of leukemic blasts and identified three types of ALL: B lymphoblastic, T lymphoblastic, and Burkitt- cell Leukemia. It was subsequently revised in 2008, excluding Burkitt- cell Leukemia as it was no longer considered distinct from Burkitt Lymphoma. In 2016, two new things were included to the catalogue of continuously occuring gene related problems and hypodiploidy has been mentioned as low hypodiploidy or hypodiploidy with TP53 mutations.^11,12,13

Risk Factors:

Acute lymphoblastic leukemia has the following risk factors:

1. Age: Children and those over the age of 50 years are at increased risk of developing acute lymphoblastic leukemia.

2. Genetic conditions: In some definite cases, the gene related problems can elevate the factors of ALL those are as follows:

· Trisomy 21

· XXY syndrome

· An inherited disease from their parents which may have an impact on the bone marrow.

· A defined disease that is occurring in pediatric population which mainly affects the brain and the other parts of the body.

· Congenital telangiectatic erythema.

· The cancer related treatment that was given previously: The people those who had been exposed to some cancer treatment drugs have a high chance of getting affected by leukemia after some years of its exposure. The chances of getting affected by leukemia is directly dependent on the amount of the cancer drugs that they had consumed. Some of the drugs include: Etoposide with cisplatin and bleomycin, Thiotepa, Busulfan and Chlorambucil.

1. Ionizing radiation exposure: The ionizing radiation can lead to neoplastic conditions since it can damage the DNA content and it also affects the cell. If a person is being exposed to an increasing level of ionizing radiation, then there is a higher chance of getting affected by acute lymphoblastic leukemia. Ionizing radiation is also used in CT scans and radiotherapy treatment. After this, there is a high chance for the pediatrics to get affected by the leukemia. Lastly, the doctor is the one who must explain the significance of the cancer related treatments.¹⁴

2. Exposure to benzene: The people those who come in contact with the chemical known as benzene at their working are has the higher chanses of getting affected by acute lymphoblastic leukemia. The people those who are working in the following industry have the higher chances of getting affected by this disease. Petrol industry, Chemical industry, pharmaceutical industry, Rubber industry, Shoe production and Printing industry. The pediatrics are at higher risk of getting affected by ALL if the mother is being exposed to the chemical known as benzene both before and after the pregnancy.

3. Weakened immunity: The people with HIV or AIDS and with the organ transplantation process followed by the treatment with drugs like immunosuppressants have been proved that these people were up to three times more likely to get leukemia than those without these factors.

4. Viruses: People infected with Epstein- Barr virus or the human T-cell leukemia virus may have an increased risk of developing ALL. A 2018 study suggested that there may be a “small and imprecise” risk between proximity to overhead power cables and childhood leukemia. According to the National Cancer Institute of cites studies, there appears to be no evidence that cell phone use increases the risk of leukemia. A 2010 study concluded that the use of cell phones did not increase the risk of leukemia.^15,16,17

Pathophysiology:

The pathogenesis of ALL involves the abnormal proliferation and differentiation of a clonal population of lymphoid cells. Studies in the pediatric population have identified genetic syndromes that predispose to a small number of cases of ALL, including Down’s syndrome, Fanconi’s anemia, Bloom’s syndrome, Ataxia telangiectasia, and Nijmegen’s breakdown syndrome. Other predisposing factors include exposure to ionizing radiation, pesticides, certain solvents, or viruses such as Epstein- Barr Virus and Human Immunodeficiency Virus. However, in most of these, it occurs as a de novo malignancy in previously healthy individuals. Chromosomal abnormalities are the common characteristic of ALL but are not enough to cause leukemia.^18,19

Signs and symptoms:

Most of the clinical manifestations of acute leukemia are related to bone marrow failure. The involvement of the tissues such as the spleen, liver, lymph nodes, and meninges is more common in acute lymphoblastic leukemia (ALL) than acute myeloblastic leukemia (AML). It includes: Paleness (pallor), Bleeding from gums, nosebleeds, or heavy menstrual periods, Fever, Bruises or purpura (bleeding within the skin), Petechiae (red or purple spots on the body), Lymphadenopathy (enlarged lymph nodes in the neck, under the arms, or in the groin region), Hepatomegaly, Splenomegaly, Bone pain, Joint pain, Weakness, Fatigue, Unexplained weight loss, Shortness of breath, Testicular enlargement, Cranial nerve palsies, Night sweats, Loss of appetite, Stomach pain and Abdominal pain. Many of the symptoms occur because the body is reacting to a lack of healthy blood cells. Leukemia cells can crowd them out in bone marrow-affected individuals. A lack of red blood cells may cause symptoms of anemia including feeling cold, dizziness and shortness of breath, fever, and more infections occur than usual. A lack of platelets can cause lots of bruising, severe nosebleeds and bleeding of the gums. Involvement of the central nervous system (CNS) may give rise to headaches, vomiting, and irritable behavior. CNS disease is rare but it develops in up to 75% of children. Less commonly patients present with the features of hypermetabolism, hyperuricemia, or generalized aches and pain.

Evaluation:

Acute lymphoblastic leukemia diagnosis should be explored initially with a laboratory evaluation consisting of a CBC (complete blood count), electrolyte and renal panel and LDH level. Additionally, imaging such as a chest X–ray for the symptoms of shortness of breath is done. This also helps to find the stage of the disease.

National Comprehensive Cancer Network (NCCN) Diagnosis guidelines:

· Have the presence of more than 20% bone marrow lymphoblasts.

· Hematoxylin and eosin-stained bone marrow clot and biopsy sections.

· Morphology of bone marrow aspirate assessed with Wright/Giemsa.

· Complete flow cytometric immunotyping.

· Baseline evaluation of the leukemia clone. Lumbar puncture is used to evaluate CNS involvement. The fluid is checked for the presence of lymphoblasts.²⁰

Medical History and Physical Exam:

Doctors undergo complete checking on the medical history of the patient that how long the patient had symptoms and if possibly been exposed to anything considered a risk factor. Physical examination is also done to check whether lymph nodes, areas of bleeding or bruising, or possibly the signs of infection. The eyes, mouth and skin will be looked at carefully. A complete nervous system examination is also done. The patient was also referred to a hematologist to check for blood-related disease.

Complete blood count and peripheral blood smear test: The peripheral smear test is done to see the changes in the numbers and appearance of the cells. It often helps to diagnose leukemia. Most of the patients with ALL have too many immature white blood cells called lymphoblasts in their blood and not enough red blood cells and platelets.

Blood chemistry tests:

Blood chemistry test measures the number of certain chemicals in blood like benzene. This test is also used to detect liver or kidney problems caused by metastasis of leukemia or the side effects which is caused by chemotherapy drugs. A blood coagulation test is done to make sure that the blood is clotting properly. The clotting time of blood is 2 – 8 minutes.

Bone Marrow Tests:

Leukemia occurs in the bone marrow. Hence bone marrow aspiration and biopsy are done. These tests are usually done at the same time. The samples are usually taken from the back of the pelvic (hip) bone and sternum (breast bone).

Chromosome tests:

In ALL, the cells sometimes have chromosomal abnormalities. The most common chromosome change in ALL is a translocation that results in a shortened chromosome 22 (called the Philadelphia chromosome). About 1 out of 4 adults with ALL have this abnormality in their leukemia cells. Some other tests done are:

· Cytogenetics

· Fluorescent in situ hybridization (FISH)

· Lumbar puncture (spinal tap)

· Lymph node biopsy and

· Ultrasonogram. Other features are the presence of high urate levels and CNS involvement were also checked.

Treatment:

Intensive combination chemotherapy is given in the hope of achieving complete remission (CR). This initial phase of treatment is termed induction or remission induction chemotherapy. Complete remission can only be achieved by virtual ablation of the bone marrow, followed by recovery of normal hemopoiesis. If two cycles of therapy fail to induce CR, an alternative drug regimen can be used. If this is unsuccessful, it is unlikely that complete remission will be achieved. Remission is defined as the absence of all clinical and microscopic signs of leukemia, less than 5% blast forms in the bone marrow and return of normal cellularity and hemopoietic elements. Despite achieving CR, occult residual disease (also termed minimal residual disease) will persist, and further intensive therapy is given in an attempt to sustain the remission. The post-remission consolidation therapy may comprise chemotherapy or a combination of chemotherapy and bone marrow transplantation. Treatment for ALL lasts for 2-2.5 years, combination chemotherapy developed before 1970 has developed with dose adjustments based on tolerance, response to therapy, individual pharmacodynamics, pharmacogenomics and pharmacokinetics. Allogenic hematopoietic cell transplantation (HCT) is used for patients with very high risk. In recent years immunotherapy and molecularly targeted agents are used as novel drugs. In acute lymphoblastic leukemia, the combination of Vincristine (Vinca alkaloid), Prednisolone (Glucocorticoid), Anthracyclines (Anti cancer antibiotic) and Asparaginase induces complete remission in about 90% of children with ALL and 80% of adults. Although sadly, relapse is far more common in adults. Other active drugs in the treatment of acute lymphoblastic leukemia include Methotrexate (Folate antimetabolite), 6-Mercaptopurine (Purine antimetabolite), Cyclophosphamide (Nitrogen mustard) and Mitoxantrone (Topoisomerase II inhibitor). Patients treated with recent protocols have experienced musculoskeletal effects which may be due to the intensive use of Dexamethasone (Glucocorticoid) and Asparaginase (Enzyme). Treatment typically comprises 3 phases: Induction (remission induction), Consolidation (intensification) and Maintenance.

Induction phase:

It is the first phase of chemotherapeutic treatment. The induction phase aims to kill most of the leukemic cells in the blood and bone marrow and restore normal hematopoiesis. Induction chemotherapy usually lasts for a month or more than a month. Different combinations of chemotherapeutic drugs may be used, but they typically include: Vincristine, Dexamethasone or Prednisone, Anthracycline (Doxorubicin or Daunorubicin). Based on the prognostic factors some regimens may also include Cyclophosphamide, Asparaginase, or a high dose of Methotrexate or Cytarabine. The 4-week of induction schedule includes Cyclophosphamide on days 1 and 3, Daunorubicin on consecutive days, Vincristine for 1 week, L-asparaginase for 2 weeks, Prednisone for 3 weeks. For ALL patients whose leukemic cells have the Philadelphia chromosome, a targeted drug such as Imatinib, Dasatinib is often included well. Mortality occurs due to induction therapy in elderly patients hence dose reductions of Daunorubicin and cyclophoshamide has been implemented and the duration of prednisone was also reduced to 7 days in elderly patients. In each phase of chemotherapy, CNS prophylactic therapy should be given to prevent the metastasis of leukemia to the CNS region. Intrathecal chemotherapy – Methotrexate, Cytarabine, or steroid-like Prednisone are used. Radiation therapy is given to the brain and spinal cord but the use of radiation therapy is reduced.

Consolidation phase:

Consolidation treatment aims to kill the remaining leukemic cells. The higher-risk patients receive consolidation therapy that is more intensive and lower-risk patients receive less consolidation therapy. It consists of another fairly short course of chemotherapy, using many of the same drugs that were used for the induction therapy. A combination of drugs is used. High dose Methotrexate, Cytarabine, 6- Mercaptopurine (6-MP), Cyclophosphamide, Thioguanine, Vincristine, Corticosteroids, and L-asparaginase / Pegaspargase are frequently used in the consolidation phase. This typically lasts for a few months. It involves 4 to 6 cycles of therapy and a duration of 8 months. The drugs are given in high doses so that the treatment is fairly intense.

Maintenance phase: The main goal of maintenance or continuation therapy is to prevent the disease getting relapsed after post-remission induction and consolidation therapy. After consolidation, the patient is generally put on a maintenance chemotherapy program of Methotrexate and 6-Mercaptopurine (6-MP). In some cases, it is combined with other drugs such as Vincristine and Prednisone. Age, gender, and genetic polymorphisms can affect the bioavailability of 6 - Mercaptopurine. Oral intake of 6-Mercaptopurine can have a high variable of drug and metabolite concentrations in patients. The efficacy of the maintenance phase is determined by the metabolism of 6 - Mercaptopurine to the antimetabolite chemotherapeutic agent 6-thioguanine nucleotide. For Acute Lymphoblastic Leukemia patients whose leukemic cells have the Philadelphia chromosome, a targeted drug such as Imatinib, Dasatinib is often included. For elder patients dose reduction is needed. Maintenance usually lasts for about 2 to 3 years. CNS prophylactic treatment is typically continued at this time. the overall recovery rate is in the range of 40%. recovery rates tend to be higher in younger patients.

Relapse of ALL:

In general, about 80% to 90% of adults will have complete remission at some point during these treatments. This means leukemic cells are no longer seen in their bone marrow. Unfortunately, about half of these patients relapsed. Relapse is the return of ALL in the complete remission achieved in patients. It most commonly occurs in children 85% and adults 15%. Relapse occurs in the following criteria if white blood cell count is greater than 50*109 cells/L and in patients younger than one year or older than nine years. After a first relapse patients should receive re-induction therapy to achieve complete remission. The anti-CD19 Tisagenlecleucel (Kymriah) is the first chimeric antigen receptor (CAR) T-cell therapy for the treatment of patients of 25 years of age with B-cell ALL. This is given in the second or later relapse and it is approved in the United States. Chemotherapy for T-cell ALL results in better therapeutic outcomes. For high-risk patient, allogeneic stem cell transplantation can be given.

Hematopoietic Stem cell transplantation:

This is an intravenous administration of hematopoietic stem cells to restore blood cell production in patients whose bone marrow and the immune system are damaged. There are two types of transplantation 1) autologous transplant: here transplant comes from the own body. In cancer patients high dose intensifying chemotherapy treatment can damage the stem cells of affected patients hence, before starting the chemotherapy in those patients’ doctors will rescue stem cells from bone marrow and blood. 2) allogenic transplant: It is receiving stem cells from another called a donor. A donor match is an essential step for an allogeneic transplant. There has been an improvement in pediatric patients with ALL with evidence of persistent disease. There has been an increased survival rate in HSCT. The benefit of allogeneic hematopoietic stem cell transplantation in infants with ALL is controversial. Some studies have shown that it has a role in high-risk patients with KMT2A rearrangements and other poor risk factors.²¹

Central nervous system prophylaxis and treatment:

In each phase of chemotherapy, CNS prophylactic therapy should be taken to prevent the spreading of leukemia to the CNS and to prevent relapse, by clearing off leukemic cells in the cerebral fluid. These sites cannot be accessed with the chemotherapeutic agents because of the blood-brain barrier (BBB). Intrathecal chemotherapy – Methotrexate, Cytarabine, or steroid-like Prednisone are used. Cranial irradiation therapy is given to the brain and spinal cord. Systemic chemotherapy – Dexamethasone, high dose Methotrexate, intermediate or high dose Cytarabine, and L-Asparaginase. This prophylactic treatment is given throughout the entire course of ALL therapy in induction, maintenance, and consolidation.

Molecularly targeted agents:

Targeted therapy is a type of treatment. It identifies and attacks specific cancer cells. It treats cancer by attacking the proteins that are responsible for the growth, division, and spread of cancerous cells. Molecularly targeted therapy is less harmful to normal cells and also has fewer side effects than other types of cancer treatment. Molecular targeted therapy includes two types small molecule drugs and macromolecules such as monoclonal antibodies, polypeptides, antibody-drug conjugates and nucleic acids.^22,23

Small–molecule drugs:

These drugs are small so they enter easily into the leukemic cells so they are used for targets that are inside the cell.

Monoclonal antibodies:

They are immune proteins these antibodies get attached to a specific target on cancerous cells. These antibodies kill the cancer cells, block their growth and prevent metastasis. Blinatumomab and Inotuzumab ozogamicin are monoclonal antibodies used along with stem cell transplantation to treat adult ALL. A-CD22-Directed therapy CD22 is a B-lineage differentiation antigen expressed in B-cell ALL in 50-100% of adults and 90% of children.^24,25,26 Epratuzumab is an unconjugated monoclonal antibody that targets CD22 that has been studied in pediatric and adult relapsed/refractory ALL.²⁷ Inotuzumab ozogamicin (INO) is a CD22-directed monoclonal antibody it conjugates to the potent cytotoxin, calicheamicin through an acid-labile linker. It shows a higher response rate in relapsed ALL. The adverse effects of INO treatment include thrombocytopenia and neutropenia. Combotox is a combination of two immunotoxins, anti-CD19 and anti-CD22 antibodies, which both conjugate to the cytotoxin deglycosylated ricin-A chain. Ofatumumab is a second-generation anti-CD20 antibody. It first showed benefit in fludarabine-refractory chronic lymphocytic leukemia, irrespective of prior rituximab exposure.²⁸ It was administered at a dose of 2g on days 1 and 11 of the first 4 cycles of induction therapy. Administering in pregnant women causes B-cell depletion in the fetus. It is mainly indicated in chronic lymphoblastic leukemia.

Tyrosine kinase inhibitor therapy:

This therapy is given to block the tyrosine kinase which causes stem cells to develop into more white blood cells. Imatinib mesylate, Dasatinib, and Nilotinib are tyrosine kinase inhibitors used to treat adult ALL. With the increased understanding of genetic alterations in ALL, approaches targeting the driving genetic mutation associated with the signaling pathway. In pediatric Philadelphia - positive ALL, adding an ABL1 tyrosine kinase inhibitor, Imatinib mesylate (340mg/m²/day) is given. Newer generations of tyrosine kinase inhibitors are available and a randomized study showed that pediatric patients who received chemotherapy with 80mg/m²/day of Dasatinib. Ponatinib has potent activity in both wild-type and mutant BCR-ABL1 ALL, including cells harboring the gatekeeper ABL1 T315I mutation. Combination chemotherapy with ponatinib and hypofractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (hyper-CVAD) alternating with high-dose Methotrexate and Cytarabine resulted in excellent efficacy in newly diagnosed Ph-positive acute lymphoblastic leukemia. For patients with Ph-like ALL and ABL – class gene fusions (ABL1, ABL2, CSF1R, LYN, PDGFRA, or PDGFRB), ABL1 inhibitors can be combined with chemotherapy. For those patients with alterations that activate the JAK-STAT signaling pathway, such as rearrangement or a mutation occurring in the following gene of CRLF2 (IGH-CRLF2, P2RY8-CRLF2 F232C), rearrangements of JAK2, EPOR or TYK2 or mutations/deletions of IL7R, SH2B3, JAK1, JAK3, TYK2, or IL2RB, clinical trials of JAK inhibitor, Ruxolitinib, are ongoing.

ABBREVIATION:

1. ALL - Acute Lymphoblastic Leukemia

2. MLL - Mixed lineage leukemia gene

3. AML - Acute myeloid leukemia

4. HTLV - Human T lymphotropic virus

5. HIV - Human immunodeficiency virus

6. FAB - French American British system

7. BCR - Breakpoint cluster region protein

8. ABL - Tyrosine-protein kinase

9. JAK - Janus kinase

10. PDGFRB - Platelet-derived growth factor receptor beta

11. CRLF2 - Cytokine receptor-like factor 2

12. EPOR - Erythropoietin receptor

13. IL7R - Interleukin 7 receptor

14. FLT3 - FMS like tyrosine kinase 3

15. SH2B3 - lymphocyte adapter protein

16. LNK - Large cell non-keratinizing

17. CSF1R - Colony stimulating factor 1 receptor

18. TKIs - Tyrosine kinase inhibitors

19. ETV6-NTRK3 - Chimeric protein tyrosine kinase

20. ALK - Anaplastic lymphoma kinase

21. IKAROS - a central regulator of lymphocyte differentiation

22. IKZF2 - Zinc finger protein Helios

23. RB1 - Retinoblastoma 1 gene

24. CNS - Central nervous system

25. CSF - Cerebrospinal fluid

26. MRI - Magnetic resonance imaging

27. CAR - Chimeric antigen receptor

CONCLUSION:

There has been a significant improvement in the ALL treatment in both adults and pediatric oncology. However, there is a high chance of developing a high-risk disease, relapse and toxicity due to the use of chemotherapeutic agents which can hinder the treatment outcome. This article represents the overall review of acute lymphoblastic leukemia’s etiology, pathophysiology, signs and symptoms, and newer therapeutic agents in the market. It is important to reduce the treatment-induced toxicity for better compliance and outcome.

REFERENCE:

1. Hiroto Inaba, Prof. Mel Greaves, Charles G. Mullighan; Acute Lymphoblastic Leukemia. Summary. 2013. Cited by 1184.

2. T Terwilliger and M Abdul-Hay. Acute Lymphoblastic Leukemia. Blood Cancer Journal. 2017. Cited by 752.

3. National Cancer Institute. SEER Cancer Statistics Review, 1975-2013: Leukemia, Annual Incidence Rates.

4. Paul S, Kantarjian H, Jabbour EJ. Adult Acute Lymphoblastic Leukemia. Mayo Clin Proc. 2016; 91:1645-1666.

5. Jabbour E, O’Brien S, Konopleva M, Kantarjian H. New insights into adult acute lymphoblastic leukemia pathophysiology and therapy. Cancer. 2015; 121: 2517-2528.

6. Dr. Ayush Garg. Acute Lymphoblastic Leukemia. Slideshare. Jan 14, 2018.

7. Trip Adler, Jared Friedman, and Tikhon Bernstam. Acute Lymphoblastic Leukemia. Scribd Inc. 2007.

8. Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukemia. Nature Rev Cancer. 2003; 3: 639-49.

9. Greaves MF. Etiology of acute leukemia. Lancet. 1997; 349: 344 - 49.

10. Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural history. Blood. 2003; 102: 2321-33.

11. Mihaela Onciu MD. Acute lymphoblastic leukemia. ScienceDirect. Com.

12. M. Bruggemann et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006.

13. S. Tito’s Unit M5, M. Arivumani. Acute lymphoblastic leukemia. 2010. Slideshare.net.

14. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller- Hermelink HK, Vardiman J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting – Airlie House, Virginia. J Clin Oncol. 1999; 17: 3835-3849.

15. Vardiman JW, Thiele J, Arber DA, Brunning RD, Boroueitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009; 114: 937 -951.

16. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391-2405.

17. KF Brown and others British Journal of cancer. The fraction of cancer attributable to known risk factors. 2018; 118(8): 1130 – 1141.

18. K Leuraud and others Lancet Haematology; ionizing radiation and risk of death from leukemia in radiation monitored workers (in Workers); an international cohort study; 2015; 2: 276-281.

19. VT De Vita, S Hellman, and SA Rosenberg Lippin Cott, Williams and Wilkins; Principles and Practice of Oncology (11^th edition) 2019.

20. Puckett Y, Chan O. Acute Lymphocytic Leukemia.

21. Terwilliger T, Abdul-Hay MJ. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer Journal. 2017 Jun; 7(6):e577-.

22. Wilkes GM. Targeted therapy: attacking cancer with molecular and immunological targeted agents. Asia-Pacific Journal of Oncology Nursing. 2018 Apr 1; 5(2): 137-55.

23. Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: Treating cancer with specificity. European Journal of Pharmacology. 2018 Sep 5; 834: 188-96.

24. Shah NN, Stevenson MS, Yuan CM, Richards K, Delbrook C, Kreitman RJ, Pastan I, Wayne AS. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatric Blood & Cancer. 2015 Jun; 62(6): 964-9.

25. Piccaluga PP, Arpinati M, Candoni A, Laterza C, Paolini S, Gazzola A, Sabattini E, Visani G, Pileri SA. Surface antigen analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia. Leukemia & Lymphoma. 2011 Feb 1; 52(2): 325-7.

26. Chevallier P, Robillard N, Houille G, Ayari S, Guillaume T, Delaunay J, Harousseau JL, Avet-Loiseau H, Mohty M, Garand R. Simultaneous study of five candidate target antigens (CD20, CD22, CD33, CD52, HER2) for antibody-based immunotherapy in B-ALL: a monocentric study of 44 cases. Leukemia. 2009 Apr; 23(4): 806-7.

27. Raetz EA, Cairo MS, Borowitz MJ, Blaney SM, Krailo MD, Leil TA, Reid JM, Goldenberg DM, Wegener WA, Carroll WL, Adamson PC. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children's Oncology Group Pilot Study. Journal of Clinical Oncology. 2008 Aug 8; 26(22): 3756.

28. Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Österborg A, Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood, The Journal of the American Society of Hematology. 2011 Nov 10; 118(19): 5126-9.

Received on 06.08.2023 Revised on 17.06.2024

Accepted on 23.11.2024 Published on 03.05.2025

Available online from May 05, 2025

Asian J. Pharm. Res. 2025; 15(2):202-208.

DOI: 10.52711/2231-5691.2025.00033

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.